2-azetidinyl-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimido[5,4-d]pyrimidine derivatives as modulators of TREM2 for the treatment of neurodegenerative diseases

Abstract

The present invention relates to compounds of Formula (I) useful for modulating Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2") expressed on myeloid cells. The present invention also relates to the use of the compounds for treating conditions associated with loss of function of TREM2, such as neurodegenerative diseases; and pharmaceutical compositions comprising the compounds.

Description

Technical Field

[0001] This invention relates to compounds that can be used to modulate triggering receptor expressed on myeloid cells-2 (“TREM2”). The invention also relates to the use of said compounds for treating conditions associated with loss of TREM2 function, such as neurodegenerative diseases; and pharmaceutical compositions comprising said compounds.

[0002] background

[0003] Trigger receptor 2 (TREM2), expressed on myeloid cells, is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene located on human chromosome 6p21. TREM2 consists of an extracellular portion including a single immunoglobulin domain and a short extracellular domain, a single transmembrane helix, and a short cytoplasmic tail (Colonna, M. et al. (2016)).

[0004] The restricted expression pattern of TREM2 provides insight into its role. It is expressed only on myeloid cells such as macrophages, microglia, dendritic cells, and osteoclasts. It plays a role in tissue maintenance as a pathological sensor in specific tissues and an inducer of innate immune signaling. In the brain, TREM2 is expressed only on microglia and is functionally required for, for example, the phagocytosis of cell debris, but is also conferred to limit inflammation and promote cell survival (Deczkowska, A. et al. (2020)).

[0005] TREM2 has a variety of ligands, such as bacterial anionic molecules / endotoxins, phospholipids (including phosphatidylserine), lipoproteins and apolipoproteins (including ApoE), and oligomeric Aβ (Hammond, TR (2019)).

[0006] Signal transduction via TREM2 through the co-receptor DAP12 has been well described. The adaptor molecule DAP12 is expressed as a homodimer on the surface of various cells involved in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. Following TREM2 binding, SRC family kinases phosphorylate the ITAM (immunoreceptor tyrosine-based activation motif) of DAP12, driving the recruitment and activation of Syk kinases and / or ZAP70 kinases. Downstream of TREM2 / DAP12 / Syk, several signaling pathways have been described involving cell survival, cell activation and differentiation, and control of the actin cytoskeleton.

[0007] Proteolytic cleavage of the extracellular domain of TREM2 by metalloproteinases (including ADAM10 and ADAM17, and possibly matrix metalloproteinases) results in the shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 has been proposed as a potential biomarker for microglial activity in early Alzheimer's disease (Suárez-Calvet, M. et al. (2016)).

[0008] Deficiency of TREM2 or DAP12 impairs the response of microglia to pathological substances. The effects of TREM2 deficiency have been demonstrated in vitro in response to stimulation with typical TLR ligands such as LPS. Loss-of-function variants of TREM2 are associated with neurodegenerative diseases and support the central role of microglia 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, JD et al. (2017)), while heterozygous loss-of-function TREM2 variants are associated with an increased risk of several neurodegenerative diseases, such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndromes, and amyotrophic lateral sclerosis (ALS). The most common mutation associated with AD is the loss-of-function mutation R47H, which has been shown to eliminate ligand binding and phagocytosis (Atagi, Y. et al. (2015); Kleinberger, G. et al. (2014)).

[0009] Neurodegenerative diseases that can be treated by modulating TREM2 activity and / or signal transduction include, but are not limited to, Alzheimer's disease (AD), frontotemporal degeneration (FTLD), FTLD-like syndromes, Parkinson's disease, Huntington's disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, and amyotrophic lateral sclerosis (ALS). Therefore, there is a high and unmet medical need for TREM2 modulators to address these indications. Summary of the Invention

[0010] This invention relates to compounds that regulate TREM2.

[0011] In one aspect, the present invention relates to a compound of formula (I):

[0012] Formula (I)

[0013] in: X 1 It is N or C(H); X 2 For O, CH2 or N(R) 4 ); R 4 For H or C 1-3 alkyl; R 1 C 1-3 alkyl; R 2 Selected from: pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and 1,3,4-thiadiazolyl, each optionally substituent R by 1 to 3 independently selected substituents. 5 replace; R 5 Independently selected from: Optionally selected by C 3-5 cycloalkyl and / or 1 to 3 F-substituted C 1-3 Alkyl; C substituted with 1 to 3 F atoms1-3 Alkoxy; C 3-5 cycloalkyl; CN; and halogen; and R 3 Selected from: , , , , , and , Or its pharmaceutically acceptable salt.

[0014] In one aspect, the present invention relates to compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for the treatment of diseases associated with loss of TREM2 function, such as neurodegenerative diseases.

[0015] definition

[0016] Unless the context clearly indicates otherwise, as used herein, the singular forms “a” and “the” include plural references.

[0017] The terms “approximately” and “about” used herein are synonymous. In some implementations, “about” refers to the stated quantity, value, or duration ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5%.

[0018] Unless otherwise specified, the term “compound” as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structure described.

[0019] As used in this article, the term "C" 1-3 Alkyl", C 1-5 Alkyl and C 1-6 "Alkyl" refers to straight-chain or branched hydrocarbon chains containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. C 1-3 Alkyl, C 1-5 Alkyl and C 1-6 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0020] As used in this article, the term "C" 3-6 "Cycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbon atoms. 3-6 Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] As used in this article, the term "C" 1-3"alkoxy" and "C" 1-6 "Alkoxy" refers to -OR # , where R # They represent C as defined in this article. 1-3 Alkyl and C 1-6 Alkyl group. C 1-3 Alkoxy and C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0022] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0023] The term "halogenated," as used herein as a prefix to another term for a chemical group, refers to a modification of that chemical group in which one or more hydrogen atoms are replaced by a halogen as defined herein. The halogen is chosen independently each time it appears. For example, the term "C"... 1-6 "Halogenated alkyl" refers to C as defined herein. 1-6 Alkyl group, wherein one or more hydrogen atoms are replaced by halogens. C 1-6 Representative examples of alkyl halides include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). Furthermore, the term "C"... 1-6 "Haloalkoxy" refers, for example, to C as defined herein. 1-6 Alkoxy groups, in which one or more hydrogen atoms are replaced by halogens. C 1-6 Representative examples of haloalkoxy groups include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2 and -OCH(CH2F)(CF3).

[0024] The term "CN" is used in this document to represent cyano ( ).

[0025] As described herein, the compounds of the present invention may contain a “substituted” moiety. Generally, the term “substituted” means that one or more hydrogen atoms in a specified moiety are replaced by a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted by more than one substituent selected from the specified group, the substituents may be the same or different at each position, i.e., the substituents may be selected individually / independently from the group of substituents. The combinations of substituents contemplated in this invention are preferably those combinations that result in the formation of stable or chemically viable compounds.

[0026] As used herein, the term "stable" means that a compound does not undergo material alteration when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0027] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within a reasonable medical diagnostic scope, are suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, or similar effects, and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the relevant technical field. Invention Details

[0029] In one aspect, the present invention relates to a compound of formula (I):

[0030] Formula (I)

[0031] in: X 1 It is N or C(H); X 2 For O, CH2 or N(R) 4 ); R 4 For H or C 1-3 alkyl; R 1 C 1-3 alkyl; R 2 Selected from: pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and 1,3,4-thiadiazolyl, each optionally substituent R by 1 to 3 independently selected substituents. 5 replace; R 5 Selected independently from: C 1-3 Alkyl group, optionally C 3-5 Cycloalkyl and / or 1 to 3 F-substituted; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; C 3-5cycloalkyl; CN; and halogen; and R 3 Selected from: , , , , , and , Or its pharmaceutically acceptable salt.

[0032] In some implementation schemes, X 1 For N. In some implementations, X 1 It is C(H).

[0033] In some implementation schemes, X 2 For O. In some implementations, X 2 For CH2. In some implementations, X 2 For N(R) 4 ), and R 4 For H or C 1-3 Alkyl group. In some embodiments, R 4 For H. In some implementations, R 4 C 1-3 Alkyl group. In some embodiments, R 4 For CH3. In some implementations, X 2 For N(H). In some implementations, X 2 It is N(CH3).

[0034] In some implementation schemes, R 1 It is CH3.

[0035] In some implementation schemes, R 2 For optional substituents R selected independently 5 Substituted pyrazol group. In some embodiments, R 2 For optional substituents R selected independently 5 Substituted pyridinyl group. In some embodiments, R 2 For optional substituents R selected independently 5 Substituted pyrazinyl group. In some embodiments, R 2 For optional substituents R selected independently 5 Substituted pyridazine group. In some embodiments, R 2 For optional substituents R selected independently 5 Substituted pyrimidine group. In some embodiments, R 2 For optional substituents R selected independently5 Substituted 1,3,4-thiadiazole group.

[0036] In some implementation schemes, R 5 C 1-3 Alkyl group. In some embodiments, R 5 For CH3. In some implementations, R 5 It is CH2CH3. In some implementations, R 5 It is CH2CH2CH3. In some implementations, R 5 It is CH2(CH3)2. In some implementations, R 5 C replaced by 1 to 3 Fs 1-3 Alkyl group. In some embodiments, R 5 CH3 substituted with 1 to 3 F atoms. In some implementations, R... 5 For CF3. In some implementations, R 5 For CHF2. In some implementations, R 5 CH2CH3 substituted with 1 to 3 F atoms. In some implementations, R... 5 For CH2CF3. In some implementations, R 5 It is CH2CHF2. In some implementations, R 5 C 1-3 Alkyl group. In some embodiments, R 5 For -OCH3. In some implementations, R 5 C replaced by 1 to 3 Fs 1-3 Alkyl group. In some embodiments, R 5 For -OCH3. In some implementations, R 5 For -OCHF2. In some implementations, R 5 For being C 3-5 Cycloalkyl-substituted C 1-3 Alkyl group. In some embodiments, R 5 It is -CH2-cyclopropyl. In some embodiments, R 5 C 3-5 Cycloalkyl. In some embodiments, R 5 It is cyclopropyl. In some embodiments, R 5 It is cyclobutyl. In some embodiments, R 5 It is cyclopentyl. In some embodiments, R 5 For CN. In some implementations, R 5 It is a halogen. In some implementations, R 5 It is Cl.

[0037] In some implementation schemes, R 2Having formula (II):

[0038] Equation (II)

[0039] in: R 6 Selected from: H; C 1-3 Alkyl group, optionally C 3-5 Cycloalkyl and / or 1 to 3 F-substituted; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; and C 3-5 cycloalkyl; R 7 For H, C 1-3 Alkyl or halogen; and R 8 For H, C 1-3 Alkyl or halogen.

[0040] In some implementation schemes, R 6 For H. In some implementations, R 6 C 1-3 Alkyl group. In some embodiments, R 6 For CH3. In some implementations, R 6 It is -(CH2)2CH3. In some implementations, R 6 It is -C(H)(CH3)2. In some implementations, R 6 C replaced by 1 to 3 Fs 1-3 Alkyl group. In some embodiments, R 6 CH3 substituted with 1 to 3 F atoms. In some implementations, R 6 For CHF2. In some implementations, R 6 CH2CH3 substituted with 1 to 3 F atoms. In some implementations, R... 6 For CH2CF3. In some implementations, R 6 It is CH2CHF2. In some implementations, R 6 For being C 3-5 Cycloalkyl-substituted C 1-3 Alkyl group. In some embodiments, R 6 It is -CH2-cyclopropyl. In some embodiments, R 6 C 3-5 Cycloalkyl. In some embodiments, R 6 It is cyclopropyl. In some embodiments, R 6 It is cyclobutyl. In some embodiments, R 6 It is cyclopentyl.

[0041] In some implementation schemes, R7 For H. In some implementations, R 7 C 1-3 Alkyl group. In some embodiments, R 7 It is CH3.

[0042] In some implementation schemes, R 8 For H. In some implementations, R 8 C 1-3 Alkyl group. In some embodiments, R 8 For CH3. In some implementations, R 8 It is a halogen. In some implementations, R 8 It is Cl.

[0043] In some implementation schemes, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for .

[0044] In some implementation schemes, R 2 Having Equation (III):

[0045] Equation (III)

[0046] Where R 9 For H or C 1-3 alkyl.

