Agonists of trem2 activity

Abstract

The present disclosure relates to compounds of Formula I and their use as TREM2 agonists for the treatment and prevention of neurodegenerative disorders associated with loss of function of human TREM2. The disclosed TREM2 agonists can be used to treat Alzheimer’s disease and related neurological conditions. (I).

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 692,981, filed September 10, 2024, and U.S. Provisional Application No. 63 / 612,010, filed December 19, 2023, the entire contents of each of which are incorporated herein by reference. Technical Field

[0002] This disclosure provides certain compounds that are TREM2 agonists. These compounds can be used to treat and prevent neurodegenerative conditions associated with loss of TREM2 function in humans. The disclosed TREM2 agonists can be used to treat Alzheimer's disease and related neurological conditions. Background Technology

[0003] Alzheimer's disease (AD) is a neurodegenerative disease and the leading cause of dementia in the United States. More than 50 million people worldwide suffer from dementia, and the prevalence is projected to triple by 2050. AD is the only leading cause of morbidity and death in the United States without adequate preventative, slowing, or curative treatments (2017 Alzheimer's Association report). Current therapies for AD, such as acetylcholinesterase inhibitors (e.g., donepezil) and N-methyl-D-aspartate receptor antagonists (e.g., memantine), have shown limited and transient benefits to cognitive and behavioral parameters in AD patients, but do not slow or stop disease progression (Cummings (2004)). N Engl J Med , 351:56-67).

[0004] Trigger receptor-2 (TREM2), an immunoglobulin-like transmembrane receptor expressed on myeloid cells, has shown to play a crucial role in AD pathology. Heterozygous mutations in the TREM2 gene have been found to increase the risk of AD by up to 3 times (Guerreiro et al., (2013)). N Engl J Med , 368: 117-127; Jonsson et al., (2013) N Engl J Med (Rajagopalan et al., 368: 107-116), and increase the rate of brain volume shrinkage (Rajagopalan et al., (2013)). N Engl J Med (369: 1565-1567). Even individuals without AD carrying a heterozygous TREM2 mutation showed cognitive impairment compared to individuals with two normal TREM2 alleles. In the context of AD pathology, TREM2 expression influences amyloid pathology, regulates neurotrophic dystrophism, tau hyperphosphorylation and aggregation, and affects synaptic and neuronal loss (Jay et al., (2017)). Mol Neurodegener, 12(1):56). Furthermore, TREM2 has been shown to play a crucial role in limiting the development of tau pathology around plaques (Leyns et al., (2019)). Nat Neurosci Recent studies using mouse genetic models also strongly support the crucial role of TREM2 in AD, with TREM2 deficiency or defect being associated with increased pathological changes (Cheng-Hathaway et al., (2018)). Mol Neurodegener , 13(1):29; Wang et al., (2015) Cell, 160: 1061-1071; Wang et al., (2016) J Exp Med , 213:667-675; Yuan et al., (2016) Neuron, 90:724-739).

[0005] As its name suggests, TREM2 is primarily expressed in myeloid lineage cells, including microglia (Colonna & Wang (2016)). Nat Rev Neurosci Microglia are resident macrophages of the central nervous system (CNS) and are thought to play an important protective role in Alzheimer's disease when properly activated through their housekeeping functions, such as promoting the clearance of cellular debris through phagocytosis and the secretion of growth factors. In the CNS, TREM2 is specifically expressed on microglia. TREM2 expression has been shown to regulate microglia's chemotaxis and phagocytosis, and enhance their survival, proliferation, and differentiation. Furthermore, TREM2 is well known to be essential for maintaining the nutritional function of microglia in the aging brain, and studies have shown an overlap between the phenotype of aging microglia and the molecular imprinting of microglia found in animal models of AD, including the TREM2 pathway (Krasemann et al., (2017)). Immunity , 47(3):566-581).

[0006] Some reports suggest that TREM2 plays a crucial role in amyloid-based experimental AD models by acting as an overexpression of the protein within microglia entrained plaques, driving these innate immune cells to transform into a disease-associated microglia (DAM) state. This transformation is marked by microglia initiation, which can be demonstrated by a set of overexpressed genes and increased phagocytic capacity (George, Neural Regeneration Research , 18(12): 2680-81 (2023)).

[0007] These findings suggest that TREM2 activation can improve AD symptoms and enhance cognitive function by activating the innate immune system, thus TREM2 agonists could be used to treat Alzheimer's disease and other dementias and related neurodegenerative conditions. There is a need in the art for novel TREM2 agonists and methods for treating neurodegenerative conditions using such agonists. Summary of the Invention

[0008] This invention relates to certain carbonyl-substituted fused heteroaryl derivatives. Surprisingly and advantageously, these compounds have been shown to exhibit agonistic activity against the TREM2 receptor. The invention also relates to the use of these compounds in the treatment or prevention of neurodegenerative diseases in subjects with such need. The invention provides compounds adaptable to pharmaceutical compositions that can be administered to subjects suffering from neurodegenerative diseases.

[0009] The compounds disclosed herein contain a core having two fused nitrogen-containing aryl groups and exhibit excellent potency in activating TREM2 receptors (such as the human TREM2 receptor). In some embodiments, the compounds of the present invention exhibit excellent potency as TREM2 agonists, as demonstrated by the data reported herein. The compounds of the present invention can be used to treat or prevent neurodegenerative diseases (or one or more symptoms associated with such diseases) involving TREM2, including Alzheimer's disease and other indications, diseases, and conditions as described herein. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, and methods of using such compounds and compositions for the treatments described herein.

[0010] In some respects, this paper provides compounds having formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 It is C or N; X 2 It is C or N, and the condition is X. 1 and X 2 They are not both N; X 3 It is C or N; X 4 It is C or N; X 5 It is C or N; X 6 Selected from -CH2-, -N(CH3)- and -O-, and y is 0 or 1; R 1 It is -C 1-10 Alkyl group, -(CH2) z -OH or -(CH2)-N(CH3); R 2 It is -C 1-10 Alkyl or -OC 1-6 alkyl; Where R 1 and R 2 C 1-10 Alkyl and R 2 -OC 1-6 Alkyl groups are unsubstituted or independently converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; Alternatively, R 1 and R 2 Connected together to form C 3-7 Cycloalkyl or three- to seven-membered heterocyclic groups Wherein C 3-7 The cycloalkyl or three- to seven-membered heterocyclic group is unsubstituted or converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 They must be connected together to form C 3-7 Cycloalkyl or three- to seven-membered heterocyclic groups; A is selected from (i)C 3-7 cycloalkyl groups and (ii) heterocyclic groups consisting of the following: (1) Seven carbon atoms and one nitrogen atom, (2) Six carbon atoms and (i) one O atom, (ii) one N atom, or (iii) one O and one N atom. (3) Four carbon atoms and one nitrogen atom, or (4) ,in: Y 1 It is CH, CF, O, or N; Y 2 It is CH or N; Y 3 It is CH or N; R 5 Selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluorine and =O; Where R5 -C(=O)-C 3-8 The cycloalkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine atoms each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, and -SCH3; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 16a and R 16b It can be hydrogen, fluorine, or methyl independently; R 6 Selected from hydrogen, C 3-7 Cycloalkyl, heterocyclic and heteroaryl groups, Where R 6 C 3-7 The cycloalkyl moiety is either unsubstituted or substituted with a heteroaryl group or one or two fluorine atoms. Where R 6 The heterocyclic or heteroaryl group is unsubstituted or substituted by one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 3 Selected from: (a) (b) (c) (d) (e) , (f) (g) (h) (i) and (j) , R 7 and R 9 Independently selected from hydrogen, methyl, and halogen; R 8 R 10 and R 11 Independently selected from hydrogen, halogen, -C 1-4 Alkyl groups, -CF3, and -SCH3; X 7 It is C or N; R 12 and R 12’ Each is independently selected from hydrogen, -CF3, -OCF3, -(CH3)2, and fluorine; R 13 and R 13’ Each is independently selected from hydrogen and fluorine; R 4 R 14 and R 17 Each is independently selected from hydrogen and fluorine; Where X 4 When it is C, R 17 It is fluorine; and When X 5 When it is N, R 4 It is hydrogen.

[0011] All structural formulas, embodiments, and categories described herein include pharmaceutically acceptable salts of the compounds defined therein. References to compounds of formula (I) herein encompass compounds of each of formulas (II)-(VI) and all embodiments and categories thereof. Unless otherwise stated, compounds of the present invention are referred to as compounds of a particular formula or embodiment, such as formula (I), (II), (III), (IV), (V), or (VI), or embodiments thereof, or any other general structural formula or particular compound described or claimed herein, intended to include one or more particular compounds falling within the scope of that formula or embodiment, including their salts, particularly pharmaceutically acceptable salts, solvates (including hydrates) of such compounds, and their solvated salt forms, wherein such forms are possible.

[0012] The present invention also covers pharmaceutical compositions comprising an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Detailed Implementation

[0013] This disclosure relates to compounds of formula (I), including compounds of formulas (II)-(IX), which exhibit activity as TREM2 receptor agonists. Pharmaceutical formulations comprising any of these compounds and pharmaceutically acceptable carriers are also provided herein. Methods for treating and preventing neurodegenerative conditions are also provided herein, comprising administering any of these compounds to a subject. Methods for treating and preventing conditions associated with loss of TREM2 function in a subject are also provided herein.

[0014] The compounds disclosed herein In some embodiments of the compound of formula (I), R 3 Selected from the following: , , , , , , , , , , and .

[0015] In one embodiment, the compound of formula (I) has the formula (II). (II) in: X 1 It is C or N; X 2 It is C or N, where X 1 When it is N, X 2 It is C, and the condition is X. 1 and X 2 They are not both N; Y 1 It is O or N; Y 2 It is CH or N; R 1 It is -C 1-4 alkyl; Where R 1 C 1-4 The alkyl moiety is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; R 2 It is -C 1-4 Alkyl or -OC 1-4 alkyl; Where R 2 C 1-4 The alkyl moiety is unsubstituted or -OC 1-3Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; or R 1 and R 2 They are linked together to form three- to seven-membered cycloalkyl or heterocyclic groups; The three- to seven-membered cycloalkyl or heterocyclic group is optionally oxidized by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 They must be linked together to form three- to seven-membered cycloalkyl or heterocyclic groups; R 10 Selected from hydrogen, halogens, -C 1-3 Alkyl groups, -CF3, and -SCH3; R 7 R 8 R 9 R 10 and R 11 Independently selected from hydrogen, methyl, and halogen; R 5 Selected from hydrogen, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -C(=O)-heteroaryl and -C(=O)-C(CH3)2-heteroaryl; Where Y 1 When it is O, R 5 It does not exist; Where R 5 -C(=O)-C 3-8 The cycloalkyl group is unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or substituted with one or two fluorine groups of -C. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, -SCH3, and one or two fluorine molecules. Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -C(=O)-heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one or two substituents, which are independently selected from -C each time they appear. 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl groups, -CF3 groups, and fluorine; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; R 6 Selected from hydrogen and heteroaryl groups; Where R 6 The heteroaryl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from -C. 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl groups, -CF3 groups, and fluorine; and y is 0 or 1.

[0016] In some embodiments of the compounds of formula (I) or (II), X 1 It is C, X 2 It is N, and R 1 and R 2 Linked together to form a three- to seven-membered cycloalkyl or heterocyclic group, which is unsubstituted or bound by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution.

[0017] In other embodiments of the compounds of formula (I) or (II), X 1 It is N.

[0018] In some embodiments of the compounds of formula (I) or (II), R 1 and R 2 Each is a methyl group.

[0019] In other embodiments of the compounds of formula (I) or (II), R 1 and R 2 Together they form C 5-8 Cycloalkyl or heterocyclic groups containing one O atom.