[0047] In some implementation schemes, R 2 for In some implementations, R 2 for In some implementations, R 2 for .

[0048] In some implementation schemes, R 2 Having formula (IV):

[0049] Formula (IV)

[0050] Where R 10 Selected from: H; C 1-3 Alkyl group, optionally substituted with 1 to 3 F atoms; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; CN; and C 3-5 Cycloalkyl.

[0051] In some implementation schemes, R 10 For CN. In some implementations, R 10 C 1-3 Alkyl group. In some embodiments, R 10 For CH3. In some implementations, R 10 C replaced by 1 to 3 Fs 1-3 Alkyl group. In some embodiments, R 10 For CF3. In some implementations, R 10 For CHF2. In some implementations, R 10 C 1-3 Alkyl group. In some embodiments, R 10 For -OCH3. In some implementations, R 10 C replaced by 1 to 3 Fs 1-3 Alkyl group. In some embodiments, R 10 For -OCHF2. In some implementations, R 10 C 3-5 Cycloalkyl. In some embodiments, R 10 It is cyclopropyl.

[0052] In some implementation schemes, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for In some implementations, R 2 for .

[0053] In some implementation schemes, R 2 The pyrazinyl group is optionally substituted with CN. In some embodiments, R 2 For optional use by C 1-3 Alkyl-substituted pyrazine group. In some embodiments, R 2 The pyrazinyl group is optionally substituted with CH3.

[0054] In some implementation schemes, R 2 for In some implementations, R 2 for In some implementations, R 2 for .

[0055] In some implementation schemes, R 2 The pyridazinyl group is optionally substituted with a halogen. In some embodiments, R 2 The pyridazinyl group is optionally substituted with Cl. In some embodiments, R 2 for .

[0056] In some implementation schemes, R 2 For optional use by C 1-3 Alkyl-substituted pyrimidinyl group. In some embodiments, R 2 The pyrimidine group is optionally substituted with CH3.

[0057] In some implementation schemes, R 2 for In some implementations, R 2 for In some implementations, R 2 for .

[0058] In some implementation schemes, R 3 for In some implementations, R 3 for R 3 for In some implementations, R 3 for In some implementations, R 3for R 3 for .

[0059] In some implementation schemes, R 3 for .

[0060] In some implementation schemes, X 1 For N and R 3 for In some implementations, X 1 For N and R 1 For CH3. In some implementations, X 1 For N, R 1 It is CH3, and R 3 for In some implementations, X 1 For N and X 2 For O. In some implementations, X 2 For O and R 2 For optional substituents R selected independently 5 The substituted pyrazol group. In some embodiments, X 1 Let N, X 2 For O and R 2 For optional substituents R selected independently 5 The substituted pyrazol group. In some embodiments, X 1 For N and R 1 For CH3. In some implementations, X 1 For N, R 1 It is CH3, and R 3 for In some implementations, X 1 For N, R 1 CH3, R 3 for X 2 It is O, and R 2 For optional substituents R selected independently 5 Substituted pyrazol group.

[0061] In some embodiments, the compound is 4-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-2-(3-(((5-methyl-1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((5-ethyl-1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-8-oxo-2-(3-(pyrazin-2-yloxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 5-((1-(4-(4-cyano-2-fluorophenyl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)azacyclobutane-3-yl)oxy)pyrazine-2-carboxynitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1,5-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(2-(3-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1,3-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(2-(3-((1-isopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-8-oxo-2-(3-((1-propyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((5-chloro-1-methyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1-cyclobutyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(2-(3-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1-cyclopentyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-8-oxo-2-(3-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-((1-(4-(4-cyano-2-fluorophenyl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)azacyclobutane-3-yl)oxy)pyridine-2-carboxynitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(2-(3-((2-methoxypyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((2-cyclopropylpyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((2-(difluoromethyl)pyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((2-(difluoromethoxy)pyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-fluoro-4-(7-methyl-8-oxo-6-(trifluoromethyl)-2-(3-((2-(trifluoromethyl)pyridin-4-yl)oxy)azacyclobutan-1-yl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((6-chloropyridazin-4-yl)oxy)azacyclobutan-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-8-oxo-2-(3-(pyrimidin-5-yloxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(7-methyl-2-(3-((4-methylpyridin-5-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-(3-((2-methylpyridin-4-yl)oxy)azacyclobutane-1-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)(methyl)amino)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-(3-(((2-methylpyridin-4-yl)methyl)azacyclobutane-1-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2-fluoro-4-methoxyphenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 5-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)pyridine-2-carboxylon, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-8-(1-methyl-6-oxo-1,6-dihydropyrimidin-3-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.

[0062] In one aspect, the present invention relates to a compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0063] In one aspect, the present invention relates to a compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt thereof.

[0064] In some implementations, the compound is Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0065] The compounds of this invention also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers in isoprotonated states having the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms may be in equilibrium or spatially locked into one form through appropriate substitution. Tautomers may also include methyltropic tautomers, which are produced by the exchange of single bonds with adjacent double bonds and the accompanying migration of methyl groups.

[0066] The compounds of the present invention also include all isotopes of the atoms appearing in the intermediates or final compounds. Isotopes include those atoms with the same number of atoms but different mass numbers. In some embodiments, the compounds of the present invention include one or more isotopes of atoms in an amount greater than the natural abundance of that isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom in an amount greater than the natural abundance of deuterium (e.g., the compound is rich in deuterium).

[0067] All compounds described herein and their pharmaceutically acceptable salts may exist with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0068] In one aspect, the present invention relates to an intermediate compound or a pharmaceutically acceptable salt thereof, which can be used to synthesize the compounds of the present invention. For example, in some embodiments, the intermediate compound is one of the intermediate compounds described in the Examples section disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present invention are selected from any of the intermediate compounds disclosed in any of Examples 1 to 41 herein or a pharmaceutically acceptable salt thereof.

[0069] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist in stereoisomer, enantiomer, and diastereomer forms. Therefore, unless the stereochemistry is specifically identified, the scope of the invention should be understood to cover all possible stereoisomers of the compounds shown, including the pure stereoisomeric forms and mixtures of stereoisomers of any chemical structure disclosed herein. If the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, then that structure or part thereof should be interpreted to cover all its stereoisomers. If the stereochemistry of a structure or part thereof is indicated by, for example, a thick or dashed line, then that structure or part thereof should be interpreted to cover only the indicated stereoisomer.

[0070] As used herein, a "stereoisomer" or "stereoisopure" compound refers to a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisopure compound having one chiral center will substantially be free of its mirror-image enantiomers, and a stereoisopure compound having two chiral centers will substantially be free of its other enantiomers and diastereomers. Typical stereoisopure compounds contain more than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

[0071] In some implementations, the compounds defined herein are stereoisomerically pure.

[0072] Mixtures of stereoisomers can be separated using standard techniques, such as chiral columns or chiral resolving agents, as outlined in the Examples section.

[0073] Pharmaceutical Composition

[0074] The present invention also relates to a pharmaceutical composition comprising, for example, a pharmaceutically effective amount of a compound disclosed herein as an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0075] Although the compounds disclosed herein may be administered in their original chemical compound form for use in therapy, it is generally preferred to introduce the active ingredient into a pharmaceutical composition, optionally in the form of a pharmaceutically acceptable salt, and one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical excipients.

[0076] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or preventative ingredients known and used in the art. The carrier must be "acceptable" in the sense of compatibility with other ingredients in the formulation and harmless to the recipient. Examples of excipients and their use can be found in Remington's Pharmaceutical Sciences, 20th edition (Lippincott Williams & Wilkins, 2000).

[0077] A therapeutic dose or therapeutically effective dose or dosage refers to the amount of an active ingredient (i.e., the compounds or compositions disclosed herein) that treats, relieves, reduces, or diminishes the symptoms of a disease in a subject, or reduces its severity (such as improving one or more symptoms of the condition or the condition itself). Therapeutic doses of the compounds described herein can improve patient survival, increase survival time or survival rate, reduce symptoms, make injury, disease, or condition (e.g., neurodegenerative diseases) more tolerable, slow the rate of degeneration or decline, or improve the physical or mental health of a patient.

[0078] Therapeutic efficacy and toxicity, such as ED 50 The therapeutic effect can be determined in cell cultures or laboratory animals using standard pharmacological procedures. The dose ratio between therapeutic effect and toxic effect is the therapeutic index, which can be expressed as the ratio between the plasma level producing a therapeutic effect and the plasma ratio producing a toxic effect. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. In some embodiments, the therapeutically effective dose of the compounds disclosed herein is in the range of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day.

[0079] Of course, the dosage must be carefully adjusted based on the individual's age, weight and condition, as well as the route of administration, dosage form and regimen, and the desired outcome. The precise dosage should, of course, be determined by a licensed physician.

[0080] Administration refers to a method of delivering an agent, compound, or composition to a desired site of biological action. These methods include, but are not limited to, enteral delivery, oral delivery, local delivery, non-enteric delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0081] In some embodiments, the compounds of the present invention are suitable for use as pharmaceutical agents. Therefore, in some embodiments, the compounds have suitable pharmacological activities, such as target efficacy, affinity, and / or selectivity. In some embodiments, the compounds have suitable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. For example, in some embodiments, the compounds have acceptable levels of off-target effects, including low hERG channel (human Ether-à-go-go-Related Gene) inhibition, low off-target toxicity, genotoxicity, carcinogenicity, and / or hepatotoxicity. In some embodiments, the compounds exhibit suitable pharmacokinetics, such as bioavailability, half-life, and / or clearance. In some embodiments, the compounds exhibit suitable pharmacodynamics, such as efficacy and / or potency. In some embodiments, the compounds exhibit chemical stability and / or metabolic stability. These parameters can be evaluated by conventional in vitro tests, animal studies, and / or clinical trials known to those skilled in the art. In some embodiments, the compounds exhibit characteristics suitable for oral formulations using pharmaceutically acceptable excipients. For example, a compound exhibits suitable solubility in the relevant medium.

[0082] In one aspect, the present invention relates to a pharmaceutical composition comprising compounds selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0083] Bioactivity

[0084] As demonstrated in Example 42, the compounds of the present invention are capable of regulating TREM2. Therefore, in some embodiments, the compounds of the present invention are TREM2 modulators, such as TREM2 agonists. The assays described in Example 42 can be used to assess and characterize the ability of the compounds to act as TREM2 agonists. In some embodiments, the compounds of the present invention can be used to activate TREM2. In some embodiments, the compounds of the present invention activate TREM2. In some embodiments, the compounds of the present invention enhance TREM2 activity. In some embodiments, the compounds of the present invention induce phosphorylation of kinases interacting with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b. In some embodiments, the compounds of the present invention enhance or activate TREM2 signaling via DAP12. In some embodiments, the compounds of the present invention enhance or activate the degree of phosphorylation of TREM2-induced Syk kinase. In some embodiments, if the degree of Syk phosphorylation in a sample treated with the compound of the present invention increases 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 compared to a control, such as an increase of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more compared to a control, then the compound of the present invention induces or enhances Syk phosphorylation.

[0085] In some embodiments, the potency of the compounds of the present invention is measured in EC. 50 EC 50 This corresponds to a compound concentration capable of activating the phosphorylated Syk AlphaScreen signal to 50% of its maximum response. In some embodiments, the compounds of the present invention have an EC50 of less than 1000 nM. 50 Values, such as EC between 100 nM and 1000 nM 50 Values, such as EC between 10 nM and 100 nM 50 Values, such as EC between 1 nM and 10 nM 50 Values, such as EC < 1 nM 50 value.

[0086] In some embodiments, the compounds of the present invention can increase the expression of one or more TREM2-regulated genes. In some embodiments, the compounds of the present invention increase the expression of one or more TREM2-regulated genes. In some embodiments, the compounds of the present invention can increase the expression levels of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7, and TMEM119, such as at brain expression levels.

[0087] In some embodiments, the compound of the present invention increases the expression level, such as the brain expression level, if the expression level of the gene in a sample treated with the compound of the present invention increases 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 compared with the control value, such as by at least 1.5, 2, 2.5, 3, 3.5, 4, 5 or more times compared with the control value (e.g., untreated control / solvent).