[0020] In some embodiments of the compounds of formula (I) or (II), R 5 Selected from -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl and -C(=O)-C(CH3)2-heteroaryl; Where R 5The -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl (i.e., the heteroaryl moiety of such groups) consists of the following: (1) Four carbon atoms and one O atom, (2) Three carbon atoms and (i) N and O, (ii) N and S, or (iii) N and NH; (3) Two carbon atoms and three nitrogen atoms; (4) Seven carbon atoms and N and O; and Where R 5 The -C(=O)- heterocyclic group (i.e., the heterocyclic moiety of such groups) consists of the following: (1) Three, four, five, six or seven carbon atoms and one O atom, (2) Four carbon atoms and (i) two O atoms or (ii) N atoms and O atoms, or (3) Six carbon atoms, two O atoms, and one N atom.

[0021] In some embodiments of the compounds of formula (I) or (II), R 6 It is in position 1 by -C 1-10 Alkyl-substituted pyrazoles.

[0022] In a specific embodiment of the compound of formula (I) or (II), R 10 It is either fluorine or chlorine, R 9 It is fluorine, and R 7 It is hydrogen.

[0023] In other specific embodiments of the compounds of formula (I) or (II), R 10 It is chlorine, R 9 It is fluorine, and R 7 It is hydrogen.

[0024] In some embodiments, the compound of formula (I) has the characteristics of formula (IV). (IV) in: X 1 It is C or N; X 2 It is C or N, and the condition is X. 1 and X 2 They are not both N; R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring CZ yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated, and contains a heteroatom selected from N, O, and S; or (iii) A 9- or 10-membered bicyclic heterocyclic alkyl group, wherein the 9- or 10-membered bicyclic heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 With X 1 and X 2 Together they must form a ring C Z ; Y 2 It is C(H) or N; Y 4 It is CH2 or O; R 6 yes: (a) Ring C 6 Among them, ring C 6 yes: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) A 4- to 6-membered saturated monocyclic heterocyclic alkyl group containing a heteroatom selected from N, O and S; (iii) A 6- to 10-membered fused or bridged heterobicyclic system containing one or two heteroatoms independently selected from N, O, and S; wherein the 6- to 10-membered heterobicyclic system is: (a) Fully saturated, or (b) Contains one aromatic ring and one partially unsaturated ring; (iv) C 3-7 Saturated cycloalkyl; or (v) Phenyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or R 6ac R 6a Substituent substitution; Where R6ac It is -(CH2) v -C ac ; C ac yes (I)C 3-6 Monocyclic cycloalkyl; (II)C 7-12 Bicyclic cycloalkyl; (III) 3 to 6-membered monocyclic heterocyclic alkyl groups, wherein the 3 to 6-membered monocyclic heterocyclic alkyl groups are saturated and contain 1 to 2 heteroatoms independently selected from N, O and S; (IV) 6 to 10-membered bicyclic heterocyclic alkyl groups, wherein the 6 to 10-membered bicyclic heterocyclic alkyl groups are saturated or partially saturated and contain 1 to 2 heteroatoms independently selected from N, O and S; (V) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O and S; (VI) A 6- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, and S; or (VII) Phenyl or naphthyl; Where C ac It is unsubstituted or composed of one or two independent molecules selected from halogen, amino, oxo, C 1-12 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkylamino, C 1-3 Dialkylamino, C 1-3 Alkoxy and C 1-3 Alkoxy (C 1-3 Alkyl substituents; (b) C 1-6 alkyl; (c)C 1-6 fluoroalkyl; (d)C 1-6 Alkoxy; (e)C 1-3 Alkoxy (C 1-3 )alkyl; (f)C 1-3 Hydroxyalkyl; Each R A Independently, it is fluorine C 1-3 Alkyl or C 1-3 Alkoxy; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen, methyl, or trifluoromethyl; q is 1 or 2; r is 0, 1, or 2; s is 0 or 1; and v is 0, 1, or 2.

[0025] In some embodiments, the compound of formula (I) has the characteristics of formula (V). (V), in: R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring C Z yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; or (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two other factors. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; Y 2 It is C(H) or N; R 6 yes (a) Ring C 6 , that is: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) 4 to 6-membered saturated heterocyclic alkyl groups containing a heteroatom selected from N, O and S; (iii) A 6- to 10-membered fused or bridged heterobicyclic system containing one or two heteroatoms independently selected from N, O, and S; wherein the 6- to 10-membered heterobicyclic system is: (a) Fully saturated, or (b) Contains one aromatic ring and one partially unsaturated ring; or (iv) C 3-6 cycloalkyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkoxy or R 6ac R 6aSubstituent substitution; Where R 6ac It is -(CH2) v -C ac ; C ac yes (I)C 3-6 Monocyclic cycloalkyl; (II) A 3- to 6-membered monocyclic heterocyclic alkyl group, wherein the 3- to 6-membered monocyclic heterocyclic alkyl group is saturated and contains 1 to 2 heteroatoms independently selected from N, O and S; or (III) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O and S; Where C ac It is unsubstituted or has one or two groups selected from halogen, amino, cyano, oxo, C 1-12 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkylamino, C 1-3 Dialkylamino, C 1-3 Alkoxy, C 1-3 Alkoxy (C 1-3 Alkyl substituents, (b) C 1-6 alkyl; (c)C 1-3 Hydroxyalkyl; (d)C 1-3 Halogenated alkyl; or (e) Cyano group; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen; and R 16a and R 16b Independently, it consists of H, fluorine, and C. 1-3 Alkyl or C 1-3 fluoroalkyl; Alternatively, R 16a and R 16b Together with the carbon atom to which it is attached, they form C 3-6 cycloalkyl; and y is 0 or 1.

[0026] In some embodiments of the compound of formula (V), R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z .

[0027] In a specific embodiment of the compound of formula (V), part yes , , , or ;as well as Where p is 0, 1 or 2.

[0028] In some embodiments of the compound of formula (V), Y 2 It is N. In other embodiments, Y 2 It is C(H).

[0029] In some embodiments of the compound of formula (V), partial yes or .

[0030] In a specific embodiment of the compound of formula (V), R 6 It is an unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuranyl group.

[0031] In some embodiments of the compound of formula (V), part yes , or ; where t is 0, 1 or 2.

[0032] In other embodiments, the compound of formula (I) has the formula (VI). (VI) in: Y 2 It is C(H) or N; Y 4 It is C(H) or O; Each R Z Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; R 6 yes: (a) Ring C 6 Among them, ring C 6 yes: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) A 5- to 6-membered saturated heterocyclic alkyl group containing a heteroatom selected from N, O, and S; or (iii) C 3-7 cycloalkyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent elements selected from halogens, C 1-3 Alkyl, cyano, C1-3 Alkoxy or C 3-6 cycloalkyl R 6a Substituent substitution; or (b) C 1-6 alkyl; R A Is it fluorine or C? 1-3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen; and p is 0, 1, or 2; q is 1 or 2; r is 0, 1, or 2; and s is 0 or 1.

[0033] In some embodiments of the compound of formula (VI), part yes , , or .

[0034] In a specific embodiment of the above-described portion, R 6 It is an unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuranyl group.

[0035] In other embodiments of the compound of formula (VI), part yes , , , , , , , , , , or .

[0036] In a specific embodiment of the compound of formula (VI), part yes or .

[0037] In other embodiments, the compound of formula (I) has the formula (VII). (VII), in: Ring C z It is a cyclopentenyl, cyclohexenyl, dihydrofuran, or dihydropyran ring; Each RZ Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; Ring C 6 yes (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) Five- to six-membered saturated monocyclic or bicyclic heterocyclic alkyl groups containing one O heteroatom; or (iii) C 3-7 cycloalkyl; Each R 6a Independently selected from halogens, C 1-3 Alkyl, cyano, C 1-3 Alkoxy and C 3-6 cycloalkyl; or Each R A It is independently fluorine or C1-C3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is a halogen; methyl or trifluoromethyl; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0038] In some embodiments of the compound of formula (VII), part yes , , , and .

[0039] In some embodiments of the compound of formula (VII), part yes , , , , , , , or .

[0040] In a specific embodiment of the compound of formula (VII), part yes , , or .

[0041] In other embodiments, the compound of formula (I) has the formula (VIII). (VIII), in: Ring C z It is a cyclopentenyl, cyclohexenyl, dihydrofuran, or dihydropyran ring; Each R Z Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; Y 4 It is C(H2) or O; Ring C 6 yes (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) 5- to 6-membered saturated heterocyclic alkyl groups containing one O heteroatom; or (iii) C 3-7 cycloalkyl; Each R 6a Independently selected from halogens, C 1-3 Alkyl, cyano, C 1-3 Alkoxy and C 3-6 cycloalkyl; or Each R A It is independently fluorine or C1-C3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is a halogen; methyl or trifluoromethyl; p is 0, 1, or 2; q is 1 or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0042] In some embodiments of the compound of formula (VIII), part yes , , , , , , , or .

[0043] In other embodiments, the compound of formula (I) has the formula (IX). (IX), in: R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring C Z yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; or (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two other factors. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; R 5 Selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluorine and =O; Where R 5 -C(=O)-C 3-8 The cycloalkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine atoms each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, and -SCH3; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 16a and R 16b Independently, it consists of H, fluorine, and C. 1-3 Alkyl or C 1-3 fluoroalkyl; Alternatively, R 16a and R 16b Together with the carbon atom to which it is attached, they form C 3-6 cycloalkyl; R 7 R 8 and R 11 It is independently H or halogen; and R 10 It is a halogen; methyl or trifluoromethyl.

[0044] In some aspects, this application provides compounds having formula (I), wherein: X 1 It is C or N; X 2 It is C or N, and the condition is X. 1 and X 2 They are not both N; X 3 It is C or N; X 4 It is C or N; X 5 It is C or N; X 6 Selected from -CH2-, -N(CH3)- and -O-, and y is 0 or 1; R 1 It is -C 1-10 Alkyl group, -(CH2) z -OH or -(CH2)-N(CH3); R 2 It is -C 1-10 Alkyl or -OC 1-6 Alkyl; or R 1 and R 2 They are linked together to form three to seven-membered cycloalkyl or heterocyclic groups, which are unsubstituted or converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution.

[0045] The condition is when X 1 It is C and C2 When it is N, then R 1 and R 2 They must be connected together; A is selected from (i)C 3-7 Cycloalkyl and (ii) heterocyclic groups, which consist of the following: (1) Seven carbon atoms and one nitrogen atom, (2) Six carbon atoms and (i) one O atom, (ii) one N atom, or (iii) one O and one N atom. (3) Four carbon atoms and one nitrogen atom, or (4) ,in: Y 1 It is CH, CF, O, or N; Y 2 It is CH or N; Y 3 It is CH or N; R 5 Selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -C(R) 15 ) z -heteroaryl, fluorine and =O, Where R 15 Selected from hydrogen, (=O)- and (=O)-C(CH3)-, and z is 0 or 1, and Where R 5 Any cycloalkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine atoms each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, -SCH3, and fluorine; and R 16 It is hydrogen or methyl; R 6 Selected from hydrogen, C 4-7 Cycloalkyl, heterocyclic and heteroaryl, wherein R 6 Any cycloalkyl moiety is either unsubstituted or substituted with a heteroaryl group or one or two fluorine atoms. Where R 5 and R 6 Any heteroaryl or heterocyclic moiety is either unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from -C. 1-10Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 cycloalkyl, methylbenzyl, -CF3, fluorine and =O, and Where R 1 R 2 and R 5 Any -C 1-10 The alkyl moiety is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; R 3 Selected from the following: (a) (b) (c) (d) (e) (f) (g) (h) (i) and (j) , Where R 7 and R 9 Independently selected from hydrogen, methyl, and halogen, and R 8 R 10 and R 11 Independently selected from hydrogen, halogen, -C 1-4 Alkyl groups, -CF3 and -SCH3, and X 7 Is it C or N, and R 12 and R 12’ Each is independently selected from hydrogen, -CF3, -OCF3, -(CH3)2, and fluorine, and R 13 and R 13’ Each is independently selected from hydrogen and fluorine; and R 4 R 14 and R 17 Each is selected from hydrogen and fluorine, where X 4 When it is C, R 17 It is fluorine, and when X 5 When it is N, R 4 It is hydrogen.

[0046] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, wherein X 3 and X 4 It is N. In some embodiments of the compound of formula (I), wherein X 3 X 4 and X 1It is N. In some embodiments of the compound of formula (I), wherein X 3 X 4 and X 2 It is N.

[0047] In other respects, this application provides compounds having formula (II), wherein: X 1 It is C or N; X 2 It is C or N, where X 1 When it is N, X 2 It is C, and the condition is X. 1 and X 2 They are not both N; Y 1 It is O or N; Y 2 It is CH or N; R 1 It is -C 1-4 alkyl; R 2 It is -C 1-4 Alkyl or -OC 1-4 alkyl; or R 1 and R 2 Linked together to form a three- to seven-membered cycloalkyl or heterocyclic group, which is unsubstituted or bound by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 They must be connected together; R 10 Selected from hydrogen, halogens, -C 1-3 Alkyl groups, -CF3, and -SCH3; R 7 and R 9 Independently selected from hydrogen, methyl, and halogen; R 8 and R 11 Both are H; R 5 Selected from hydrogen, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -C(=O)-heteroaryl, and -C(=O)-C(CH3)-heteroaryl; and R 6 Selected from hydrogen and heteroaryl groups, Where R 5 and R 6 Any heteroaryl or heterocyclic moiety is either unsubstituted or substituted with one or two substituents, which are independently selected from -C each time they appear. 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -CF3 and fluorine, wherein R 5 Any cycloalkyl moiety is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or substituted with one or two fluorine groups of -C. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl group, -OCH3, -CH2CH2OCH3, -SCH3 and one or two fluorine groups, wherein R 1 R 2 and R 5 Any alkyl moiety is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; and y is 0 or 1.

[0048] In various embodiments, the compounds are compounds of formulas (I) and (II), where y is 0. In some embodiments, the compounds are compounds of formulas (I) and (II), where y is 1 and x. 6 It is -CH2-. In other embodiments, y is 1 and X. 6 It is -N(CH3)-.

[0049] In some embodiments, the compounds of formulas (I) and (II) are bicyclic. Sub-implementations of these embodiments are compounds of formulas (I) and (II), wherein R... 1 and / or R 2 It is C 1-4 Alkyl group. In some such sub-implementations, R 1 and / or R 2 It is a methyl group. In some such sub-implementations, R 1 and R 2 All are methyl groups. In this type of sub-implementation, the compounds are as exemplified below. , Or its pharmaceutically acceptable salt.

[0050] In some embodiments, the compounds of formulas (I) and (II) are tricyclic. Sub-implementations of these embodiments are compounds of formulas (I) and (II), wherein R... 1 and R 2 Together to form unsubstituted or C-shaped compounds substituted with one or two fluorine or methyl groups. 5-8 Cycloalkyl or heterocyclic group. In the sub-implementation, R 1 and R 2 Together to form unreplaced C 5-8 Cycloalkyl. In the sub-implementation, R 1 and R 2 Together, they form a five- to eight-membered heterocyclic group containing one O atom. In the sub-implementation, R 1 and R 2 Together, they form a five- to eight-membered heterocyclic group containing one nitrogen atom. In such sub-implementations, the following are exemplary compounds: , , and Or its pharmaceutically acceptable salt.

[0051] In the sub-implementations of these tricyclic compound embodiments, there are compounds of formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 1 and R 2 It forms a spiro, cage-like, or bridged five- to eight-membered cycloalkyl or heterocyclic group together with multiple intermediate atoms (e.g., two intermediate atoms). In such sub-implementations, it is a compound as exemplified by the following compounds: and , Or a pharmaceutically acceptable salt thereof. In the sub-implementations of these tricyclic compound embodiments, compounds of formulas (I) and (II) or pharmaceutically acceptable salts thereof are used, wherein R... 1 and R 2 Formed together with multiple intermediate atoms Or its pharmaceutically acceptable salt.

[0052] In some embodiments, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein X 1 It is C, X 2 It is N, and R 1 and R 2 They are linked together to form three to seven-membered cycloalkyl or heterocyclic groups, which are unsubstituted or converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens, C1-3 Alkyl or C 3-6 Cycloalkyl substitution.

[0053] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is , where Y 1 Y 2 Y 3 R 5 R 6 and R 16 It is as defined above. In some implementations, R 16 It is hydrogen. In some embodiments, Y 2 It is N. In some implementations, Y 1 It is O, Y 2 It is N, and Y 3 It is CH. In some implementations, Y 1 It is N, Y 2 It is N, and Y 3 It is CH. In some implementations, Y 1 It is CH.

[0054] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 It is a 4- to 8-membered cycloalkyl or heterocyclic group. In some embodiments, R 5 It is a 4- to 8-membered spiro, cage-like, or bridged 4- to 8-membered cycloalkyl or heterocyclic group. In some embodiments, R 5 It is a 5- to 8-membered heterocyclic group containing at least one O atom. In some embodiments, R 5 It is a 5- to 8-membered heterocyclic group containing at least one nitrogen atom. In some embodiments, R 5 It is a spirochete, cage-like, or bridged 5- to 8-membered heterocyclic group containing at least one nitrogen atom, such as in compounds .

[0055] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic and -C(R) 15 ) z -heteroaryl, where z is 1, and R 15 It is hydrogen or (=O)-. In the sub-implementations of these embodiments, R 5 -C(R) 15 )-Heteroaryl groups are four to nine-membered heterocyclic groups. In the sub-implementations of these embodiments, R 5 -C(R)15 )-Heteroaryl groups are four to nine-membered heteroaryl groups. In one embodiment of these embodiments, R 5 -C(R) 15 )-Heteroaryl is a five-membered heteroaryl.

[0056] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Any cycloalkyl moiety is substituted with one or two substituents, wherein each substituent is unsubstituted or substituted with one or two fluorine atoms or heteroaryl groups. 1-2 Alkyl group. In the sub-implementations of these embodiments, R 5 The cycloalkyl moiety is replaced by -C substituted with five- to six-membered heteroaryl groups. 1-2 Alkyl substitution.

[0057] In some embodiments, it is a compound of formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, wherein R 5 It is a four- to eight-eight-membered heteroaryl group. 5 Any such heteroaryl moiety may consist of the following: (1) Four carbon atoms and one O atom, (2) Three carbon atoms and (i) N and O, (ii) N and S or (iii) N and NH; (3) Two carbon atoms and three nitrogen atoms; (4) Seven carbon atoms and N and O.

[0058] In some embodiments, it is a compound of formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, wherein R 5 It is a four- to eight-membered heterocyclic group. R 5 Any such heterocyclic base moiety may consist of the following: (1) Three, four, five, six or seven carbon atoms and one O atom, (2) Four carbon atoms and (i) two O atoms or (ii) N atoms and O atoms, or (3) Six carbon atoms, two O atoms, and one N atom.

[0059] In some embodiments, it is a compound of formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6 It is a five- to eight-membered heteroaryl group, for example, a five- to eight-membered heteroaryl group containing one or two nitrogen atoms. This heteroaryl group can be converted to -C 1-10 Alkyl substitution. In the sub-implementations of these embodiments, R 6 It is either unsubstituted or -C in position 1. 1-10 Alkyl-substituted pyrazole. In one sub-implantation, R 6 It is a pyrazole with a methyl group substituted at the 1 position.

[0060] In other sub-implementations of these implementations, R 6 It is a six-membered heteroaryl group containing one nitrogen atom. This heteroaryl group can be converted to -C 1-10 Alkyl (e.g., methyl) substitution. In some such sub-implementations, R 6 yes .

[0061] In some embodiments, it is a compound of formula (I), wherein R 3 yes .

[0062] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 yes In these sub-implementations, X 7 It is C. In a further sub-implementation of these embodiments, R 8 and R 11 Each is hydrogen, making R 3 yes .

[0063] In some embodiments of this type of implementation, the compounds are those of formulas (I) and (II), wherein R 9 It is fluorine. In some embodiments of this type of implementation, it is a compound of formula (I) and formula (II), wherein R 10 It is chlorine. In some embodiments of this type of implementation, it is a compound of formula (I) and formula (II), wherein R 7 It is hydrogen. Therefore, in some embodiments, R 10 It is chlorine, R 9 It is fluorine, and R 7 It is hydrogen.

[0064] In other respects, this application provides compounds having formula (III), (III) Where X 1 X 2 R 1 R 2 and R 10 It is as defined above.

[0065] In certain embodiments, the compounds are selected from Examples 1-1 to 1-259, 2-1 to 2-235, 3-1 to 3-98, 4-1 to 4-30, 5-1 to 5-2, 6-1 to 6-9, and 7-1 to 7-5.

[0066] In some embodiments, this document provides pharmaceutically acceptable salts (e.g., hydrochlorides) of any of the disclosed compounds. In other embodiments, the compounds provided herein are isolated as trifluoroacetate salts. In some embodiments, the phase of any of the disclosed compounds is crystalline. In some embodiments, the phase of any of the disclosed compounds is amorphous.

[0067] In some embodiments, any of the disclosed compounds exhibit high potency in activating the TREM2 receptor (e.g., the human TREM2 receptor). TREM2 receptor activation can be measured using any of a number of assays known in the art. For example, TREM2 activation can be measured using a spleen tyrosine kinase (pSYK) phosphorylation assay. In addition to the pSYK assay, other biomarkers can be used to measure TREM2 activation in vivo (e.g., in subjects), including but not limited to TREM2 interaction with the adaptor protein DAP12, pDAP12 elevation, TREM2 clustering, and cytokine elevation (e.g., IP10 or CCL4 cytokine elevation). Some of these biomarkers (such as DAP12) constitute proteins that are activated in the TREM2 pathway downstream of the TREM2 receptor and upon ligand binding to the TREM2 receptor. The potency of activation can be expressed as IC50. 50 or EC 50 TREM2 activation can be measured in vitro.

[0068] Treatment of neurodegenerative diseases The disclosed compounds and pharmaceutical compositions can be used to treat and / or prevent one or more neurodegenerative conditions. For example, they can be used to treat or prevent one or more of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, demyelinating diseases, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), tau disease, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonoglobinization and glial pigmentary disorders (ALSP). In some embodiments, the disclosed compounds and compositions can be used to treat Alzheimer's disease. In some embodiments, the disclosed compounds and compositions are used to treat dementia, such as frontotemporal dementia.

[0069] In some aspects, any of the disclosed compounds and compositions may be administered to a subject suffering from Alzheimer's disease. In various embodiments, the subject is a human being. Administration of these compositions may improve cognitive and / or functional benefits by stabilizing amyloid-negative status in the subject or further modulating multiple biomarkers of Alzheimer's disease pathology or progression. In some embodiments, the disclosed compositions promote stabilization of amyloid-negative status in the subject. Modulation of biomarkers of Alzheimer's disease pathology or progression in the subject can be observed by measuring any of the following biomarkers in the subject's blood, plasma, and / or cerebrospinal fluid samples: Ab42 / 40 ratio, pTau and / or total Tau, NfL, GFAP, soluble Trem2 (sTrem2), and YKL-40. In some embodiments, any of the disclosed compounds improves (i.e., reduces) the subject's Ab42 / 40 ratio, pTau and / or total Tau, NfL, GFAP, sTrem2, and / or YKL-40 in plasma or cerebrospinal fluid (CSF). In some embodiments, administration of any of the disclosed compounds improves the subject's Ab42 / 40 ratio. In some embodiments, administration of any of the disclosed compounds reduces sTREM2 in the subject's CSF.