[0088] Medical Use

[0089] As TREM2 modulators, the compounds of the present invention have the use of treating diseases and conditions in living organisms, including humans. As used herein, the term "treatment" includes treating, preventing, and / or alleviating or improving one or more diseases and conditions or one or more symptoms of a disease or condition. In one aspect, the compounds described herein are used as pharmaceuticals.

[0090] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of conditions associated with TREM2 loss of function. In another aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of conditions associated with TREM2 mutations.

[0091] In one aspect, the invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of neurodegenerative diseases.

[0092] In some embodiments, the compounds described herein are used to treat neurodegenerative diseases characterized by loss of TREM2 function. In some embodiments, the compounds described herein are used to treat neurodegenerative diseases characterized by TREM2 mutations.

[0093] In one aspect, the present invention relates to a method for enhancing or increasing TREM2 activity in a subject in need, such as a subject suffering from a neurodegenerative disease, the method comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0094] In one aspect, the present invention relates to a method for use in a subject in need, such as a subject suffering from a neurodegenerative disease, for one or more of the following: i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of a kinase interacting with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; iii) enhancing the level of phosphorylation of TREM2-induced Syk kinase; iv) increasing the expression level of one or more TREM2-regulated genes, such as brain expression levels; and / or v) increasing the expression level of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7, and TMEM119, such as brain expression levels; the method comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0095] In some implementations, neurodegenerative diseases are referred to as tauopathy. Tauopathy describes a range of neurodegenerative conditions characterized by tau deposits in the brain, accompanied by symptoms of dementia and Parkinsonism. In some implementations, the neurodegenerative disease is selected from the following tau diseases: 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-17 associated with chromosome 17).

[0096] In some implementations, the neurodegenerative disease is a TDP-43-related neurodegenerative condition (TDP-43 proteinopathy or TDP-43-opathies). Pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are clearly visible in the brain and spinal cord of patients with a range of neurodegenerative diseases.

[0097] In some implementations, the neurodegenerative disease is selected from the following TDP-43 protein diseases: 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-U (types a, b, and c), facial onset sensory and motor neuronopathy (FOSMN), and limbic-predominant age-related TDP-43 encephalopathy. encephalopathy (LATE), 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 known as inclusion body myopathy (IBM), associated with early-onset Paget's disease and FTLD dementia), Perry's disease, and conditions associated with TDP-43 pathology, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE).

[0098] In some implementations, the neurodegenerative disease is referred to as a multisystem protein disease (MSP). MSP is a dominant, pleiotropic human degenerative disease that affects the muscles, bones, and / or central nervous system. Clinically, MSP can manifest as classic amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease (PDB), or a combination of these conditions (IBMPFD, IBMPFD / ALS).

[0099] In some implementations, the neurodegenerative disease is referred to as synucleinopathy. Synucleinopathy (also known as α-synucleinopathy) is a neurodegenerative disease characterized by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibers, or glial cells.

[0100] In some implementations, the neurodegenerative disease is selected from the following synucleinopathies: Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), neuroaxonal dystrophies, and Alzheimer's disease with amygdalar restricted Lewy bodies (AD / ALB).

[0101] In some implementations, the neurodegenerative disease is cognitive impairment and / or memory loss. In some implementations, the neurodegenerative disease is dementia. In some implementations, neurodegenerative diseases are selected from the following dementias: Alzheimer's disease, Parkinson's disease dementia, Huntington's disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, Lewy body dementia, prion disease dementia, argyrophilic graindementia, 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 dementia caused by another medical condition (such as brain tumor, subdural hematoma). Other forms of dementia include hematoma, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, certain leukodystrophies, certain neurological disorders such as epilepsy, and multiple sclerosis.

[0102] Peripheral neuropathy is the most common neurological complication of systemic amyloidosis. In some implementations, the neurodegenerative disease is referred to as peripheral amyloidosis (peripheral neuropathy within systemic amyloidosis).

[0103] 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 such as myelinoclastic disorders or demyelinating disorders selected from the following: multiple sclerosis, neuromyelitis optica (Devi's disease), and idiopathic inflammatory demyelinating diseases. In some implementations, demyelinating disorders are such as leukodystrophic or dysmyelinating disorders selected from the following: CNS neuropathies, such as vitamin B12 deficiency and central pontine myelinolysis; myelopathies, such as tabes dorsalis (syphilitic myelopathy); leukoencephalopathies; and leukodystrophies.

[0104] In some implementations, the neurodegenerative disease is a demyelinating condition of the peripheral nervous system (PNS). In some implementations, the demyelinating condition is selected from: Guillain–Barré syndrome and its chronic counterparts: chronic inflammatory demyelinating polyneuropathy; anti-MAG peripheral neuropathy; Charcot-Marie-Tuss disease and its counterparts: hereditary neuropathy with liability to pressurepalsy; copper deficiency-related conditions (peripheral neuropathy, myelopathy, and rare optic neuropathy); and progressive inflammatory neuropathy.

[0105] 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 lobe 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's 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-Barré syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathy. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tuss disease. In some embodiments, the neurodegenerative disease is a 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 disorder (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).

[0106] In some implementations, the neurodegenerative disease is referred to as leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term used to describe all diseases of the white matter, regardless of whether their molecular etiology is known. In some implementations, the neurodegenerative disease is selected from the following leukoencephalopathy: progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with vanishing white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, megalencephalicleukoencephalopathy with subcortical cysts, and hypertensive leukoencephalopathy. In some implementations, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonalspheroids and pigmented glia).

[0107] In some implementations, the neurodegenerative disease is selected from: 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).

[0108] In some implementations, the neurodegenerative disease is leukodystrophy. In other implementations, the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophy is a group of rare, inherited disorders that affect the white matter of the brain. In some implementations, the neurodegenerative disease is selected from the following leukodystrophy: 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 leukoencephalopathy. In some implementations, the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some implementations, the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some implementations, the neurodegenerative disease is Nasu-Hakola disease, also known as polycystic fat membrane dysplasia with sclerotic leukoencephalopathy (PLOSL).

[0109] In some implementations, the neurodegenerative disease is transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease (GSS), kuru, and fatal familial insomnia.

[0110] In one aspect, the present invention relates to a method for treating neurodegenerative diseases, comprising administering to a subject in need a compound described herein or a pharmaceutically acceptable salt thereof.

[0111] In one aspect, the present invention relates to a method for treating a neurodegenerative disease, comprising one or more steps of administering a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof to a subject in need.

[0112] In some implementations, the subjects are mammals, such as humans.

[0113] In one aspect, the present invention relates to the use of the compounds described herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of neurodegenerative diseases.

[0114] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with dysfunction of community-stimulating factor 1 receptor (CSF1R, also known as macrophage community-stimulating factor receptor / M-CSFR, or differentiation cluster 115 / CD115). In some embodiments, the disease or condition associated with CSF1R dysfunction is a neurodegenerative disease associated with CSF1R dysfunction.

[0115] In some embodiments, the disease or condition is caused by a heterozygous mutation in CSF1R, a homozygous mutation in CSF1R, a splicing mutation in the csf1r gene, a missense mutation in the csf1r gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in the immunoglobulin domain of CSF1R, a mutation in the extracellular domain of CSF1R, or a loss-of-function mutation in CSF1R. In some embodiments, the disease or condition is caused by changes in CSF1R activity (e.g., increase, decrease, or termination) and / or a decrease or termination of CSF1R activity.

[0116] In some implementations, the neurodegenerative disease associated with CSF1R dysfunction is leukoencephalopathy.

[0117] In some implementations, the neurodegenerative diseases associated with CSF1R dysfunction are selected from: Adult-onset leukoencephalopathy with axonoglobulinization and pigmented glial cells (ALSP). CSF1R 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 Autosomal dominant cerebral arteriosclerosis (CADASIL) with subcortical infarction or leukoencephalopathy.

[0118] In some implementations, neurodegenerative disease is defined as a condition associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0119] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of lysosomal storage disorder (LSD). Most lysosomal storage disorders cause progressive neurodegeneration, leading to premature death.

[0120] In some implementations, LSD stands for lipid storage diseases, such as those selected from the following: cholesterol ester storage disease, fucosidosis, Schindler disease, and Wolman disease.

[0121] In some implementations, LSD refers to sphingolipidoses, such as those selected from: Fabry disease, Gaucher disease, Krabby disease (globose cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (types A, B, and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency, and Tay-Sachs disease.

[0122] In some implementations, LSD stands for mucopolysaccharidoses, such as those selected from the following: Hunter syndrome, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, and Natowicz syndrome.

[0123] In some implementation schemes, LSD is selected from Batten disease, cyctinosis, Danon disease, and Pompe disease.

[0124] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions of bone and / or joints. In some embodiments, the diseases or conditions are selected from: arthritis, rheumatoid arthritis, Pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, and dysosteoplasia.

[0125] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of autism spectrum disorders, autism, and Asperger's syndrome.

[0126] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of traumatic brain injury (TBI) and spinal cord injury. Traumatic brain injury (TBI) may also be referred to as intracranial injury. Traumatic brain injury occurs when the brain is traumatized by external force. Spinal cord injury (SCI) includes any spinal cord injury caused by trauma rather than disease. In some embodiments, TBI is chronic traumatic encephalopathy (CTE).

[0127] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of muscular dystrophy, such as myotonic dystrophy (DM), including type 1 DM (DM1) and type 2 DM (DM2).

[0128] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of inflammation. In some embodiments, the inflammation is selected from inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain intestinal conditions including inflammatory bowel disease (IBD).

[0129] Decreased TREM2 function levels lead to lipid metabolism disorders. In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for the treatment of dysregulated lipid metabolism disorders. In some embodiments, the lipid metabolism disorder comprises an increased intracellular and / or extracellular accumulation of one or more lipids. In some embodiments, the lipid metabolism disorder is atherosclerosis.

[0130] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for 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.

[0131] In one aspect, the present invention relates to compounds as defined herein or pharmaceutically acceptable salts thereof for 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.

[0132] 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 includes administering to a subject a compound described herein or a pharmaceutical composition comprising a compound described herein.

[0133] The compounds of this invention can be used to treat animal patients of any category. 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.

[0134] Unless otherwise specified, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Therefore, the scope of the methods and uses described herein should be understood to encompass all methods and uses employing all such forms.

[0135] Depending on the specific condition or disease to be treated, additional therapeutic agents typically administered to treat that condition may be used in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific disease or condition are referred to as “the disease or condition to be treated.” In some embodiments, the provided combinations or compositions are administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method of treating the disclosed disease or condition, comprising administering to a patient in need an effective amount of the compounds disclosed herein or pharmaceutically acceptable salts thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents. In some embodiments, the method comprises co-administering one or more additional therapeutic agents. Examples of therapeutic agents that may also be combined with the combinations of the present invention include, but are not limited to, treatments for Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke. In some embodiments, therapeutic agents that can also be combined with the combinations of the present invention include, but are not limited to, therapeutic agents for diseases selected from: tau proteinopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, demyelinating diseases of the CNS, demyelinating diseases of the PNS, leukoencephalopathy, leukodystrophy, infectious spongiform encephalopathy (TSE), and lysosomal storage disease (LSD). As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combinations of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form.

[0136] In one aspect, the present invention relates to a method for treating a condition associated with TREM2 dysfunction, comprising administering to a subject a therapeutically effective amount of a compound selected from: , , , , , , , , , , , , , , , , , , , , , , , , and , Or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is frontotemporal degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tuss disease, prions, and stroke. In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0137] Manufacturing method

[0138] The compounds of this invention can be prepared according to any conventional chemical synthesis method known to those skilled in the art, such as those described in the working examples. The starting materials used in the methods described herein are known or can be readily prepared from commercially available chemicals using conventional methods known to those skilled in the art. The final products of the reactions described herein can be separated using conventional techniques such as extraction, crystallization, distillation, chromatography, etc.

[0139] Generally, compounds of formula (I) as described herein can be synthesized according to the following procedure. All starting materials are commercially available or known in the art and can be synthesized using known procedures. Starting materials can also be synthesized using the procedures disclosed herein. The reaction conditions (such as reaction temperature, solvents, and reagents) used in this section for the procedure can be found in the experimental section of this document.