[0070] The regulation of the Ab42 / 40 ratio, pTau, and / or total Tau in subjects can be achieved using imaging measurements of the markers, including positron emission tomography (PET) of amyloid or tau proteins, respectively. Therefore, in some embodiments, amyloid PET and / or tau PET are performed on subjects or subject samples after administration of any of the disclosed compositions.

[0071] Therefore, this document further provides methods of treatment and prevention, including the administration of any of the disclosed compounds. This document also provides the use of these compounds as medicaments for the treatment or prevention of neurodegenerative conditions such as Alzheimer's disease. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to prepare a medicament for: (a) (e.g., in humans) a therapy, (b) a medicament, (c) TREM2 receptor activation, (d) the treatment or prevention of Alzheimer's disease and / or its neurological symptoms, (e) the treatment or prevention of dementia, or (f) the treatment, prevention, or delay of the onset or progression of Alzheimer's disease, dementia, and / or its neurological symptoms. In these uses, the compounds of the present invention may optionally be used in combination with one or more other active agents, such as β-amyloid-targeting therapy or tau-targeting therapy.

[0072] This article further provides methods for treating or preventing conditions associated with loss of TREM2 function in subjects (e.g., human subjects). In some embodiments, the condition associated with loss of TREM2 function is dementia or cognitive impairment associated with Alzheimer's disease. In some embodiments, the condition is cognitive impairment associated with Parkinson's disease. In some embodiments, the condition is cognitive impairment associated with frontotemporal dementia, demyelinating diseases, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), tau proteinosis, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonoglobinization and glial pigmentary gliosis (ALSP).

[0073] This disclosure further provides methods for administering any of the disclosed compounds or compositions to a subject. In some embodiments, the disclosed methods can result in (i) a reduction in amyloid plaques, (ii) increased disease-associated microglia (DAM) mRNA expression, (iii) increased lipid metabolism, (iv) increased DAM chemotaxis, DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and / or (v) a reduction in dystrophic neurites in the subject. In some embodiments, the disclosed methods result in a reduction in amyloid plaques. In some embodiments, the disclosed methods result in increased disease-associated microglia (DAM) mRNA expression. In some embodiments, the disclosed methods result in increased lipid metabolism in the subject. In some embodiments, the disclosed methods result in increased DAM chemotaxis, DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and / or a reduction in dystrophic neurites.

[0074] In some aspects, this article provides methods for treating or preventing abnormal motor symptoms associated with Parkinson's disease (including, but not limited to, bradykinesia, rigidity, and resting tremor). Another embodiment provides methods for treating or preventing abnormal nonmotor symptoms associated with Parkinson's disease (including, but not limited to, cognitive impairment, autonomic dysfunction, mood changes, and sleep disturbances), Lewy body dementia, and levodopa-induced motor disorders.

[0075] In some respects, this article provides methods for the treatment or prevention of Alzheimer's disease, mild cognitive impairment, the transition from mild cognitive impairment to Alzheimer's disease, tau protein disorders characterized by tau protein hyperphosphorylation such as auricula-jergic granuloma, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia, and chromosome 17-linked Parkinson's disease. Other indications include neuroinflammatory diseases, including microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury, and spinal cord injury.

[0076] In some embodiments, any of the compounds, compositions, and methods described herein provide a reduction in the likelihood or severity of Alzheimer's disease symptoms in one or more subjects. In some embodiments, any of these compounds, compositions, and methods can provide partial or complete reduction / inhibition of one or more symptoms. Any of the disclosed compounds, compositions, and methods can provide partial or complete activation of the TREM2 receptor. Any of the disclosed compounds, compositions, and methods can provide partial or complete reversal of TREM2 function loss in subjects. Any of the disclosed methods can provide improvement in cognitive function following administration of any of the disclosed compounds.

[0077] definition The definitions of the various terms used herein are listed below. Unless otherwise limited in a particular case, these definitions apply individually or as part of a larger group to the terms used throughout this specification and claims.

[0078] The terms used herein have their general meanings, and the meaning of these terms is independent each time they appear. Nevertheless, and unless otherwise stated, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures are used interchangeably to describe the same structures. Unless otherwise stated, these definitions apply whether a term is used alone or in combination with other terms. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0079] As used herein and throughout this disclosure, unless otherwise stated, the following terms shall be understood to have the following meanings: The “subject” is a human or a non-human mammal. In one embodiment, the subject is a human. In another embodiment, the subject is a primate. In yet another embodiment, the subject is a non-human primate, such as a monkey. In some embodiments, the subject is a rhesus monkey. In still another embodiment, the subject is a rodent, such as a rat. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a laboratory animal.

[0080] As used herein, the term "effective amount" refers to the amount of a compound and / or additional therapeutic agent or combination thereof that, when administered to a subject suffering from neurodegenerative disease, effectively activates human TREM2 receptors and produces the desired therapeutic, ameliorative, or preventative effect. In any combination therapy disclosed herein, an effective amount may refer to each individual agent or the entire combination, wherein the amounts of all agents administered together are effective, but wherein the component agents in the combination may not be present individually in an effective amount.

[0081] As used herein, in relation to neurodegenerative conditions, the term "treating" or "treatment" includes inhibiting the severity of a neurodegenerative condition, for example, preventing or reducing the progression of the neurodegenerative condition or its clinical symptoms; or improving or alleviating the symptoms of a neurodegenerative condition, for example, leading to a reduction in the severity of the neurodegenerative condition or its symptoms. For example, the disclosed compounds, pharmaceutical compositions, and methods can be used to prevent or reduce the progression of Alzheimer's disease or neurodegenerative conditions associated with Alzheimer's disease or to alleviate its symptoms.

[0082] As used herein, in relation to neurodegenerative diseases, the term "preventing" or "prophylaxis" encompasses the prevention of the development or progression of clinical symptoms of a disease, condition, or ailment in a mammal that may be exposed to or susceptible to the disease, condition, or ailment but has not yet experienced or exhibited symptoms of the disease.

[0083] "Alkyl" and other groups prefixed with "alkane" (such as alkoxy groups) refer to carbon chains that can be straight-chain, branched, or a combination thereof, containing the indicated number of carbon atoms. For example, C 1-6 Alkyl refers to an alkyl group having 1 (i.e., methyl) to 6 (i.e., hexyl) carbon atoms. In certain embodiments, straight-chain alkyl groups have 1 to 6 carbon atoms, and branched alkyl groups have 3 to 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc.

[0084] "Alkoxy" and "alkyl-O-" are used interchangeably and refer to alkyl groups bonded to oxygen. "Haloalkoxy" refers to monohalogenated or polyhalogenated alkoxy groups. The bond with the parent group is through the oxygen atom of the group.

[0085] “Hydroxyalkyl” refers to HO-alkyl-, where the alkyl group is as defined previously. The bond with the parent moiety is through a carbon atom of the alkyl group. Preferred hydroxyalkyl groups comprise lower alkyl groups. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

[0086] "Alkoxyalkyl" refers to RO-alkyl, where the alkyl and alkoxy groups are as defined previously. The bond to the parent moiety is through a carbon atom of the alkyl group. Suitable, non-limiting examples of alkoxyalkyl groups include 2-ethoxyethyl and 2-methoxyethyl.

[0087] “Cycloalkyl” refers to a cyclic hydrocarbon group. Unless otherwise stated, “cycloalkyl” refers to a saturated cycloalkyl group. In certain embodiments, the cycloalkyl group has 3-12 carbon atoms, thereby forming 1-3 carbon rings, wherein ring systems having 2-3 rings can be fused. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc. In some embodiments, for example, the cycloalkyl group is fused with a heteroaryl ring, and the cycloalkyl group can be a non-aromatic, partially unsaturated ring.

[0088] "Fluoroalkyl" includes mono-substituted and polyfluorosubstituted alkyl groups, up to perfluorosubstituted alkyl groups. Examples include fluoromethyl, 1,1-difluoroethyl, trifluoromethyl, or 1,1,1,2,2-pentafluorobutyl. The bond to the parent group is through a single carbon atom of the alkyl moiety.

[0089] A "bicyclic ring system" refers to two linked rings. A "tricyclic ring system" refers to three linked rings. A "tetracyclic ring system" refers to four linked rings. Heterocyclic and cycloalkyl rings can be fused, i.e., sharing two adjacent atoms, or "spirocyclic," i.e., sharing only one atom, or "bridged," i.e., sharing three or more atoms, where two bridgehead atoms are connected by a bridge containing at least one atom. Heteroaryl rings can be fused.

[0090] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I. The specific classes of halogen substituents of interest for compounds of formula (I) and embodiments thereof are fluorine (-F) and chlorine (-Cl). The term "haloalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (i.e., -F, -Cl, -Br, and / or -I).

[0091] The term "substituted" refers to the selective substitution of one or more hydrogen atoms on a specified atom by a specified group, provided that the substitution does not exceed the normal valence of the specified atom under existing conditions and that the substitution results in a stable compound. Such combinations are permitted only if the combination of substituents and / or variables produces a stable compound. "Stable compound" or "stable structure" refers to a compound that is robust enough to be isolated from the reaction mixture to a usable level of purity and formulated into an effective therapeutic agent. When any substituent or variable (e.g., R...)... 1 When a substance appears more than once in any component or in Formula I or Formula II, unless otherwise stated, the definition of each occurrence is independent of the definition of each other occurrence. It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, routes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy the valence.

[0092] When a functional group in a compound is referred to as “protected,” it means that the group is in a modified form to prevent undesirable side reactions at the protected site when the compound reacts. Suitable protecting groups are recognized by those skilled in the art and determined by referring to standard textbooks, such as, for example, TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0093] When a portion is specified as "optionally substituted" in Formula (I) or any embodiment thereof, this means that Formula I or Formula II or any embodiment thereof covers compounds in which the portion is substituted by the said substituent (or multiple substituents) and compounds in which the portion is not substituted by the said substituent (or multiple substituents) (i.e., where the portion is unsubstituted). As an example, when R 1 C is a C that can be optionally replaced by halogens. 1-10 When alkyl, then R 1 It can be C 1-10 Alkyl or C 1-10 Halogenated alkyl groups.

[0094] When any variable (e.g., R) 1 R X R Y When a component appears more than once in any component, in formula (I), or in any other formula depicting or describing the compounds of the present invention, the definition of each occurrence is independent of the definition of each subsequent occurrence. Furthermore, such combinations are permitted only if the combination of substituents and / or variables produces a stable compound. Unless expressly stated to the contrary, substitution of any atom in the ring (e.g., cycloalkyl, aryl, or heteroaryl) with a specified substituent is permitted, provided that such ring substitution is chemically permissible and produces a stable compound.

[0095] Unless explicitly stated to the contrary, all ranges stated herein include the endpoints and may be combined independently. For example, the range “between about 0.5% and about 95%” includes the endpoints (about) 0.5% and (about) 95% as well as all intermediate values. Any values ​​of the ranges and endpoints disclosed herein are not limited to precise ranges or values; they are sufficiently imprecise to include values ​​close to these ranges and / or values.