[0140] Process 1A:

[0141] As shown in process 1A, (CF3CO)2O is condensed with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to form a 2-substituted pyrimidine[5,4-d][1,3]oxazine-4,6,8-trione. (The text then abruptly shifts to a seemingly unrelated topic about R.) 1 NH2 is used for addition and cyclization to give [1,3]diazino[5,4-d]pyrimidin-2,4,8-trione. For example, activation with POCl3 or POBr3 yields 6,8-dihalo-pyrimidin[5,4-d][1,3]diazino-4-one, where Y is a Cl or Br leaving group. R 3 Substituents are added via cross-coupling reactions, for example, where W is boric acid, borate ester, or other organometallic coupling agents, such as organomagnesium, organotin, or organozinc agents. Substituents can then be introduced via nucleophilic substitution reactions.

[0142] In process 1B, (CF3CO)2O is reacted with 3-amino-2,6-dihalopyridinyl-4-carboxamide. Cyclization forms a 6,8-dihalopyridinyl-2,3-disubstituted pyridopyrimidinone, R. 3 Substituents are added via cross-coupling reactions, for example, where W 1 It is a boric acid, borate ester or other organometallic coupling agent, such as organomagnesium, organotin or organozinc reagent. Substituents can then be introduced via nucleophilic substitution reactions or metal-catalyzed coupling.

[0143] Process 1B:

[0144] In processes 2A to D, the methods used for synthesis are described. Different methods, of which X 2 and R 2 As defined in this article.

[0145]

[0146] In process 2A, N-protected (e.g., with Boc) 3-halogen-substituted azacyclobutane is reacted with hydroxyl-substituted R 2 The substituents undergo nucleophilic substitution reactions, deprotection, and subsequently yield substituted NH-azacyclobutanes, which are used as described in procedures 1A and 1B.

[0147] In process 2B, N-protected (e.g., with Boc) 3-hydroxy-substituted azacyclobutane reacts with halogen-substituted R 2 The substituents undergo nucleophilic substitution reactions, deprotection, and subsequently yield substituted NH-azacyclobutanes, which are used as described in procedures 1A and 1B.

[0148] In process 2C, the protected azacyclobutane substituted with carbonyl or methylene groups is reacted with halogen-substituted R... 2 The substituent reaction forms a substituted methylene intermediate. Subsequent reduction and deprotection yield the substituted NH-azacyclobutane, which is used as described in procedures 1A and 1B.

[0149] In process 2D, the carbonyl-substituted protected aziridine reacts with the amino-substituted R 2 Reductive amination was performed, followed by alkylation of the intermediate secondary amine to introduce R. 4 Subsequently, deprotection is performed to obtain substituted NH-azacyclobutane, which is used as described in processes 1A and 1B.

[0150] In one aspect, the present invention relates to a method for synthesizing a compound of formula (I) as defined herein, comprising one or more steps described above. In another aspect, the present invention relates to a method for manufacturing a compound of formula (I) as defined herein, the method comprising the step of: causing a compound of formula (SI)...

[0151] Formula (SI)

[0152] Where R 1 R 3 and X 1 As defined in this article, and Y is Br or Cl, Reaction with compounds of formula (SII):

[0153] Formula (SII)

[0154] Where X 2 and R 2 As defined in this article, To produce compounds of formula (I).

[0155] project

[0156] 1. A compound of formula (I):

[0157] Formula (I)

[0158] in: X 1 It is N or C(H); X 2 For O, CH2 or N(R) 4 ); R 4 For H or C 1-3 alkyl; R 1 C 1-3 alkyl; R 2 Selected from: pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and 1,3,4-thiadiazolyl, each optionally substituent R by 1 to 3 independently selected substituents. 5 replace; R 5 Selected independently from: C 1-3 Alkyl group, optionally C 3-5 Cycloalkyl and / or 1 to 3 F-substituted; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; C 3-5 cycloalkyl; CN; and halogen; and R 3 Selected from: , , , , , and , Or its pharmaceutically acceptable salt.

[0159] 2. As in Project 1, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

[0160] 3. A pharmaceutical composition comprising a compound as described in item 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0161] 4. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0162] 5. A pharmaceutical composition comprising a compound as described in item 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0163] 6. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0164] 7. A pharmaceutical composition comprising a compound such as that in item 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0165] 8. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0166] 9. A pharmaceutical composition comprising a compound as described in item 8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0167] 10. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0168] 11. A pharmaceutical composition comprising a compound such as that in item 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0169] 12. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0170] 13. A pharmaceutical composition comprising a compound such as that in item 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0171] 14. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0172] 15. A pharmaceutical composition comprising a compound as described in item 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0173] 16. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0174] 17. A pharmaceutical composition comprising a compound as described in item 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0175] 18. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0176] 19. A pharmaceutical composition comprising a compound as described in item 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0177] 20. The compound in Project 1, wherein the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0178] 21. A pharmaceutical composition comprising a compound such as that of item 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0179] 22. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0180] 23. A pharmaceutical composition comprising a compound as described in item 22 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0181] 24. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0182] 25. A pharmaceutical composition comprising a compound as described in item 24 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0183] 26. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0184] 27. A pharmaceutical composition comprising a compound as described in item 26 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0185] 28. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0186] 29. A pharmaceutical composition comprising a compound as described in item 28 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0187] 30. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0188] 31. A pharmaceutical composition comprising a compound such as that in item 30 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0189] 32. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0190] 33. A pharmaceutical composition comprising a compound as described in item 32 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0191] 34. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0192] 35. A pharmaceutical composition comprising a compound as described in item 34 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0193] 36. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0194] 37. A pharmaceutical composition comprising a compound as described in item 36 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0195] 38. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0196] 39. A pharmaceutical composition comprising a compound as described in item 38 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0197] 40. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0198] 41. A pharmaceutical composition comprising a compound such as that in item 40 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0199] 42. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0200] 43. A pharmaceutical composition comprising a compound as described in item 42 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0201] 44. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0202] 45. A pharmaceutical composition comprising a compound as described in item 44 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0203] 46. ​​As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0204] 47. A pharmaceutical composition comprising a compound as described in item 46 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0205] 48. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0206] 49. A pharmaceutical composition comprising a compound as described in item 48 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0207] 50. The compound in Project 1, wherein the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0208] 51. A pharmaceutical composition comprising a compound such as that in item 50 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0209] 52. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0210] 53. A pharmaceutical composition comprising a compound as described in item 52 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0211] 54. As in Project 1, the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0212] 55. A pharmaceutical composition comprising a compound as described in item 54 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0213] 56. A method for treating a condition associated with loss of TREM2 function, comprising administering to a subject a therapeutically effective amount of a compound such as that in item 1 or a pharmaceutically acceptable salt thereof.

[0214] 57. As in Project 56, where the condition is a neurodegenerative disease.

[0215] 58. The method of Project 56, wherein the neurodegenerative disease is frontotemporal degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tuss disease, prions, stroke, and traumatic brain injury (TBI).

[0216] 59. The method of Project 57, wherein the neurodegenerative disease is Alzheimer's disease.

[0217] Example

[0218] abbreviation

[0219] Ac: Acetyl group

[0220] aq.: water-based

[0221] dba: Dibenzylacetone

[0222] DCM: Dichloromethane

[0223] DIPEA: Diisopropylethylamine

[0224] DMAP: 4-Dimethylaminopyridine

[0225] DMF: Dimethylformamide

[0226] DMSO: Dimethyl sulfoxide

[0227] Dppf: 1,1'-bis(diphenylphosphine)ferrocene

[0228] EtOAc: Ethyl acetate

[0229] eq.: equivalent

[0230] g: gram

[0231] h: hours

[0232] HATU: 1-[bis(dimethylamino)methylene]-1-hexafluorophosphate H -1,2,3-triazolo[4,5- b ] Pyridium 3-oxide

[0233] HPLC: High Performance Liquid Chromatography

[0234] LCMS: Liquid Chromatography-Mass Spectrometry

[0235] MeOH: Methanol

[0236] Me₂NH₂,HCl: Methylamine hydrochloride

[0237] mg: milligram

[0238] min: minutes

[0239] mmol: millimole

[0240] mL: milliliters

[0241] mm: millimeter

[0242] MS: Mass Spectrometry

[0243] m / z: Mass-to-charge ratio

[0244] NH4OAc: Ammonium acetate

[0245] NBS: N-bromosuccinimide

[0246] NMR: Nuclear Magnetic Resonance

[0247] rt: room temperature

[0248] Rt: Duration of stay

[0249] RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[0250] sat.: saturation

[0251] THF: Tetrahydrofuran

[0252] TFA: Trifluoroacetic acid

[0253] Xanphos: (9,9-dimethyl-9 H -oxanthracene-4,5-diyl)bis(diphenylphosphine)

[0254] LCMS conditions

[0255] Condition A

[0256] LCMS column - Acquity BEH C18 (50 × 2.1 mm, 1.7 u), maintained initially (90% [water containing 0.05% HCOOH] and 10% [CH3CN:water (90:10) containing 0.05% HCOOH] to 0.75 min, then reaching 50% [water containing 0.05% HCOOH] and 50% [CH3CN:water (90:10) containing 0.05% HCOOH] within 1.00 min, then reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN:water (90:10) containing 0.05% HCOOH] within 2.00 min, maintained this mobile phase composition until 2.25 min, and finally returned to initial conditions within 2.60 min and maintained until 3.00 min). Flow rate: 0.60 ml / min.

[0257] Condition B

[0258] Column-Xbridge C18 (4.6 × 50 mm, 5 u) mobile phase: 90% [10 mM ammonium acetate aqueous solution] and 10% [CH3CN], reaching 70% [10 mM ammonium acetate aqueous solution] and 30% [CH3CN] within 1.5 min, further reaching 10% [10 mM ammonium acetate aqueous solution] and 90% [CH3CN] within 3.00 min, maintaining this mobile phase composition until 4.00 min, and finally returning to initial conditions within 5.00 min. Flow rate = 1.20 ml / min

[0259] Condition C

[0260] LCMS column - Acquity BEH C8 (50 × 2.1 mm, 1.7 u), initial (95% [water containing 0.05% HCOOH] and 5% [CH3CN:water (90:10) containing 0.05% HCOOH]) was maintained for 0.75 min, then reached 75% [water containing 0.05% HCOOH] and 25% [CH3CN:water (90:10) containing 0.05% HCOOH] within 1.50 min, then reached 5% [water containing 0.05% HCOOH] and 95% [CH3CN:water (90:10) containing 0.05% HCOOH] within 3.00 min, and this mobile phase composition was maintained until 4.00 min. Finally, the initial conditions were returned within 4.50 min and maintained until 5.10 min. Flow rate: 0.80 ml / min.

[0261] Condition D

[0262] The mobile phase was maintained at an Xbridge C18 column (3.5 µm, 50 × 3 mm) for 0.75 min, initially at 95% [5 mM NH4OAc aqueous solution] and 5% [5 mM NH4OAc in CH3CN:water (90:10) solution], then increased to 70% [5 mM NH4OAc aqueous solution] and 30% [5 mM NH4OAc in CH3CN:water (90:10) solution] within 1.00 min, and finally increased to 2% [5 mM NH4OAc aqueous solution] and 98% [5 mM NH4OAc in CH3CN:water (90:10) solution] within 2.00 min. This mobile phase composition was maintained for 2.50 min, and finally returned to the initial conditions within 2.75 min and maintained for 3.0 min. Flow rate: 1.20 ml / min.

[0263] Condition E

[0264] The column was YMC Triart C18 (33 × 2.1 mm, 3u) with an initial mobile phase composition of 98% [water containing 0.05% HCOOH] and 2% [CH3CN:water (90:10) containing 0.05% HCOOH] held for 0.75 min, then reaching 90% [water containing 0.05% HCOOH] and 10% [CH3CN:water (90:10) containing 0.05% HCOOH] within 1.0 min, further reaching 2% [water containing 0.05% HCOOH] and 98% [CH3CN:water (90:10) containing 0.05% HCOOH] within 2.00 min, maintaining this mobile phase composition until 2.50 min, and finally returning to the initial conditions within 4.90 min, maintaining this composition until 3.0 min. Flow rate: 1.0 ml / min.

[0265] Reverse-phase preparative purification method: Prep-A Preparative HPLC was performed on a Waters automated purification system. Column name: LONG-YMC, C18 (20 × 250 mm), 5 µm, operated at ambient temperature, flow rate: 16 mL / min. Mobile phase: A = acetonitrile, B = 10 mM ammonium acetate aqueous solution; gradient profile: initial mobile phase composition was 30% A and 70% B, then reached 45% A and 55% B within 3 min, then 78% A and 22% B within 18 min, then 100% A and 0% B within 19 min, held at this composition until 21.5 min for column washing, then returned to the initial composition within 22 min and held until 24 min.

[0266] Prep-B

[0267] Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Actus C18 (250×20mm, 5µ), operated at ambient temperature, flow rate: 16 mL / min. Mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile; gradient profile: initial mobile phase composition was 60% A and 40% B, then reached 40% A and 60% B within 3 min, then 20% A and 80% B within 20 min, then 5% A and 95% B within 21 min, maintained at this composition until 22 min for column washing, then returned to the initial composition within 23 min and maintained until 25 min.

[0268] Synthesis of intermediates: Preparation of 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazole (intermediate I-1)

[0269] Step 1

[0270] Preparation of tert-butyl 3-[(1-cyclopropyl-1H-pyrazol-4-yl)oxy]azacyclobutane-1-carboxylate

[0271] Cs₂CO₃ (9.50 g, 27.5 mmol) was added to a stirred solution of 1-cyclopropyl-1H-pyrazol-4-ol (2 g, 18.35 mmol) in DMF (40 mL), followed by the addition of tert-butyl 3-iodoazacyclobutane-1-carboxylate (7.75 g, 27.5 mmol), and the resulting mixture was heated at 70 °C for 16 h. The reaction mixture was diluted with ethyl acetate. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (50% ethyl acetate-hexane) to give tert-butyl 3-[(1-cyclopropyl-1H-pyrazol-4-yl)oxy]azacyclobutane-1-carboxylate (3.5 g, 68.3% yield) as a pale yellow liquid.

[0272] 1H NMR (400 MHz, DMSO D6) δ 7.50 (1H, s), 7.16 (1H, s), 4.70-4.67(1H, m), 4.20-4.16 (2H, t), 3.74 (2H, d, J=4 MHz), 1.19 (9H, m), 0.99-0.93(2H, m), 0.92-0.87 (2H, m); LCMS condition E: Rt = 3.16 min. m / z 280.1 [M+H] + .

[0273] Step 2

[0274] Preparation of 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazole, TFA salt:

[0275] 500 mg (0.307 mmol, 1 equivalent) of tert-butyl 3-[(1-cyclopropyl-1H-pyrazol-4-yl)oxy]azacyclobutane-1-carboxylate ester (10 mL) was added to a stirred solution in DCM and cooled to 0 °C. TFA (1.5 mL) was added dropwise. The reaction mixture was gradually heated to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give a pale yellow viscous liquid as a TFA salt of 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazol.

[0276] 1H NMR (400 MHz, DMSO D6) δ 7.57 (1H, s), 7.21 (1H, s), 4.78-4.74(1H, m), 4.35 (2H, dd, J=16 Hz, J=4 Hz), 3.95 (2H, d, J=4 Hz), 3.62-3.57 (1H, m), 0.99-0.93 (2H, m), 0.92-0.89 (2H, m).

[0277] Intermediates I-2 to I-28 were synthesized using a procedure similar to that used to prepare intermediate I-1.

[0278]

[0279] Synthesis of tert-butyl 3-((5-cyanopyrazin-2-yl)oxy)azacyclobutane-1-carboxylate (intermediate I-30): Step 1

[0280] Preparation of tert-butyl 3-((5-cyanopyrazin-2-yl)oxy)azacyclobutane-1-carboxylate:

[0281] At 0 °C, NaH (31 mg, 1.3 mmol; 60% determination) was added to a stirred solution of tert-butyl 3-hydroxyazyrazine-1-carboxylate (150 mg, 0.86 mmol) in DMF (5 mL) and stirred for 10 min. Subsequently, 5-chloropyrazine-2-carboxynitrile (140 mg, 1.3 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (50% ethyl acetate-hexane) to give tert-butyl 3-((5-cyanopyrazine-2-yl)oxy)azyrazine-1-carboxylate (120 mg, 50% yield) as a pale yellow liquid.

[0282] 1H NMR (400 MHz, DMSO D6) δ 7.83 (1H, s), 7.54 (1H, s), 5.39-5.38 (m,1H), 4.30-4.26 (m, 2H), 3.91-3.89(m, 2H), 1.38 (s, 6H)

[0283] Step 2

[0284] Preparation of 5-(azacyclobutane-3-yloxy)pyrazine-2-carboxynitrile, TFA salt:

[0285] 500 mg (0.307 mmol, 1 equivalent) of tert-butyl 3-((5-cyanopyrazin-2-yl)oxy)azacyclobutane-1-carboxylate was added dropwise to a stirred solution in DCM (10 mL) and cooled to 0 °C. TFA (1.5 mL) was added dropwise. The reaction mixture was gradually heated to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give a pale yellow viscous liquid as a TFA salt of 5-(azacyclobutane-3-yloxy)pyrazin-2-carboxynitrile.

[0286] LCMS condition E: Rt = 0.2 min. m / z 177.01 [M+H] + .

[0287] Synthesis of 4-(azacyclobutane-3-ylmethyl)-1-cyclopropyl-1H-pyrazole, TFA salt (intermediate I-31): Step 1

[0288] Preparation of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)methylene)azacyclobutane-1-carboxylate:

[0289] To a stirred solution of 2,2,6,6-tetramethylpiperidine (247 mg, 1.75 mmol) in 10 mL of THF at -30 °C, n-BuLi (0.8 mL, 2.5 M hexane solution, 1.75 mmol) was added and stirred for 30 min. The reaction mixture was cooled to -78 °C, and bis[(pinacolyl)boronyl]methane (391 mg, 1.46 mmol) was added and stirred at the same temperature for 30 min. Subsequently, tert-butyl 3-oxazolidinyl-1-carboxylate (250 mg, 1.46 mmol) was added to the reaction mixture, and the mixture was heated to room temperature and stirred for 16 h. The reaction mixture was stopped with ice-cold ammonium chloride solution, extracted with ethyl acetate, and concentrated under reduced pressure. The crude substance was purified by column chromatography (35% ethyl acetate-hexane) to obtain liquid tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methylene)azacyclobutane-1-carboxylate (250 mg, 58% yield).

[0290] LCMS condition B: Rt = 3.87 min.m / z 296.3 [M+H]) + .

[0291] Step 2

[0292] Preparation of tert-butyl 3-((1-cyclopropyl-1H-pyrazole-4-yl)methylene)azacyclobutane-1-carboxylate:

[0293] Potassium carbonate (162 mg, 1.27 mmol) was added to a stirred solution of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methylene)azacyclobutane-1-carboxylate (173 mg, 0.588 mmol) and 4-bromo-1-cyclopropyl-1H-pyrazole (110 mg, 0.588 mmol) in dioxane (6 mL) and water (2 mL), and the mixture was degassed with argon. PdCl₂ (dppf) (43 mg, 0.059 mmol) was added under an inert atmosphere. The resulting mixture was heated at 90 °C for 2 h. The reaction mixture was diluted with ethyl acetate, filtered through a short diatomaceous earth mat, and washed with ethyl acetate. The combined organic fraction was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography (silica gel; 35% ethyl acetate-hexane) to obtain liquid tert-butyl 3-(1-cyclopropyl-1H-pyrazol-4-yl)methylene)azacyclobutane-1-carboxylate (70 mg, 43% yield).

[0294] LCMS condition A: Rt = 1.87 min. m / z 276.3 [M+H] +

[0295] Step 3

[0296] Preparation of tert-butyl 3-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)azacyclobutane-1-carboxylate

[0297] Under a nitrogen atmosphere, Pd / C (20 mg, 10% / charcoal) was added to a stirred solution of 70 mg (1-cyclopropyl-1H-pyrazole-4-yl)methylene)azacyclobutane-1-carboxylic acid tert-butyl ester in ethanol (5.0 mL). The reaction mixture was stirred at room temperature under hydrogen balloon pressure for 4 h. The reaction mixture was filtered through a diatomaceous earth mattress, washed with ethyl acetate, and concentrated under reduced pressure to give 60 mg (85% yield) of 3-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester in liquid form.

[0298] LCMS condition B: Rt = 3.21 min. m / z 278.3 [M+H] +

[0299] Step 4

[0300] Preparation of 4-(azacyclobutane-3-ylmethyl)-1-cyclopropyl-1H-pyrazole, TFA salt:

[0301] 400 mg (1.54 mmol) of tert-butyl 3-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)azacyclobutane-1-carboxylate was added to a stirred solution in DCM (10 mL) and cooled to 0 °C. TFA (1.5 mL) was added dropwise and stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and washed with diethyl ether to give a pale yellow viscous liquid as a TFA salt of 4-(azacyclobutane-3-ylmethyl)-1-cyclopropyl-1H-pyrazol.

[0302] LCMS conditions: B; Rt = 1.27 min. m / z 178.1 [M+H] +

[0303] Synthesis of N-(azacyclobutane-3-yl)-1-cyclopropyl-N-methyl-1H-pyrazole-4-amine (intermediate I-32): Step 1

[0304] Preparation of 1-cyclopropyl-4-nitro-1H-pyrazole:

[0305] Under an oxygen atmosphere, cyclopropylboronic acid (7.59 g, 88 mmol), 2,2-bipyridine (7.59 g, 48.63 mmol), and sodium carbonate (13.37 g, 137 mmol) were added to a stirred solution of 4-nitro-1H-pyrazole (5 g, 44.20 mmol) in dichloroethane (200 mL). Finally, copper acetate (8.86 g, 48.63 mmol) was added to the reaction mixture. The resulting mixture was heated to 65 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth mattress, washed with methanol, and concentrated under reduced pressure. The crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by combi-flash chromatography (silica gel; 10% ethyl acetate-hexane) to give 1-cyclopropyl-4-nitro-1H-pyrazole (3 g, 44% yield) as a colorless liquid.

[0306] LCMS conditions: A; Rt = 1.68 min. m / z 153.1 [M+H] +

[0307] Step 2

[0308] Preparation of 1-cyclopropyl-1H-pyrazole-4-amine:

[0309] Under a nitrogen atmosphere, Pd / C (1.6 g, 10% / charcoal) was added to a stirred solution of 1-cyclopropyl-4-nitro-1H-pyrazole (5 g, 18.7 mmol) in an EtOAc-ethanol mixture (50.0 mL; 1:1). Finally, the reaction mixture was pressurized with hydrogen under vacuum. The resulting reaction mixture was stirred at room temperature for 2 h. The reactants were filtered through a diatomaceous earth mattress, washed with ethyl acetate, and concentrated under reduced pressure to give 1-cyclopropyl-1H-pyrazole-4-amine (2.4 g, 70% yield) as a liquid.

[0310] 1H NMR (400 MHz, DMSO D6) δ 7.00 (s, 1H), 6.86 (s, 1H), 3.86 (brs,2H), 3.51-3.45 (m, 1H), 0.91-0.78 (m, 4H).

[0311] Step 3

[0312] Preparation of tert-butyl 3-((1-cyclopropyl-1H-pyrazole-4-yl)amino)azacyclobutane-1-carboxylate:

[0313] Sodium cyanoborohydride (240 mg, 3.82 mmol) was added to a stirred solution of 1-cyclopropyl-1H-pyrazole-4-amine (94 mg, 0.764 mmol), tert-butyl 3-oxozycyclobutane-1-carboxylate (392 mg, 2.29 mmol), and acetic acid (0.2 mL) in methanol (4 mL). The resulting mixture was heated at 50 °C for 2 h. After the reaction was complete, the reaction was stopped with water, extracted with DCM, and concentrated. The crude product was purified by column chromatography (silica gel; 10% ethyl acetate-hexane) to give tert-butyl 3-((1-cyclopropyl-1H-pyrazole-4-yl)amino)azacyclobutane-1-carboxylate (40 mg, 19% yield) as a yellow gel.