[0096] As used herein, "heteroaryl" or "heteroaromatic ring" refers to a ring structure of aromatic monocyclic, bicyclic, tricyclic, or tetracyclic rings, wherein one or more atoms (heteroatoms) in the ring are elements other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrroleyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0097] "Heterocyclic alkyl," "heterocyclic ring," "heterocycle," or "heterocyclic group" (when the ring is partially bonded to the parent compound) refers to a non-aromatic monocyclic, bicyclic, tricyclic, or tetracyclic ring system containing about 3 to about 17 ring atoms, preferably about 3 to about 10 ring atoms, wherein one or more atoms in the ring system, individually or in combination, are elements other than carbon, such as nitrogen, oxygen, phosphorus, or sulfur. Adjacent oxygen and / or sulfur atoms are not present in the ring system. In some embodiments, the heterocyclic alkyl contains about 5 to about 6 ring atoms. The prefixes nitro, oxo, phosphorus, or sulfide preceding the name of the heterocyclic group indicate that at least one nitrogen, oxygen, phosphorus, or sulfur atom is present as a ring atom, respectively. Non-limiting examples of suitable monocyclic heterocyclic groups include piperidinyl, pyrrolyl, piperazine, morpholinyl, thiomorpholinyl, thiazolyl, 1,4-dioxanehexyl, tetrahydrofuranyl, tetrahydrothiophene, etc. "Spirocycloalkyl" refers to a fused ring system in which the rings share only a single atom and at least one ring is a heterocycloalkyl.

[0098] In some embodiments, the compounds disclosed herein comprise a heteroaryl substituent containing one nitrogen atom. It should also be understood that any scope referenced herein includes all subscopes within that scope. Thus, for example, "heterocyclic" is intended to include, as an aspect, a heterocyclic ring containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. For example, the ring may contain one or more nitrogen atoms (e.g., 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms. Any cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally be substituted with one or more groups. As used herein, “optionally substituted with one to five groups” is intended to include, in its aspect, cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substituents, 4 to 5 substituents, 5 substituents, 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent. Similarly, as used herein, “optionally substituted with one to three groups” is intended to include, in its aspect, cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent.

[0099] As used herein, the term "composition" is intended to cover products containing specified amounts of specific ingredients, and any product obtained from a combination of specified amounts of specific ingredients.

[0100] As used herein, the term "salt" refers to an acidic salt formed with inorganic and / or organic acids, and a basic salt formed with inorganic and / or organic bases. Furthermore, when a compound contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acids), an zwitterion ("internal salt") may be formed, and this is included in the term "salt" as used herein. Compounds may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable (e.g., it is non-toxic to the recipient and not otherwise harmful).

[0101] Compounds of formula (I) containing one or more basic groups (i.e., protonable groups) can be used according to the invention in the form of acid addition salts with inorganic or organic acids, such as, but not limited to, salts with hydrogen chloride, hydrogen fluoride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc.

[0102] In some embodiments, one or more N atoms of any Formula I compound (e.g., N atoms in a heteroaryl or heterocyclic ring, or N atoms in an NH2 group) are protonated in salt form. In some embodiments, N atoms that are ring members of a heteroaryl or heterocyclic ring of any Formula (I) compound are protonated in salt form. In some embodiments, the N atom is protonated in the form of a salt of trifluoroacetic acid. If the Formula (I) compound contains both acidic and basic groups in the molecule, the invention also includes an inner salt or betaine (zwitterion) in addition to the salt forms described above. Salts can be obtained from Formula (I) compounds by conventional methods known to those skilled in the art, such as by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts. This disclosure also includes all salts of Formula (I) compounds that are not directly applicable to pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0103] This disclosure covers any composition consisting of a compound of formula (I) or a compound as a salt thereof, including, for example but not limited to, compositions formed by association of said compound with one or more additional molecular and / or ionic components, which may be referred to as a “eutectic.” As used herein, the term “eutectic” refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (usually in stoichiometric ratio) are held together by nonionic interactions (including, but not limited to, hydrogen bonds, dipole-dipole interactions, dipole-quadrupole interactions, or dispersive forces (van der Waals forces)). There is no proton transfer between the different components, and the solid phase is neither a simple salt nor a solvate. For a discussion of eutectics, see, for example, Aitipamula et al. Crystal Growth and Design , 2012, 12 (5), pp. 2147-2152.

[0104] The compounds of the present invention may exist in amorphous form and / or one or more crystalline forms; therefore, all such amorphous and crystalline forms of the compounds of formula (I) and mixtures thereof are intended to be included within the scope of the present invention. Furthermore, some compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds of the present invention, particularly pharmaceutically acceptable solvates and hydrates, as well as unsolvated and anhydrous forms, are also covered within the scope of the present invention. Therefore, the compounds in the general structural formulas, embodiments, and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), their solvates and hydrates, and any combination of these forms, as well as their salts.

[0105] Salts, solvates and stereoisomers This document relates to solvates of the disclosed compounds of formula (I). One or more compounds of the present invention may exist in an unsolvated form or in a pharmaceutically acceptable solvent (such as water, ethanol, etc.), and the present invention is intended to include both solvated and unsolvated forms. “Solvate” refers to the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be separated, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. “Solvate” includes solution phases and separable solvates. Non-limiting examples of solvates include ethanolides, methanolides, etc. “Hydrate” is a solvate in which the solvent molecules are water.

[0106] One or more compounds of formula (I) can optionally be converted into solvates. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of antifungal fluconazole in ethyl acetate and its solvates in water. EC van Tonder et al., AAPS PharmSciTech. , 5(1), Article 12 (2004); and AL Bingham et al., Chem. Commun. Regulations 603-604 (2001) describe similar preparations of solvates, semi-solvates, and hydrates. Typical non-limiting methods involve dissolving the compound in a desired amount of a desired solvent (organic solvent or water or a mixture thereof) at a temperature above room temperature, cooling the solution at a rate sufficient to form crystals, and then separating it by standard methods. Analytical techniques, such as, for example, IR spectroscopy, show the presence of the solvent (or water) in the crystals as solvates (or hydrates).

[0107] Compounds of formula (I) can form salts, which are also within the scope of this invention. In some embodiments, the salt is a pharmaceutically acceptable salt. In another embodiment, the salt is not a pharmaceutically acceptable salt. Salts of compounds of formulas I and II can be formed, for example, by reacting the compound with a certain amount of an acid or base (e.g., an equimolar amount) in a medium (e.g., a medium in which the salt can precipitate) or in an aqueous medium, followed by freeze-drying.

[0108] Exemplary acid addition salts include acetates, ascorbic acid salts, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobroms, hydroiodates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as p-toluenesulfonates), etc. Additionally, for example, P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use . (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book The Food & Drug Administration (Washington, DC, on its website) discusses acids that are generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds. These publications are incorporated herein by reference.

[0109] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, and choline, and salts with amino acids (e.g., arginine and lysine). The basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long-chain halides (e.g., decyl, dodecyl, and stearyl chlorides, bromides, and iodides), and aralkyl halides (e.g., benzyl and phenethyl bromides).

[0110] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of this invention, and for the purposes of this invention, all acid salts and base salts are considered equivalent to the free form of the corresponding compound.

[0111] This disclosure includes single diastereomers, particularly epimers, i.e., compounds having the same chemical formula but with different spatial arrangements around a single atom. This disclosure also includes mixtures of diastereomers in all ratios, particularly mixtures of epimers. This disclosure includes compounds having at the asymmetry center and at any additional asymmetry center that may be present in compounds of formula (I). R or S Compounds of formula (I) with stereoisomers, and mixtures thereof. Embodiments of this disclosure also include enrichment of 51% or more of one of the enantiomers, including, for example, mixtures of enantiomers enriched by 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer. A single enantiomer is preferred. A single or mono-enantiomer refers to an enantiomer obtained by chiral synthesis and / or using generally known separation and purification techniques, which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer. Thus, the subject of this disclosure is the mono-enantiomer in pure form (as levorotatory and dextrorotatory enantiomers), racemic form, and mixtures of two enantiomers in all ratios. In the case of cis / trans isomers, this disclosure includes both the cis and trans forms and mixtures of these forms in all ratios.

[0112] If desired, the mixture can be separated by conventional methods to prepare individual stereoisomers, such as by chromatography or crystallization, by synthesis using stereochemically homogeneous starting materials, or by stereoselective synthesis. Optionally, derivatization can be performed prior to the separation of stereoisomers. The separation of the stereoisomer mixture can be carried out as an intermediate step in the synthesis of the compound of formula (I), or can be performed on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, and, if desired, by derivatization with a reagent containing a stereocenter of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. This disclosure includes all such isomers as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers and mixtures thereof.

[0113] Enantiomer mixtures can be converted into diastereomer mixtures by reacting with suitable optically active compounds (e.g., chiral auxiliaries such as chiral alcohols or moselyl chloride), diastereomers can be separated, and individual diastereomers can be converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Stereochemically pure compounds can also be prepared using chiral starting materials or by using salt resolution techniques. Furthermore, some compounds of formula (I) can be transisomers (e.g., substituted biaryl groups) and are considered part of this invention. Enantiomers can also be directly separated using chiral chromatography.

[0114] Compounds of Formula I and / or Formula II may also exist in different tautomer forms, and all such forms are included within the scope of this invention. For example, each ketone / enol and imine / enamine tautomer form of the disclosed compounds is covered in the embodiments of the disclosed compounds in which any one form is described individually. As another example, oxosubstituted pyridine substituents in the forms of hydroxypyridine and pyridinone are covered in the embodiments of the disclosed compounds in which any one form is described individually.

[0115] Unless otherwise stated, all stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of this invention (including salts, solvates, hydrates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), such as those that may exist due to asymmetric carbons on various substituents, including enantiomers (which may exist even in the absence of asymmetric carbons), rotational isomers, trans-blocking isomers, and diastereomeric forms, are contemplated within the scope of this invention. If the compound comprises a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are covered within the scope of this invention.

[0116] When depicting substituents on chiral carbon atoms without specific stereochemistry (using linear bonds with the chiral center), it should be understood that the α and β configurations of the substituents should be considered part of this invention. It should be understood that the chiral center in the compound can be... S or R It exists either in absolute configuration or as a mixture of both. Within the molecule, each bond, drawn as a straight line from the chiral center, includes... R and S Stereoisomers and their mixtures. An asterisk indicates a single configuration. R or S The stereochemical center. Unless otherwise stated in the examples or explicitly indicated in the nomenclature, the absolute stereochemistry of individual stereoisomers in the examples and intermediates may not be determined. Otherwise, for compounds containing a chiral center in the examples, mixtures of isomers may be isolated to produce the specific stereoisomers depicted.

[0117] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may, for example, be racemic or mixed with all other stereoisomers or other selected stereoisomers. The chiral center of the present invention may have IUPAC The 1974 Recommendations definition S or R Configuration. The terms “salt”, “solvent”, etc., are intended to apply equally to salts and solvates of enantiomers, stereoisomers, rotational isomers, tautomers or racemates of the disclosed compounds.

[0118] In compounds of formula (I), atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. This invention aims to include all suitable isotopic variations of compounds of general formula (I). For example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 H). Protium is the main hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide a compound that can be used as a standard for characterizing biological samples. Isotope-enriched compounds of formula (I) can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or by methods similar to those described in the routes and examples herein, using appropriate isotope enrichment reagents and / or intermediates. In one embodiment, one or more hydrogen atoms of the compound of formula (I) are replaced with deuterium.

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well-known and commonly used in the art.

[0120] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” refers to one or more elements. Furthermore, the use of the term “including” and other forms such as “including,” “containing,” and “including” is not restrictive.

[0121] As used herein, when modifying quantitative terms, the term “about” refers to plus or minus 10% of the value it modifies (rounded to the nearest integer if the value is not subdividable, such as the number of molecules).

[0122] All ranges disclosed herein include the stated endpoints and may be combined independently (e.g., a range “from 100 mg to 1500 mg” includes the endpoints 100 mg and 1500 mg, as well as all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to precise ranges or values; they are sufficiently imprecise to include values ​​close to these ranges and / or values.

[0123] As used herein, the term “comprising” can include embodiments “consisting of” and “substantially composed of”. As used herein, the terms “comprising,” “including,” “having,” “suffering from,” “may,” “containing,” and variations thereof are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified ingredient / step and allow for the presence of other ingredients / steps. However, such a description should be construed as also describing the composition or process as “consisting of the listed components” or “substantially composed of the listed components,” which allows for the presence of only the specified component or compound, and any acceptable carrier or fluid, without including other components or compounds.

[0124] TREM2 activation and neurodegenerative conditions Impaired TREM2 receptor function is associated with several human diseases. For example, mutations in both TREM2 and DAP12 are associated with the autosomal recessive genetic disorder Nasu-Hakola disease, characterized by bone cysts, muscle atrophy, and a demyelinating phenotype (Guerreiro et al., 2013). Variants of the TREM2 gene are associated with an increased risk of Alzheimer's disease (AD) and other forms of dementia, including frontotemporal dementia (Jonsson et al., 2013; Guerreiro & Lohmann et al., 2013; and Jay & Miller et al., 2015). In particular, the R47H variant has been identified in genome-wide studies as associated with an increased risk of late-onset AD, with an overall adjusted hazard ratio (overall age population) of 2.3, second only to the strong genetic association of ApoE with AD. The R47H mutation is located on the extracellular IgV-aggregate domain of the TREM2 protein and has been shown to affect lipid binding and uptake of apoptotic cells and β-amyloid protein (Wang et al., 2015; Yeh et al., 2016), suggesting a disease-associated loss of function. Furthermore, autopsy comparisons of the brains of AD patients with and without the R47H mutation support a loss of novel microglial barrier function in mutation carriers, presumably indicating that R47H carrier microglia exhibit reduced plaque compaction and the ability to limit plaque spread (Yuan et al., 2016). Impaired microglial proliferation has been reported in animal models of prion diseases, multiple sclerosis, and stroke, suggesting that TREM2 may play an important role in supporting microglial proliferation in response to pathological or invasive conditions in the CNS.

[0125] Furthermore, TREM2 knockdown has been shown to exacerbate α-synuclein-induced inflammatory responses in vitro and aggravate dopaminergic neuronal loss in vivo in response to adeno-associated virus (AAV) vectors encoding synuclein (a Parkinson's disease model). This suggests that impaired microglia TREM2 signaling exacerbates neurodegeneration by regulating microglia activation status. (Guo et al., 2019). Multiple animal models have also shown that Toll-like receptor (TLR) signaling plays a crucial role in the pathogenesis of rheumatoid arthritis (RA) through persistent expression of pro-inflammatory cytokines in macrophages. TREM2 / DAP12 signaling inhibits the TLR response by reducing MAPK (Erk1 / 2) activation, suggesting that TREM2 activation can act as a negative regulator of TLR-driven RA pathogenesis. Signaling through DAP10 and DAP12 also triggers the recruitment of PI3K and SYK, which drive multiple downstream events leading to Ca2+. 2+ Mobilization and MAPK-mediated cascades, as well as activation of other pathways.

[0126] Given that data indicate that defects in TREM2 activity affect the function of macrophages and microglia, the TREM2 agonist compounds disclosed herein are specifically intended for the treatment, prevention, and / or mitigation of the severity of the conditions described below, and more broadly for neurodegenerative diseases.

[0127] TREM2 consists of a single transmembrane domain, an extracellular stem region, and an extracellular immunoglobulin variable region-like (IgV) domain responsible for ligand interactions (Kleinberger et al.). Sci Transl Med (Peng et al., 2014). Since TREM2 lacks an intracellular signal transduction mediating domain, biochemical analysis indicates that its interaction with adaptor proteins DAP10 and DAP12 mediates downstream signal transduction after ligand recognition (Peng et al., 2014). Sci Signal 2010; Jay et al. Mol Neurodegener (2017). The TREM2 / DAP12 complex is specifically used as a signal transduction unit, and in addition to peripheral macrophages and osteoclasts, it has also been characterized as a pro-activating effect on the microglial phenotype (Otero et al., 2017). J Immunol , 2012; Kobayashi et al., J Neurosci ,2016; Jaitin et al., Cell (2019). In CNS, signal transduction via TREM2 has been studied in the context of ligands such as phospholipids, cell debris, apolipoproteins, and myelin (Wang et al., 2019). Cell , 2015; Kober and Brett, J Mol Biol , 2017; Shirotani et al., Sci Rep, (2019). In mice lacking functional TREM2 expression or expressing a mutant form of the receptor, the core observation was the insensitive microglial response to factors such as oligodendrocyte demyelination, stroke-induced brain tissue damage, and damage to protein toxic inclusion bodies in vivo (Cantoni et al., 2019). Acta Neuropathol ,2015; Wu et al., Mol Brain , 2017).

[0128] In rodent models with elevated TREM2 expression levels, brain amyloid pathology in 5XF AD transgenic mice showed reduced plaque volume and altered morphology (Lee et al.). Neuron (2018). When TREM2 is overexpressed, changes in immunohistochemical markers associated with brain amyloid pathology are also accompanied by a decrease in the presence of dystrophic neurites. Id Thus, the pharmacological agonist effect of TREM2 has attracted attention in the treatment or prevention of neurodegenerative diseases and conditions.

[0129] In human genome-wide association studies, TREM2 Genetic variations at loci are associated with late-onset Alzheimer's disease ("LOAD"), thereby linking receptor dysfunction with an increased risk of disease (Jonsson et al.). N Engl J Med 2013, Sims et al. Nat Genet (2017). Genetic variations in other genes selectively expressed by microglia in the CNS, such as CD33, PLCg2, and MS4A4A / 6A, reached genome-wide significance in their association with LOAD risk (Hollingworth et al., 2017). Nat Genet 2011, Sims et al. Nat Genet 2017, Deming et al. Sci Transl Med (2019). In summary, these genetic findings are linked together in a hypothetical biochemical circuit, highlighting the importance of microglial innate immune function in LOAD. Furthermore, an increase or elevation of the soluble form of TREM2 (“sTREM2”) in the cerebrospinal fluid (CSF) of human subjects was associated with disease progression in LOAD and the appearance of pathological markers including phosphorylated Tau (Suarez-Calvet et al., 2019). Mol Neurodegener (2019). Furthermore, natural history and human biology studies have shown that baseline sTREM2 levels in the CSF can stratify the rate of temporal lobe volume loss and episodic memory decline in longitudinal monitoring cohorts (Ewers et al., 2019). Sci Transl Med(2019). Other studies have revealed that CSF sTREM2 levels are elevated in the early stages of AD and decreased in the dementia stage (Liu et al., 2018), and are elevated after cerebral amyloidosis, CSF phosphorylation and increased total tau protein (Halaas et al., 2020).

[0130] Therefore, this document provides methods for administering any of the disclosed compounds or their pharmaceutically acceptable salts for the treatment or prevention of LOAD. This document also provides methods for treating or preventing conditions associated with loss of function of human TREM2, human DAP12, or human DAP10. This document further provides methods for reducing the amount of sTREM2 in the CSF of a subject.

[0131] In addition to human genetic evidence supporting the role of TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are also a cause of early-onset dementia syndrome, known as multicystic fatty membrane dysplasia with sclerotic leukoencephalopathy (“PLOSL”) or Nasu-Hakola disease (“NHD”) (Golde et al., Alzheimers Res Tuer 2013; Dardiotis et al. Neurobiol Aging (2017). This progressive neurodegenerative disease typically appears in the third decade of life and is pathologically characterized by loss of myelin in the brain, accompanied by glial proliferation, persistent neuroinflammation, and brain atrophy. Typical neuropsychiatric symptoms are often preceded by bone abnormalities, such as bone cysts and decreased peripheral bone density (Bianchin et al., 2017). Cell Mol Neurobiol 2004; Madry et al. Clin Orthop Relat Res 2007; Bianchin et al., Nat Rev Neural (2010). Given that osteoclasts in the myeloid lineage are also known to express TREM2, PLOSL-related symptoms of wrist and ankle pain, swelling, and fractures suggest that TREM2 may function by regulating bone homeostasis through a defined signaling pathway parallel to microglia in the CNS (Paloneva et al., 2010). J Exp Med 2003, Otero et al., J Immunol (2012). The association between TREM2 function and PLOSL / NHD and other adult-onset leukoencephalopathy suggests the importance of this receptor in maintaining the function of human myeloid cells.

[0132] Adult-onset axonoglobinopathic leukoencephalopathy with axonoglobinization (ALSP), previously thought to be hereditary diffuse axonoglobinopathic leukoencephalopathy with axonoglobinization (HDLS) or pigmented normoleukodystrophy (POLD), is an autosomal dominant central nervous system disorder characterized by variable behavioral, cognitive, and motor function changes in affected individuals. ALSP is characterized by patchy white matter abnormalities visible on magnetic resonance imaging (MRI). However, clinical symptoms and MRI changes are not specific to ALSP and are also common in other neurological conditions, including Nasu-Hakola disease (NHD) and Alzheimer's disease (AD), making the diagnosis and treatment of ALSP very challenging. Recent studies have found that ALSP is a Mendelian disorder in which patients carry a heterozygous loss-of-function mutation in the CSF-1R kinase domain, indicating reduced signaling levels along the macrophage colony-stimulating factor (M-CSF) / CSF-1R axis. CSF-1R is a macrophage colony-stimulating factor (M-CSF) that regulates the survival, proliferation, differentiation, and function of monocytes (including microglia in the central nervous system).

[0133] Therefore, this document provides methods for administering any of the disclosed compounds or their pharmaceutically acceptable salts for the treatment or prevention of PLOSL. This document also provides methods for administering any of the disclosed compounds for the treatment or prevention of NHD. This document further provides methods for administering any of the disclosed compounds for the treatment or prevention of adult-onset leukoencephalopathy with or without axonoid degeneration and glial pigmentosa. This document also provides methods for administering any of the disclosed compounds for the treatment or prevention of ALSP.

[0134] This article also provides methods for the administration of any of the disclosed compounds or their pharmaceutically acceptable salts for the treatment or prevention of argyrophilic granuloma, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia, chromosomal 17-linked Parkinson's disease, HIV-induced dementia, or neuroinflammation.

[0135] In addition to the central nervous system (CNS), TREM2 is also expressed in myeloid lineage cells of the liver. In some embodiments, these compounds, or pharmaceutically acceptable salts thereof, can be used to treat or prevent liver diseases associated with impaired TREM2 function. In some embodiments, these compounds can be used to treat or prevent alcoholic liver disease (ALD) or nonalcoholic steatohepatitis (NASH).

[0136] In any of the various embodiments of the disclosed method, the subject suffers from a disease or condition that is being treated. In all embodiments, the subject is a human being.

[0137] In other embodiments, the subject is a non-human mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a rodent. In some embodiments, the subject is a non-human primate.

[0138] preparation When administered to a subject, any of the disclosed Formula I and Formula II compounds, or their pharmaceutically acceptable salts, may be administered as a component of a composition comprising a pharmaceutically acceptable carrier. This disclosure provides pharmaceutical compositions comprising an effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the invention, the active ingredient is typically administered in combination with a suitable carrier material selected according to the intended form of administration, i.e., oral tablets, capsules (solid-filled, semi-solid-filled, or liquid-filled), powders to be prepared, oral gels, elixirs, dispersible granules, syrups, suspensions, etc., conforming to conventional pharmaceutical practices. For example, to be suitable for oral administration in tablet or capsule form, any disclosed compound may be combined with any pharmaceutically acceptable inert carrier. Solid form formulations include powders, tablets, dispersible granules, capsules, sacs, and suppositories. Tablets, powders, sacs, and capsules may be suitable for oral administration. Powders and tablets may consist of about 0.5% to about 95% of any disclosed pharmaceutical composition.

[0139] The tablets contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated to form osmotic therapeutic tablets for controlled release. Oral tablets may also be formulated for immediate release, such as fast-melting tablets or films, fast-dissolving tablets, or fast-dissolving films.