[0314] LCMS conditions: A; Rt = 1.81 min. m / z 279.3 [M+H] +

[0315] Step 4

[0316] Preparation of tert-butyl 3-((1-cyclopropyl-1H-pyrazole-4-yl)(methyl)amino)azacyclobutane-1-carboxylate:

[0317] Sodium cyanoborohydride (733 mg, 11.67 mmol) was added fractionally to a stirred solution of 3-((1-cyclopropyl-1H-pyrazole-4-yl)amino)azacyclobutane-1-carboxylate (650 mg, 2.335 mmol), HCHO (1.6 mL, 7.0 mmol), and acetic acid (1 mL) in methanol (20 mL). The resulting mixture was heated at 50 °C for 2 h. After the reaction was complete, the reaction was stopped with water, extracted with DCM, and concentrated. The crude product was purified by combi-flash chromatography (silica gel; 40% ethyl acetate-hexane) to give 3-((1-cyclopropyl-1H-pyrazole-4-yl)(methyl)amino)azacyclobutane-1-carboxylate (550 mg, 80.56% yield) as a yellow gel.

[0318] LCMS conditions: A; Rt = 1.75 min. m / z 293.3 [M+H] +

[0319] Preparation of N-(azacyclobutane-3-yl)-1-cyclopropyl-N-methyl-1H-pyrazole-4-amine, TFA salt:

[0320] 100 mg (0.342 mmol) of tert-butyl 3-((1-cyclopropyl-1H-pyrazol-4-yl)(methyl)amino)azacyclobutane-1-carboxylate was added to a stirred solution in 10 mL of DCM and cooled to 0 °C. TFA (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the crude product was washed with diethyl ether to give N-(azacyclobutane-3-yl)-1-cyclopropyl-N-methyl-1H-pyrazol-4-amine (80 mg, 76% yield) in the form of a TFA salt.

[0321] LCMS conditions: B; Rt = 1.06 min. m / z 193.3 [M+H] +

[0322] Synthesis of 4-(azacyclobutane-3-ylmethyl)-2-methylpyridine, TFA salt (intermediate I-33): Step 1

[0323] Preparation of tert-butyl 3-[(2-methylpyridin-4-yl)methylene]azacyclobutane-1-carboxylate:

[0324] 3-Methyleneazetane-1-carboxylate tert-butyl ester (1.5 g, 8.824 mmol) and triethylamine (0.686 mL, 8.824 mmol) were added to a stirred solution of 4-bromo-2-methylpyridine (500 mg, 2.941 mmol) in acetonitrile (4 mL) under a nitrogen atmosphere, followed by degassing under a nitrogen atmosphere. Pd(t-Bu3P)2 (75 mg, 0.147 mmol) was added under a nitrogen atmosphere. The resulting mixture was heated at 80 °C for 4 h. The reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was evaporated under reduced pressure. The crude product was purified by combi-flash chromatography (silica gel; 50% ethyl acetate-hexane) to give 3-[(2-methylpyridin-4-yl)methylene]azetane-1-carboxylate tert-butyl ester (140 mg, 18.28% yield) as a viscous liquid.

[0325] LCMS conditions: B; Rt = 1.66 min. m / z 261.2 [M+H] + .

[0326] Step 2

[0327] Preparation of tert-butyl 3-[(2-methylpyridin-4-yl)methyl]azacyclobutane-1-carboxylate:

[0328] Under a nitrogen atmosphere, Pd / C (50 mg, 10% / charcoal) was added to a stirred solution of 3-[(2-methylpyridin-4-yl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester (140 mg, 0.461 mmol) in EtOAc (10 mL). Finally, the reaction mixture was pressurized with hydrogen under vacuum. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through a diatomaceous earth mattress, washed with ethyl acetate, and concentrated under reduced pressure to give 3-[(2-methylpyridin-4-yl)methyl]azacyclobutane-1-carboxylic acid tert-butyl ester (100 mg, 82% yield) as a liquid.

[0329] LCMS condition A: Rt = 2.88 min. m / z 263.2 [M+H] + .

[0330] Step 3

[0331] Preparation of 4-(azacyclobutane-3-ylmethyl)-2-methylpyridine:

[0332] 3-[(2-methylpyridin-4-yl)methyl]azacyclobutane-1-carboxylic acid tert-butyl ester (100 mg, 0.57 mmol) was added to a stirred solution in DCM (10 mL) and cooled to 0 °C. TFA (1 mL) was added dropwise and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was washed with diethyl ether to give 4-(azacyclobutane-3-ylmethyl)-2-methylpyridine (55 mg, 89% yield) as a viscous liquid in the form of the TFA salt.

[0333] LCMS condition B: Rt = 1.80 min. m / z 163.2 [M+H] +.

[0334] Synthesis of 4-(2-chloro-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile (intermediate I-34): Step 1

[0335] Preparation of 2-(trifluoromethyl)-4H-pyrimidino[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione:

[0336] Trifluoroacetic anhydride (490 mL, 3.5 mol) was added dropwise to a stirred solution of 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (50 g, 292.21 mmol) at 0 °C. The resulting mixture was heated at 120 °C for 16 h in an autoclave. It was then cooled to ambient temperature and concentrated under reduced pressure. The crude product was milled with DCM and dried to give 2-(trifluoromethyl)-4H-pyrimidino[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione (50 g, 68.63% yield) as a brown solid.

[0337] 1H NMR (400 MHz, DMSO-D6) δ 9.96-9.88 (s, 1H), 8.82 (d, J=7.6 Hz, 1H), 8.82 (d, J=6.8 Hz, 1H).

[0338] Step 2

[0339] Preparation of 7-methyl-6-(trifluoromethyl)-1,7-dihydropyrimidino[5,4-d]pyrimidin-2,4,8(3H)-trione:

[0340] Sodium acetate (16 g, 202 mmol) was added to a stirred solution of 2-(trifluoromethyl)-4H-pyrimido[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione (50 g, 202 mmol) in acetic acid (1.1 L), followed by the addition of MeNH2·HCl [134 g, 2.02 mol]. The resulting mixture was heated at 120 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, and the resulting precipitate was collected and dried. It was then ground successively with diethyl ether and ethyl acetate and dried under high vacuum to give 7-methyl-6-(trifluoromethyl)-1,7-dihydropyrimido[5,4-d]pyrimido-2,4,8(3H)-trione (25 g, 48.0% yield) as a light brown solid.

[0341] LCMS condition A: Rt = 1.14 min. m / z 262.1 [M+H]+

[0342] Step 3

[0343] Preparation of 6,8-dichloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one:

[0344] DIPEA (26 mL, 152 mmol) was added dropwise to a stirred solution of 10 g (38 mmol) of 7-methyl-6-(trifluoromethyl)-1,7-dihydropyrimido[5,4-d]pyrimidin-2,4,8(3H)-trione in POCl3 (160 mL, 1.7 mol) at 0 °C. The resulting mixture was stirred at room temperature for 15 min and then heated to 100 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was cooled to 0 °C, stopped with a saturated aqueous solution of NaHCO3, and extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; 50% ethyl acetate-hexane) to give 7 g (61%) of 6,8-dichloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one as a yellow solid.

[0345] LCMS condition A: Rt = 3.26 min. m / z 299.0 [M+H]+

[0346] Step 4

[0347] Preparation of 4-(2-chloro-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile:

[0348] A stirred solution of 6,8-dichloro-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one (500 mg, 1.672 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzonitrile (620 mg, 2.5 mmol) in toluene (6 mL) and water (2 mL) was added, followed by degassing with argon. PdCl2 (dppf) (136 mg, 0.167 mmol) was added under an inert atmosphere. The resulting mixture was stirred for 3 h. The reaction mixture was diluted with ethyl acetate, filtered through a short diatomaceous earth pad, and washed with ethyl acetate. The combined organic fraction was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography (35% ethyl acetate-hexane) to give 4-(2-chloro-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile (250 mg, 39% yield) as a white solid.

[0349] Condition A: Rt = 3.21 min. m / z 384.13 [M+H] +

[0350] The following intermediates are synthesized using a procedure similar to that described for intermediate I-34 (step 4):

[0351] The table below describes the analytical data analysis and yield information for intermediates I-34 to I-40.

[0352]

[0353] Synthesis of the Implementation Examples

[0354] Examples 1-39

[0355] Example 1: 4-(2-(3-((1-cyclopropyl-1H-pyrazole-4-yl)oxy)azacyclobutane-1-yl)-7-methyl- 8-O-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile

[0356] At room temperature, 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazole (140 mg, 0.77 mmol) was added to a stirred solution of 4-(2-chloro-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile (200 mg, 0.52 mmol) in DMSO (4 mL), followed by the addition of DIPEA (0.37 mL, 0.2 mmol) and stirring for 1 h. The reaction mixture was directly provided for reversed-phase preparative HPLC (Prep-A) to give 4-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile (70 mg, 25% yield) as a yellow solid.

[0357] 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 (d, J=9.6 Hz, 1H), 7.90-7.88 (m, 1H), 7.84-7.81 (m, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 4.92-4.89 (m, 1H), 4.60 (brs,2H), 4.16-4.12 (m, 2H), 3.62- 3.58 (m, 1H), 3.55 (s, 3H), 1.0-0.96 (m, 2H), 0.92-0.88 (m, 2H).

[0358] Condition A: Rt = 2.84 min. m / z 527.45 [M+H] +

[0359] Examples 2-39 use a similar synthesis scheme as described for Example 1.

[0360]

[0361] The following table describes the analytical data analysis and yield information for Examples 2-39.

[0362]

[0363] Example 40

[0364] 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0365] Step 1

[0366] Preparation of 5-amino-2-chloro-N-methylisonicotinamide:

[0367] MeNH2·HCl (9.4 g, 139.5 mmol) was added to a stirred solution of 5-amino-2-chloroisonicotinic acid (20 g, 116.3 mmol) in DMF (250 mL) at 0 °C, followed by the addition of HATU (53 g, 139.5 mmol) and DIPEA (70.8 mL, 406.9 mmol). The resulting mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was stopped with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography (silica gel; 50-60% ethyl acetate-hexane) to give 5-amino-2-chloro-N-methylisonicotinamide (18.0 g, 83.72%) as a pale yellow solid.

[0368] 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.91 (s, 1H), 7.45 (s, 1H), 6.54 (br s, 2H), 2.72 (s, 3H).

[0369] LCMS condition A: Rt = 1.92 min. m / z 186.2 [M+H] + .

[0370] Step 2

[0371] Preparation of 3-amino-2-bromo-6-chloro-N-methylisonicotinamide:

[0372] NBS (16.3 g, 91.9 mmol) was added to a stirred solution of 5-amino-2-chloro-N-methylisonicotinamide (17 g, 91.8 mmol) in DMF (100.0 mL) at 0 °C. The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was stopped with crushed ice, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combi-flash chromatography (silica gel; 25-30% ethyl acetate-hexane) to give a pale yellow solid (11.0 g, 45.2% yield).

[0373] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.62 (s, 1H), 6.52 (s, 2H), 2.74 (s, 3H).

[0374] LCMS condition G: Rt = 2.78 min. m / z 266.2 [M+H] + .

[0375] Step 3

[0376] Preparation of 2-bromo-6-chloro-N-methyl-3-(2,2,2-trifluoroacetamido)isonicotinamide:

[0377] Pyridine (3.47 mL, 43.09 mmol) and DMAP (350 mg, 2.87 mmol) were added sequentially to a stirred solution of 3-amino-2-bromo-6-chloro-N-methylpyridine-4-carboxamide (3.8 g, 14.36 mmol) in THF (30.0 mL). The reaction mixture was then cooled to 0 °C and trifluoroacetic anhydride (6.03 mL, 43.09 mmol) was added dropwise. The mixture was then stirred at room temperature for 2 h. The reaction mixture was stopped with cold water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography (silica gel; 30-40% ethyl acetate-hexane) to give 2-bromo-6-chloro-N-methyl-3-(2,2,2-trifluoroacetamido)isonicotinamide (2.6 g, 50%) as a gray solid.

[0378] LCMS condition A: Rt = 2.21 min. m / z 362.1 [M+H] + .

[0379] Step 4

[0380] Preparation of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one:

[0381] Sodium acetate (750 mg, 9.15 mmol) was added to a stirred mixture of 2-bromo-6-chloro-N-methyl-3-(2,2,2-trifluoroacetamido)isonicotinamide (2.2 g, 6.10 mmol) in acetic acid (30.0 mL). The resulting mixture was heated at 120 °C for 16 h. The reaction mixture was evaporated to dryness and stopped with saturated sodium bicarbonate solution, and extracted with a 10% MeOH-DCM mixture. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash chromatography (30-40% ethyl acetate-hexane) to give 1.2 g (57% yield) of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one as a brown solid.

[0382] LCMS condition A: Rt = 1.89 min. m / z 342.27 [M+H] + .

[0383] Step 5

[0384] Preparation of 6-chloro-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one:

[0385] Sodium carbonate (3 mmol) was added to a stirred solution of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 1.46 mmol) and the corresponding 2,4-difluorophenylboronic acid (230 mg, 1.46 mmol) in dioxane (15 mL) and water (5 mL), and the mixture was degassed with argon. PdCl2(dppf)·DCM (120 mg, 0.14 mmol) was added under an inert atmosphere. The resulting mixture was heated at 90 °C for 3 h. The reaction mixture was diluted with ethyl acetate, filtered through a short diatomaceous earth mat, and washed with ethyl acetate. The combined organic fraction was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography (35% ethyl acetate-hexane) to give 6-chloro-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (250 mg, 45% yield) as a white solid.

[0386] LCMS condition A: Rt = 2.46 min. m / z 376.2 [M+H] + .

[0387] Step 6

[0388] Preparation of 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one:

[0389] Sodium tert-butoxide (51 mg, 0.53 mmol), RuPhos (6.21 mg, 0.01 mmol), and RuPhos-Pd-G3 (11 mg, 0.01 mmol) were added to a stirred solution of 6-chloro-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 0.26 mmol) and 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazole (71 mg, 0.40 mmol) in toluene (4 mL). The resulting mixture was heated at 100 °C for 12 h. The reaction mixture was diluted with DCM, filtered through a short diatomaceous earth pad, and washed with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC (Prep-A) to obtain 6-(3-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (25 mg; 18% yield) as a yellow solid.

[0390] 1 H NMR (400 MHz, DMSO- d 6) δ 7.65-7.59 (m, 1H), 7.57 (s, 1H), 7.40-7.35(m, 1H), 7.25-7.20 (m, 2H), 6.96 (s, 1H), 4.94-4.91 (m, 1H), 4.52-4.48 (m,2H), 4.08-4.04 (m, 2H), 3.62- 3.58 (m, 1H), 3.55 (s, 3H), 1.0-0.97 (m, 2H), 0.93-0.89 (m, 2H).

[0391] Condition A: Rt = 3.48 min. m / z 519.2 [M+H] +

[0392] Example 41

[0393] Synthesis of 4-(6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyridino[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile

[0394] Step 1

[0395] Preparation of 4-(6-chloro-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyridino[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile:

[0396] Following a similar scheme mentioned in 38 (step 5), 4-(6-chloro-3-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (white solid; 60% yield) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile was synthesized using 8-bromo-6-chloro-3-methyl-2-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile.

[0397] LCMS condition A: Rt = 3.38 min. m / z 383.08 [M+H] + .

[0398] Step 2

[0399] Preparation of 4-(6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile:

[0400] Cesium carbonate (186 mg, 0.57 mmol), Xanthphos (15 mg, 0.026 mmol), and Pd2(dba)3 (23 mg, 0.026 mmol) were added to a stirred solution of 4-(6-chloro-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyridino[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile (100 mg, 0.26 mmol) and 4-(azacyclobutane-3-yloxy)-1-cyclopropyl-1H-pyrazole (56 mg, 0.31 mmol) in toluene (5 mL). The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was diluted with DCM, filtered through a short diatomaceous earth pad, and washed with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC (Prep-A) to obtain 4-(6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyridino[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile (25 mg, 18% yield), which was a yellow solid.

[0401] 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (d, J=9.6 Hz, 1H), 7.82 (d, J=7.6 Hz,1H), 7.76 (t, J=7.2 Hz, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.01 (s, 1H), 4.92(brs, 1H), 4.50 (t, J=9.2 Hz, 2H), 4.08-4.05 (m, 2H), 3.62-3.57 (m, 1H), 3.55(s, 3H), 0.98-0.97 (m, 2H), 0.93-0.89 (m, 2H).

[0402] Condition A: Rt = 3.09 min. m / z 526.40 [M+H] +

[0403] Example 42 - Biological Evaluation

[0404] Human TREM2, using a cellular phosphorylation assay of spleen tyrosine kinase (“Syk”) to measure the activity of trigger receptor 2 expressed on myeloid cells in vitro.

[0405] cell lines : HEK-293 cells were co-transfected with plastids encoding TREM2 and DAP12, respectively, to generate stable cell lines. After antibiotic selection, functional clone pool analysis, and two consecutive limiting dilutions, the final clone “HEK293 / DAP12+TREM2” was subjected to qPCR analysis and pharmacological validation.

[0406] Determination method

[0407] The phosphorylation of Syk kinase was measured using the commercially available AlphaLISASureFire Ultra p-SYK (Tyr525 / 526) assay kit (PerkinElmer #ALSU-PSYK) based on Perkin Elmer AlphaScreen / AlphaLISA technology, and TREM2 signaling via DAP12 was monitored in HEK293 / DAP12+TREM2 stable cell lines.

[0408] Compounds were transferred to test plates for full dose-response testing at eight concentrations and four replicates. Serial dilutions of the compounds were performed in 100% DMSO on a Cybi-Felix instrument, and dose-response profiles were automatically constructed at 384 MPT on a Hamilton Starlet instrument. All stock solutions were prepared at 20 mM in 100% DMSO. For compound testing, the starting concentration was 100 µM with a dilution step of 1:6. Based on preliminary results, the concentration ranges were adjusted to target the compound's activity. Finally, all compounds were rearranged at eight concentrations and four replicates using a CyBi®-Well dispenser at 384 MPT as a "mother to child" process, where 1 µL of each compound was transferred to a target plate pre-filled with 65.6 µL of EMEM cell culture medium (BIOWHITTAKER_cat.BE12-125F), thus obtaining 3× concentrated working solutions of the compounds. Control wells are added in columns 1-2 and 23-24. Specifically, dose-response profiles for reference control agonists are included in columns 1 and 24 as reference control agonists (the reference control agonists used include human TREM2 polyclonal antibody AF1828: R&D Systems; human TREM2 monoclonal antibody MAB1828: R&D Systems). Dose-response profiles are tested starting at 30 µM with a dilution step of 1:6. Both the "source" and "target" compound plates are barcoded, thus establishing a relationship between the two plates.

[0409] HEK293 / DAP12+TREM2 cells were cultured in EMEM medium (referred to as "HEK293 medium") supplemented with IX penicillin / streptomycin (BIOWHITTAKER_cat.DE17-602E), ULTRAGLUTAMINE I 200mM, 10% fetal bovine serum, and antibiotics. The day before the experiment, cells were gently washed with DPBS to remove them, followed by incubation at 37°C with trypsin solution for 5 min. Cells were then diluted in antibiotic-free HEK293 medium, counted, and seeded at a density of 10,000 cells / well at 25 μL / well in 384-well poly-D-lysine-coated microplates with black / clear bottoms (GREINER 781946) using a MATRIX WellMate dispenser. The plates were placed in a humidified cell culture incubator at 37°C and 5% CO2 until the day of the experiment. 20 to 24 hours after inoculation, using a CyBi®-Well instrument, the maturation medium was removed and replaced with 10 μL / well of EMEM cell culture medium supplemented with 0.1% Pluronic F-68 nonionic surfactant (Thermofisher, 24040032) (referred to as "assay buffer"). Next, using a CyBi®-Well instrument, 5 µL / well of assay buffer (final DMSO concentration 0.5%) containing 3× concentrated test compound or reference control agonist was added to the cells. The cell culture plates were incubated for 30 min in a humidified cell culture incubator at 37°C and 5% CO2, followed by manual removal of the medium. Using a CyBi®-Well instrument, 20 µL / well of lysis buffer was dispensed and the plates were incubated for 10 min at room temperature on a plate shaker (350 rpm). Then, 10 µL / well of the lysate was transferred to an α-plate. Dispense 5 µL / well of IX immunoassay buffer containing AlphaLISA receptor beads using a CyBi®-Well instrument (Perkin Elmer AL000F). Then, seal the plate with heat-sealed foil, agitate for 2 minutes (350 rpm), and incubate at room temperature for 1 hour. After incubation with the AlphaLISA receptor beads, dispense 5 µL / well of IX immunoassay buffer containing AlphaLISA donor beads using a CyBi®-Well instrument. Seal the plate with heat-sealed foil, agitate for 2 minutes (350 rpm), and incubate at room temperature for 1 hour. At the end of the incubation, obtain the AlphaLISA signal from the donor and receptor beads using a Pherastar FSX instrument (a high-throughput multimode microplate reader calibrated for this plate type, equipped with an AlphaLISA mirror and filter set), in 384-well mode, with an excitation wavelength of 680–615 nm. The total integration time was 0.60 seconds, the second excitation time was 0.30 seconds, and the gain was 3600.

[0410] Data analysis was performed using Genedata Screener® software, and compound activities were reported as % of effect relative to normalized standards. AlphaScreen signals were compared to a neutral control (assessment buffer with 0.5% DMSO final concentration) and a stimulator control (reference control agonist at 0.5% DMSO final concentration in assay buffer). 100 Normalization is performed to obtain the activity [%] of each well. Normalization places the compound activity values ​​within an equivalent scale and makes them comparable across plates or different compound batches. Therefore, the compound activity values ​​are scaled (based on the two references) to a common range (two-point normalization). The software uses the following equation 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 the aperture; <cr>The median of the signal value of the center reference hole of the plate (the median of the neutral control); <sr>CR is the median signal value of the scaling reference well of the plate (the median of the stimulant control); CR is the required median normalized value (0) for the center reference, and SR is the required median normalized value (100) for the scaling reference.

[0411] The final equation for calculating activity % can be simplified as follows: Activity % = 100 (x - <neutral control>) / (<stimulant control> - <neutral control>) Full activation corresponds to an activity percentage of 100%.

[0412] Based on normalized values ​​and the application of a "smart fit" strategy, dose-response curves for each test compound were fitted in the Analyzer module of Screener software. This strategy allows for automatic selection between "Constant Fit" and "Hill Fit" models to calculate which best matches the experimental data. When no change in activity was detected between measured concentrations, constant fit was applied, and the corresponding compound was further classified as "inactive." When a significant change in activity with compound concentration was observed, Hill fit was applied. In the case of Hill fit, the concentration at which the activity reached 50% of its maximum level, i.e., AC, was determined using the Hill equation. 50 .

[0413] Y = S0 + ((S inf -S0) / (1 + (10 LogAC50 / 10 X ) n ))

[0414] Where X is the Log10 of the compound concentration.

[0415] The equation has four parameters: ● Zero activity (S0) - Tests the activity level of a compound at zero concentration; ● Unlimited activity (S) inf - Test the activity level of the compound at an infinite concentration; ● AC 50 - The concentration at which its activity reaches 50% of its maximum level. This term corresponds to EC in this assay. 50 ; ● Hill coefficient (n) - AC 50 A measure of downslope.

[0416] The potency of the tested compounds was measured using EC. 50 EC 50 This corresponds to the concentration of the test compound that can activate the phosphorylated Syk AlphaScreen signal to 50% of the maximum reaction.

[0417] EC values ​​of the exemplary compounds measured in this assay 50 The values ​​are listed in the table below:

[0418] Where "A" represents EC 50 Value < 10 nM, "B" indicates EC 50 Values ​​between 10 nM and 100 nM, where "C" indicates EC. 50 Values ​​between 100 and 1000 nM, "D" indicates EC 50 Values ​​higher than 1000 nM. Regarding E... max Values, relative to the maximum response of the reference agonist (8‐(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-[1,3]diazido[5,4-d]pyrimidin-4-one), where "+" indicates < 75%, "++" indicates 75-110%, and "+++" indicates >110% maximum response.