[0140] Oral formulations may also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in the form of soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0141] Furthermore, suitable binders, flow aids, lubricants, disintegrants, and colorants may be incorporated into the composition, particularly in formulations intended for oral administration, when desired or required. The composition can be formulated for prolonged or controlled release. In other embodiments, the composition is formulated for immediate or modulated release.

[0142] In certain embodiments, the compositions of the present invention can be formulated in a prolonged dosing or sustained-release form to provide rate-controlled release of any one or more components or active ingredients, thereby optimizing therapeutic effects, i.e., TREM2 activation. Suitable dosage forms for sustained release include long-acting injectable and implantable dosage forms. Other suitable dosage forms for sustained release include layered tablets containing a controlled-release polymer matrix with different disintegration rates or impregnated with the active ingredient and shaped into a tablet form, or capsules containing such impregnated or encapsulated porous polymer matrices.

[0143] Solid dosage forms (e.g., powders, pills, capsules, and tablets) suitable for oral administration can be prepared according to techniques known in the art, and such solid excipients, such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used. These formulations may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically aesthetically pleasing and palatable formulation. Liquid dosage forms (e.g., suspensions, syrups, elixirs, etc.) suitable for oral administration can be prepared according to techniques known in the art, and any common media, such as water, glycols, oils, alcohols, etc., can be used.

[0144] In some embodiments, any disclosed pharmaceutical composition comprises a pharmaceutically acceptable carrier suitable or adapted for administration to a subject by injection. In some embodiments, these carriers are adapted for long-acting injection. In some embodiments, these carriers are liquid formulations comprising solutions, suspensions, emulsions, or nanoemulsions for intramuscular or subcutaneous administration. In some embodiments, any disclosed pharmaceutical composition is adapted for long-acting injectable formulations.

[0145] Any disclosed composition may comprise a pharmaceutically acceptable carrier, in a unit dosage form containing an effective amount of the compound and a conventionally pharmaceutically acceptable carrier, adjuvant, and mediator, suitable or adapted for parenteral administration, including subcutaneous, intravenous, intramuscular, intraperitoneal, or intrasternal injection, or other infusion techniques (which may be administered once or multiple times at each dosing interval to deliver an appropriate amount of the active agent, as needed), for the treatment of a subject suffering from neurodegenerative diseases. The composition may also be parenterally administered via an implantable drug delivery composition or device suitable for delivering an effective amount of the compound over an extended period of time. In some embodiments, the composition is parenterally administered monthly, every three months, every six months, or every twelve months.

[0146] In some embodiments, the disclosed composition is adapted for intramuscular administration. In some embodiments, the disclosed composition is adapted for subcutaneous administration. In some embodiments, the disclosed composition is adapted for intravenous administration. In some embodiments, the disclosed composition is adapted for intraperitoneal administration. In some embodiments, the disclosed composition is adapted for intraventricular (ICV), intrathecal, or intracisional administration. In some embodiments, the disclosed composition is adaptable for inhalation spray, intranasal, vaginal, rectal, sublingual, oral, or topical administration.

[0147] Parenteral compositions can be prepared using techniques known in the art. These compositions may use sterile water as a carrier and optionally other components. Continuous dosing regimens may be used in subjects suffering from neurodegenerative diseases such as Alzheimer's disease. Any publicly disclosed pharmaceutical formulation for parenteral injection may include solutions, suspensions, or emulsions, which may contain water, suspending agents, viscosity modifiers, tension modifiers, and / or pH adjusters.

[0148] This also includes solid formulations intended to be converted into liquid formulations shortly before use for oral or parenteral administration. Such liquid forms include solutions, suspensions, emulsions, and nanoemulsions. Parenteral compositions can be prepared according to techniques known in the art, typically using sterile water as a carrier, and optionally other components such as dissolving agents. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a saline solution, a glucose solution, or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art, wherein the carrier comprises an active chemical component with a polymer and suitable excipients, or using an implantable device for drug delivery. Further descriptions of methods suitable for preparing pharmaceutical compositions used in this disclosure and of components suitable for said compositions are provided in Remington – the Science and Practice of Pharmacy, 22nd edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and earlier editions.

[0149] Formulations of Formula I compounds that cause drug supersaturation and / or rapid dissolution can be used to promote the absorption of orally administered drugs. Formulation methods that cause drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticle systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation methods and techniques used for their preparation are known in the art. For example, a review (e.g., ATM Serajuddin, J Pharm Sci, The excipients and methods for preparing solid dispersions are described in 88:10, pp. 1058-1066 (1999). Reviews such as those by Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, ...) Advanced Drug Delivery Reviews Nanoparticle systems based on grinding and direct synthesis are also described in (59:7 pp. 631-644 (2007)).

[0150] Compounds of Formula I may be administered in a dose range of, for example, 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammalian (e.g., human) body weight daily, or at other time intervals as required, as a single dose or in divided doses. Compounds of Formula I may be administered in a dose range of 0.001 to 2000 mg daily, as a single dose or in divided doses, via oral administration or other routes of administration. Examples of dose ranges are 0.01 to 1500 mg daily, or 0.1 to 1000 mg daily, as a single dose or in divided doses.

[0151] For oral administration (e.g., tablets or capsules) or other routes of administration, the dosage unit may contain 100 mg to 1500 mg of active ingredient, for example, but not limited to 0.1 mg to 1500 mg of active ingredient, for example, but not limited to 0.1, 0.25, 0.5, 1, 2, 2.5, 5, 10, 15, 20, 25, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 1000, 1250, or 1500 mg of active ingredient, to adjust the dose for the patient to be treated according to symptoms. Furthermore, the compound may be formulated into oral formulations for immediate or modulated release, such as prolonged or controlled release. When a compound of Formula I is administered as a salt, the amount of the compound mentioned in milligrams or grams is based on the free form of the compound (i.e., the non-salt form).

[0152] Daily administration can be via any suitable route of administration, but is preferably by oral administration, and can be a single dose or more than one dose staggered throughout a 24-hour period (divided daily dose). Each dose can be administered using one or more dose units. In some embodiments, the disclosed compounds and compositions are administered once daily. In some embodiments, the disclosed compounds and compositions are administered twice daily.

[0153] The specific dose level and frequency for any particular subject may vary and will depend on a variety of factors, including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, general health status, sex, diet, administration pattern and time, excretion rate, the effects of other medications the subject is taking, the severity of the specific condition, and the host being treated. In some cases, it may be necessary to deviate from the given dose upwards or downwards, depending on the potency of the compound or individual response. The amount and frequency of administration will be adjusted based on the attending physician's judgment, taking these factors into account.

[0154] The compounds of this invention can also be used to prepare and perform screening assays for TREM2 agonists. Furthermore, the compounds of this invention can be used to establish or determine binding sites for other TREM2 agonists.

[0155] Other embodiments of this disclosure include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (b) A pharmaceutical composition comprising a product prepared by combining (e.g., mixing) an effective amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0156] Further embodiments of this disclosure include each of the pharmaceutical compositions, methods, and uses set forth in the foregoing paragraphs, wherein the Formula I compound or its salts used are substantially pure. Regarding pharmaceutical compositions comprising a Formula I or II compound or its salts and a pharmaceutically acceptable carrier and optionally one or more excipients, it should be understood that the term "substantially pure" refers to the Formula I or II compound or its salts themselves.

[0157] combination therapy In some aspects, the method of the present invention for treating or preventing neurodegenerative diseases may further include the administration of one or more additional therapeutic agents, not any of the disclosed compounds.

[0158] Examples of other therapeutic agents that may be combined with the compounds disclosed herein include, but are not limited to, treatments for Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, demyelinating diseases, Huntington's disease, amyotrophic lateral sclerosis (ALS), tau proteinosis, adult-onset leukoencephalopathy, auricula-jugular syndrome, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, HIV-induced dementia, or neuroinflammatory diseases.

[0159] Therefore, in one embodiment, the present invention provides a method for treating neurodegenerative diseases in a subject, the method comprising administering to the subject: (i) at least one compound of formula I or formula II (which may include two or more different compounds) or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent other than any of the disclosed compounds, wherein the amounts administered together are effective in treating or preventing neurodegenerative diseases.

[0160] In some embodiments, an additional therapeutic agent is tau-targeted therapy. In some embodiments, an additional therapeutic agent is β-amyloid-targeted therapy. Administration of tau-targeted therapy or β-amyloid therapy has been shown to improve cognitive function, (partially) reverse the neurodegenerative effects of Alzheimer's disease, and / or treat or prevent Alzheimer's disease. Therefore, this document provides methods for administering any of the disclosed compounds, wherein said methods further include the step of administering tau-targeted therapy or β-amyloid-targeted therapy to a subject. These methods can be used to promote the treatment or prevention of neurodegenerative conditions in a subject. These methods can be used to promote the treatment or prevention of AD in a subject.

[0161] When the combination therapy of the present invention is administered to a subject, the therapeutic agents in the combination, or one or more pharmaceutical compositions containing therapeutic agents, may be administered in any order, such as sequentially, in parallel, together, simultaneously, etc. In such a combination therapy, the amounts of various active substances may be different (different doses) or the same (same dose). Therefore, for non-limiting illustrative purposes, the compounds and additional therapeutic agents may be present in a fixed amount (dose) in a single dose unit (e.g., capsules, tablets, etc.). In some embodiments, any of the disclosed compounds or their pharmaceutically acceptable salts are administered orally, and additional therapeutic agents are further administered orally. When administered orally, the compounds and other pharmaceutical agents may be administered simultaneously (i.e., one after another in separate compositions) or sequentially.

[0162] In some embodiments, the disclosed compound or its pharmaceutically acceptable salt may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours prior to the therapeutic agent. In other embodiments, the disclosed compound or its pharmaceutically acceptable salt may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0163] In one embodiment, at least one compound is administered during the time when another therapeutic agent exerts its preventive or therapeutic effect, and vice versa.

[0164] In another embodiment, at least one compound and an additional therapeutic agent are administered at a dose typically used when these agents are used as a monotherapy. In another embodiment, the dose of at least one compound and the additional therapeutic agent is lower than the dose typically used when these agents are used as a monotherapy.

[0165] In some embodiments, an additional therapeutic agent is present in the pharmaceutical composition. In one embodiment, the composition is suitable for subcutaneous administration. In another embodiment, the composition is suitable for intramuscular administration. In yet another embodiment, the composition is suitable for oral administration. In still another embodiment, the composition is suitable for intravenous administration.

[0166] At least one compound and another therapeutic agent may act additively or synergistically. Synergistic combinations may allow for the use of lower doses of one or more agents and / or lower frequencies of administration of one or more agents in combination therapy. Lower doses or lower frequencies of administration of one or more agents may reduce the toxicity of the treatment without reducing its efficacy.

[0167] The dosage and administration regimen of other pharmaceutical agents used in the combination therapy of the present invention for the treatment or prevention of neurodegenerative diseases can be determined by the attending physician taking into account the dosage and administration regimen approved in the package insert; the subject's age, sex, and general health condition; and the type and severity of the neurodegenerative disease or its neurological symptoms. When administered in combination, the compounds and other pharmaceutical agents can be administered simultaneously (i.e., as the same composition or as separate compositions one after another) or sequentially. This is particularly useful when the components of the combination are given at different dosing schedules, for example, one component is administered once daily and another component is administered every six hours, or when the pharmaceutical compositions are different, for example, one is a tablet and the other is a capsule. Therefore, kits containing individual dosage forms are advantageous.

[0168] Abbreviations The abbreviations used herein have the meanings listed in the table below. Abbreviations not listed in the table below, unless otherwise expressly stated, shall have their conventional meanings as commonly used in the art.