[0419] References

[0420] Colonna, M. et al. (2016) Nat Rev Neurosci 17, 201–207

[0421] Deczkowska, A. et al. (2020) Perspective, 181, 6, 1207-1217

[0422] Hammond, TR (2019) Immunity, 50, 4 5955-974

[0423] Suárez-Calvet, M. et al. (2016) EMBO Mol Med, 8, 466-476

[0424] Yamazaki, K. et al (2015) Clinical psychopharmacology and neuroscience: the official scientific journal of the Korean College ofNeuropsychopharmacology, 13(3), 324–326

[0425] Paloneva BM, J. et al. (2001) Neurology, 56 (11) 1552-1558;

[0426] Ulrich JD et al. (2017) Neuron., 19;94(2):237-248)

[0427] Atagi, Y. et al. (2015) J Biol Chem., 290(43), 26043-50

[0428] Kleinberger, G. et al. (2014) Sci Transl Med., 2, 6 (243):243< / sr> < / cr>

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Formula (I) in: X 1 It is N or C(H); X 2 For O, CH2 or N(R) 4 ); R 4 For H or C 1-3 alkyl; R 1 C 1-3 alkyl; R 2 Selected from: pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and 1,3,4-thiadiazolyl, each optionally substituent R by 1 to 3 independently selected substituents. 5 replace; R 5 Selected independently from: C 1-3 Alkyl group, optionally C 3-5 Cycloalkyl and / or 1 to 3 F-substituted; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; C 3-5 cycloalkyl; CN; and halogen; and R 3 Selected from: , , , , , and .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 It is C(H).

4. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X 2 It is O.

5. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X 2 It is CH2.

6. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X 2 For N(R) 4 ), and R 4 For H or C 1-3 alkyl.

7. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

8. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-3 alkyl.

9. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 4 It is CH3.

10. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X 2 It is N(H).

11. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X 2 It is N(CH3).

12. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 1 It is CH3.

13. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted pyrazol group.

14. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted pyridinyl group.

15. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted pyrazinyl group.

16. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted pyridazinyl group.

17. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted pyrimidinyl group.

18. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional substituents R selected independently 5 Substituted 1,3,4-thiadiazole group.

19. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 C 1-3 alkyl.

20. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH3.

21. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH2CH3.

22. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH2CH2CH3.

23. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH2(CH3)2.

24. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 C replaced by 1 to 3 Fs 1-3 alkyl.

25. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 CH3 is represented by 1 to 3 F atoms.

26. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CF3.

27. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CHF2.

28. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 CH2CH3 is formed by replacing 1 to 3 F atoms.

29. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH2CF3.

30. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH2CHF2.

31. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 C 1-3 Alkyl group.

32. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is -OCH3.

33. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 C replaced by 1 to 3 Fs 1-3 Alkyl group.

34. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is -OCH3.

35. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is -OCHF2.

36. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 For being C 3-5 Cycloalkyl-substituted C 1-3 alkyl.

37. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CH2-cyclopropyl.

38. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 C 3-5 Cycloalkyl.

39. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is cyclopropyl.

40. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is cyclobutyl.

41. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is cyclopentyl.

42. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 For CN.

43. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is a halogen.

44. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 It is Cl.

45. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 Having formula (II): Equation (II) in R 6 Selected from: H; C 1-3 Alkyl group, optionally C 3-5 Cycloalkyl and / or 1 to 3 F-substituted; C 1-3 Alkyl group, optionally substituted with 1 to 3 F groups; and C 3-5 cycloalkyl; R 7 For H, C 1-3 Alkyl or halogen; and R 8 For H, C 1-3 Alkyl or halogen.

46. ​​A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 For H.

47. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 C 1-3 alkyl.

48. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is CH3.

49. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is -(CH2)2CH3.

50. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C(H)(CH3)2.

51. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 C replaced by 1 to 3 Fs 1-3 alkyl.

52. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 CH3 is represented by 1 to 3 F atoms.

53. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is CHF2.

54. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 CH2CH3 is formed by replacing 1 to 3 F atoms.

55. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is CH2CF3.

56. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is CH2CHF2.

57. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 For being C 3-5 Cycloalkyl-substituted C 1-3 alkyl.

58. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is -CH2-cyclopropyl.

59. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 C 3-5 Cycloalkyl.

60. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is cyclopropyl.

61. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is cyclobutyl.

62. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 It is cyclopentyl.

63. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 7 For H.

64. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 7 C 1-3 alkyl.

65. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 7 It is CH3.

66. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 8 For H.

67. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 8 C 1-3 alkyl.

68. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 8 It is CH3.

69. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 8 It is a halogen.

70. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 8 It is Cl.

71. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

72. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

73. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

74. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

75. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

76. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

77. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

78. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

79. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

80. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

81. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

82. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

83. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

84. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

85. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 Having Equation (III): Equation (III) Where R 9 For H or C 1-3 alkyl.

86. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

87. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

88. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

89. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 Having formula (IV): Formula (IV) Where R 10 Selected from: H; C, optionally replaced by 1 to 3 Fs. 1-3 Alkyl; C substituted with 1 to 3 F atoms 1-3 Alkoxy; CN; and C 3-5 Cycloalkyl.

90. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 For CN.

91. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 C 1-3 alkyl.

92. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is CH3.

93. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 C replaced by 1 to 3 Fs 1-3 alkyl.

94. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is CF3.

95. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is CHF2.

96. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 C 1-3 Alkyl group.

97. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is -OCH3.

98. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 C replaced by 1 to 3 Fs 1-3 Alkyl group.

99. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is -OCHF2.

100. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 C 3-5 Cycloalkyl.

101. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 10 It is cyclopropyl.

102. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

103. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

104. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

105. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

106. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

107. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

108. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

109. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 The pyrazinyl group is optionally substituted with CN.

110. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional use by C 1-3 Alkyl-substituted pyrazine group.

111. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 The pyrazinyl group is optionally substituted with CH3.

112. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

113. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

114. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

115. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 The pyridazinyl group is optionally substituted with a halogen.

116. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 It is a pyridazinyl group that is optionally substituted with Cl.

117. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

118. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 For optional use by C 1-3 Alkyl-substituted pyrimidinyl group.

119. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 The pyrimidine group is optionally substituted with CH3.

120. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

121. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

122. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 2 for .

123. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

124. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

125. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

126. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

127. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

128. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

129. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 3 for .

130. The compound of any of the preceding claims, wherein X 1 For N and R 3 for .

131. The compound of any of the preceding claims, wherein X 1 For N and R 1 It is CH3.

132. The compound of any of the preceding claims, wherein X 1 For N, R 1 It is CH3, and R 3 for .

133. The compound of any of the preceding claims, wherein X 1 For N and X 2 It is O.

134. The compound of any of the preceding claims, wherein X 2 For O and R 2 For optional substituents R selected independently 5 Substituted pyrazol group.

135. The compound of any of the preceding claims, wherein X 1 Let N, X 2 For O and R 2 For optional substituents R selected independently 5 Substituted pyrazol group.

136. The compound of any of the preceding claims, wherein X 1 For N and R 1 It is CH3.

137. The compound of any of the preceding claims, wherein X 1 For N, R 1 It is CH3, and R 3 for .

138. The compound of any of the preceding claims, wherein X 1 For N, R 1 CH3, R 3 for X 2 It is O, and R 2 For optional substituents R selected independently 5 Substituted pyrazol group.

139. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(7-methyl-2-(3-(((5-methyl-1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 4-(2-(3-((5-ethyl-1,3,4-thiadiazol-2-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(7-methyl-8-oxo-2-(3-(pyrazin-2-yloxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 3-Fluoro-4-(7-methyl-2-(3-(((6-methylpyrazin-2-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 5-((1-(4-(4-cyano-2-fluorophenyl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)azacyclobutane-3-yl)oxy)pyrazine-2-carboxylonitrile; 4-(2-(3-((1,5-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1,3-dimethyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(2-(3-((1-isopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 3-Fluoro-4-(7-methyl-8-oxo-2-(3-((1-propyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 4-(2-(3-((5-chloro-1-methyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1-cyclobutyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((1-cyclopentyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(7-methyl-8-oxo-2-(3-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 4-((1-(4-(4-cyano-2-fluorophenyl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-2-yl)azacyclobutane-3-yl)oxy)pyridine-2-carboxylonitrile; 3-Fluoro-4-(2-(3-(((2-methoxypyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 4-(2-(3-((2-cyclopropylpyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((2-(difluoromethyl)pyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 4-(2-(3-((2-(difluoromethoxy)pyridin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(7-methyl-8-oxo-6-(trifluoromethyl)-2-(3-((2-(trifluoromethyl)pyridin-4-yl)oxy)azacyclobutane-1-yl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 4-(2-(3-((6-chloropyridazin-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)-3-fluorobenzonitrile; 3-Fluoro-4-(7-methyl-8-oxo-2-(3-(pyrimidin-5-yloxy)azacyclobutane-1-yl)-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 3-Fluoro-4-(7-methyl-2-(3-(((2-methylpyrimidin-5-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 3-Fluoro-4-(7-methyl-2-(3-((4-methylpyrimidin-5-yl)oxy)azacyclobutane-1-yl)-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 8-(2,4-difluorophenyl)-3-methyl-6-(3-((2-methylpyridin-4-yl)oxy)azacyclobutane-1-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)(methyl)amino)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 8-(2,4-difluorophenyl)-3-methyl-6-(3-((2-methylpyridin-4-yl)methyl)azacyclobutane-1-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 4-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)benzonitrile; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2-fluoro-4-methoxyphenyl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 5-(2-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-7-methyl-8-oxo-6-(trifluoromethyl)-7,8-dihydropyrimidino[5,4-d]pyrimidin-4-yl)pyridine-2-carboxylonitrile; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4(3H)-one; 6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one; and 4-(6-(3-((1-cyclopropyl-1H-pyrazol-4-yl)oxy)azacyclobutane-1-yl)-3-methyl-4-oxo-2-(trifluoromethyl)-3,4-dihydropyridino[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile.

140. A compound of any 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.

141. A compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein the compound enhances or activates TREM2 signaling via DAP12; and / or wherein the compound induces phosphorylation of a kinase interacting with the TREM2 / DAP12 signaling complex, such kinase as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; and / or wherein the compound enhances the degree of phosphorylation of TREM2-induced Syk kinase.

142. A compound of any of the preceding claims 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 CXCL10, CCL2, CST7 and TMEM119.

143. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

144. The compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 143, used as a medicament.

145. A compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 143, for the treatment of conditions associated with loss of TREM2 function, such as conditions associated with TREM2 mutations.

146. The compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 143, for the treatment of neurodegenerative diseases.

147. The compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 143, for the treatment of neurodegenerative diseases selected from: tau proteinopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, demyelinating diseases of the CNS, demyelinating diseases of the PNS, leukoencephalopathy, leukodystrophy, infectious spongiform encephalopathy (TSE), and lysosomal storage disease (LSD).

148. The compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 143, for the treatment of neurodegenerative diseases selected from: Alzheimer's disease, frontotemporal degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tuss disease, prions, stroke, and traumatic brain injury (TBI).

149. A compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 143, for the treatment of a disease selected from: arthritis, rheumatoid arthritis, Pye's disease, osteoporosis, osteopenia, osteosclerosis, skeletal dysplasia, osteomalacia, autism spectrum disorder, autism and Asperger's syndrome, traumatic brain injury (TBI), spinal cord injury, muscular dystrophy, myotonic dystrophy, inclusion body myositis, systemic lupus erythematosus (SLE), RA, gout, intestinal condition, inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, amyloidosis.

150. The compound used in any one of claims 144 to 149, wherein the compound is administered at an amount of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day.

151. The compound used in any one of claims 144 to 149, wherein the compound is administered via enteral delivery, oral delivery, local delivery, non-enteric delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

152. A method for treating conditions associated with loss of TREM2 function, such as neurodegenerative diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 143.

153. The use of a compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 143 for the manufacture of a medicament for the treatment of conditions such as neurodegenerative diseases associated with loss of TREM2 function.

154. A method for enhancing or increasing TREM2 activity in a subject in need, such as a subject suffering from a neurodegenerative disease, comprising one or more of the following methods: i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases interacting with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; iii) enhancing the level of phosphorylation of TREM2-induced Syk kinases; iv) increasing the expression level of one or more TREM2-regulated genes, such as brain expression levels; and / or v) increasing the expression level of one or more TREM2-regulated genes selected from CXCL10, CCL2, CST7, and TMEM119, such as brain expression levels; said method comprising administering to the subject a compound of any one of claims 1 to 142 or a pharmaceutically acceptable salt thereof.

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