[0169] General synthetic route The following reaction routes and examples illustrate methods that can be used to synthesize compounds of structural formula I as described in this invention. These reaction routes and examples are provided to illustrate the invention and should not be construed as limiting the invention in any way. Unless otherwise stated, all substituents are as defined above. Several strategies based on synthetic transformations known in the organic synthesis literature can be used to prepare compounds of structural formulas I and II.

[0170] The compounds disclosed herein can be prepared using suitable materials according to the procedures of the following examples. However, the compounds shown in the examples should not be construed as constituting the only class covered by this invention. The examples further illustrate the details of the preparation of the compounds of this disclosure. It will be readily understood by those skilled in the art that known variations of protecting groups and the conditions and treatments of the following preparation procedures can be used to prepare these compounds. It will also be understood that such chemical reagents can be readily prepared according to one of the many methods described in the literature, provided that the particular chemical reagent is not commercially available.

[0171] Route 1-1 Route 1-1 outlines some general synthetic pathways for chemical substances. In the first step of Route 1-1, R... 1 and R 2 The group is introduced from commercial starting material using a condensation reaction. In step two, R can be introduced via the Suzuki reaction. 3 R 4S and R 5S The introduction of the group was accomplished via palladium-catalyzed CN coupling.

[0172] Route 1-2 Route 1-2 outlines some general synthetic pathways for chemical substances. In the first step of Route 1-2, R is introduced via nickel-catalyzed CC coupling. 4S and R 5S Group.

[0173] Route 2-1 Route 2-1 outlines some general synthetic pathways for chemical substances. In the first step of Route 2-1, R... 1 and R 2 The group is introduced via an acid-catalyzed condensation reaction with a ketone ester, followed by a Pd-catalyzed CN coupling reaction to introduce R. 3S and R 4S Finally, palladium-catalyzed C-C bond formation introduces R... 3 .

[0174] Route 2-2 Route 2-2 outlines general synthetic pathways for some chemical substances. In the first step of Route 2-2, R... 3S and R 4S The group is introduced via nickel-catalyzed C / C bond formation, followed by Pd-catalyzed C / C coupling to introduce R. 3 .

[0175] Route 2-3 Route 2-3 outlines some general synthetic pathways for chemical substances. In the first step of Route 2-3, R is introduced via a palladium-catalyzed C / C bond formation reaction. 3 Finally, R is introduced through a metal-catalyzed CN or C-C bond formation reaction. 3S and R 4S .

[0176] Route 3-1 Route 3-1 outlines general synthetic pathways for some chemical substances. In the first step of Route 3-1, R... 1 and R 2 The group is introduced from commercial starting material using a condensation reaction. In step two, R can be introduced via the Suzuki reaction. 3 Finally, R is introduced through a metal-catalyzed CN or C-C bond formation reaction. 3S and R 4S .

[0177] Synthesis of intermediates Intermediate 1: (S and R)-2,2-difluoro-6-(2-methylpyridin-4-yl)morpholine Step 1: 1-(2-methylpyridin-4-yl)-2-nitroethanol TEA (23.01 mL, 165 mmol) was added to a solution of 2-methylisononial (10 g, 83 mmol) in nitromethane (106 mL, 1981 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 5 h. The reaction solution was filtered and concentrated under vacuum. The crude product was immediately purified by rapid silica gel chromatography (eluting with a 100% ethyl acetate gradient) to give 1-(2-methylpyridin-4-yl)-2-nitroethanol. MS (ESI) m / z: Calculated value C8H 11 N₂O₃[M+H] + 183.0, measured value: 183.2.1 H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 5.25 Hz, 1 H), 7.25 (s, 1 H), 7.17 (d, J = 5.01 Hz, 1 H), 5.46 (dd, J = 8.58, 4.05 Hz, 1H), 4.52 - 4.58 (m, 2H), 2.53 (s, 3H).

[0178] Step 2: 2-Amino-1-(2-methylpyridin-4-yl)ethanol Under N2, Pd-C (5.96 g, 5.60 mmol) was added to a solution of 1-(2-methylpyridin-4-yl)-2-nitroethanol-1-ol (10.2 g, 56.0 mmol) in THF (400 mL) / MeOH (50 mL) / AcOH (2 mL). The mixture was stirred at 30 °C for 30 h under H2 (30 psi). The reaction mixture was filtered, washed with THF / MeOH (200 mL x 3, V / V = 1 / 1), and concentrated under reduced pressure to give 2-amino-1-(2-methylpyridin-4-yl)ethanol-1-ol, which was used directly without purification. MS (ESI) m / z Calculated value C8H 13 N2O [M+H] + : 153.2, Measured value: 153.2. 1 H NMR (CDCl3, 400MHz): δ 8.25-8.39 (m, 1H), 7.13-7.19 (m, 1H), 7.10 (br d, J = 5.1 Hz, 1H), 4.77(br dd, J = 9.3, 2.6 Hz, 1H), 2.94-3.10 (m, 1H), 2.68-2.83 (m, 1H), 2.41-2.54(m, 3H).

[0179] Step 3: 2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethanol-1-ol A solution of 2-amino-1-(2-methylpyridin-4-yl)ethanol-1-ol (10 g, 46 mmol) and AcOH (0.1 mL) in MeOH (100 mL) was stirred for 0.5 h at 15 °C, followed by the addition of NaBH3(CN) (5.8 g, 92 mmol). The mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a 40% ethyl acetate / petroleum ether gradient) to give 2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethanol-1-ol.

[0180] MS (ESI) m / z Calculated value C 22 H 25 N2O [M+H] + 333.2, measured value [M+H] + :333.2. 1 H NMR (CDCl3, 400 MHz): δ 8.41 (d, J = 5.1 Hz, 1H), 7.28-7.41 (m, 10H), 7.04 (s, 1H), 6.97 (d, J = 5.2 Hz, 1H), 4.62 (dd, J = 10.2, 3.5 Hz, 1H), 3.91 (d, J = 13.5 Hz, 2H), 3.53 (d, J = 13.4 Hz, 2H), 2.66-2.72 (m, 1H), 2.58 (dd, J = 12.8, 10.3 Hz, 1H), 2.53 (s, 3H).

[0181] Step 4: 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid At 0 °C, NaH (1.81 g, 45.1 mmol) was added to a solution of 2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-1-ol (7.5 g, 22.6 mmol), TBAI (833 mg, 2.26 mmol), and sodium 2-chloro-2,2-difluoroacetate (4.47 g, 29.3 mmol) in THF (80 mL), and the resulting mixture was heated to 65 °C. The mixture was stirred at 65 °C for 3 days. The mixture was quenched with water (100 mL) and extracted with EtOAc (80 mL x 3). The organic layer was concentrated to give 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid. The aqueous layer was concentrated under reduced pressure to obtain the crude product 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid, which was used directly. MS (ESI) m / z Calculated value C 24 H 25 F2N2O3[M+H] + : 427.2, Measured value: 427.2.

[0182] Step 5: Methyl 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetate At 0 °C, a solution of 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid (7.5 g, 16.71 mmol) in DCM (90 mL) / MeOH (30 mL) was added with (trimethylsilyl)diazomethane (8.35 mL, 16.71 mmol), and the resulting mixture was stirred at 15 °C for 16 h under N2. The mixture was concentrated to obtain a residue, which was purified by rapid silica gel chromatography (eluent 30% ethyl acetate / petroleum ether gradient) to give methyl 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetate. MS (ESI) m / z Calculated value C 25 H 27 F2N2O3[M+H] + : 441.2, Measured value: 441.2. 1 H NMR (CDCl3, 400 MHz): δ 8.40-8.46 (m,1H), 7.27-7.32 (m, 4H), 7.22-7.27 (m, 6H), 6.86 (s, 2H), 5.18 (t, J= 6.3 Hz, 1H), 3.87 (s, 3H), 3.69-3.76 (m, 2H), 3.58-3.66 (m, 2H), 2.90-2.98 (m, 1H), 2.76-2.84 (m, 1H), 2.52 (s, 3H).

[0183] Step 6: 2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholin-3-one NIS (10.4 g, 46.3 mmol) was added to a solution of methyl 2-(2-(dibenzylamino)-1-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetate (3.4 g, 7.72 mmol) in DCM (80 mL) at 15 °C under N2. The resulting mixture was stirred at 40 °C for 20 h. The mixture was poured into water (100 mL) and extracted with DCM (60 mL x 3). The combined organic fractions were washed with saturated Na2SO3 (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by rapid silica gel chromatography (5% MeOH / DCM gradient eluent) to give 2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-3-one. MS (ESI) m / z Calculated value C 10 H 11 F2N2O2[M+H] + 229.1, measured value [M+H] + :229.1. 1 H NMR (CDCl3, 400 MHz): δ 8.54-8.59 (m, 1H), 7.22(s, 1H), 7.13 (br d, J = 4.6 Hz, 1H), 5.41 (dd, J = 10.2, 3.9 Hz, 1H), 3.57-3.75(m, 2H), 2.62 (s, 3H).

[0184] Step 7: (S and R)-2,2-difluoro-6-(2-methylpyridin-4-yl)morpholine Under N2 at 0 °C, BH3·DMS (0.776 mL, 7.76 mmol) was added to a solution of 2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-3-one (590 mg, 2.59 mmol) in THF (15 mL). The reaction mixture was stirred at 55 °C for 3 h. After cooling to 0 °C, 10 mL of MeOH was added dropwise, and the mixture was stirred at 55 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by rapid silica gel chromatography (eluent 5% MeOH / DCM gradient) to give (S and R)-2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin. MS (ESI) m / z Calculated value C 10 H 13 F2N2O [M+H] + 215.2, measured value [M+H] + :215.1. 1 H NMR (CDCl3, 400 MHz): δ 8.48-8.54 (m, 1H),7.16 (s, 1H), 7.06 (br d, J = 4.6 Hz, 1H), 5.09 (dd, J = 11.1, 2.7 Hz, 1H), 3.35(br d, J = 13.6 Hz, 1H), 3.13-3.21 (m, 1H), 2.98-3.10 (m, 1H), 2.69-2.80 (m,1H), 2.58 (s, 3H).

[0185] Intermediate 2: (S and R)-4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine Step 1: 3-(2-methylpyridin-4-yl)-4-oxoperpiperidine-1-carboxylic acid tert-butyl ester At 25 °C, tert-butyl 4-oxopiperidinium-1-carboxylate (18.5 g, 93 mmol), XPhos (2.77 g, 5.81 mmol), Pd(OAc)₂ (0.653 g, 2.91 mmol), and sodium tert-butoxide (16.8 g, 174 mmol) were added to a solution of 4-bromo-2-methylpyridine (10 g, 58.1 mmol) in THF (200 mL). The mixture was stirred at 45 °C for 16 h under N₂ protection. The solvent was removed under reduced pressure, and the residue was dissolved in water (200 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was repeatedly extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a 47% ethyl acetate / petroleum ether gradient) to give tert-butyl 3-(2-methylpyridin-4-yl)-4-oxopiperidin-1-carboxylic acid. MS (ESI) m / z Calculated value C 16 H 23 N₂O₃[M+H] + 291.2, measured value [M+H] + : 290.9.

[0186] Step 2: 4,4-Difluoro-3-(2-methylpyridin-4-yl)piperidine-1-carboxylic acid tert-butyl ester DAST (4.55 mL, 34.4 mmol) was added dropwise to a mixture of tert-butyl 3-(2-methylpyridin-4-yl)-4-oxopiperidin-1-carboxylic acid (1 g, 3.44 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was added dropwise to an aqueous solution of NaHCO3 in ice water (200 mL) and the pH was adjusted to ~9. The mixture was extracted with DCM (50 mL × 3). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by pre-HPLC (water (0.1% TFA) / MeCN) to give tert-butyl 4,4-difluoro-3-(2-methylpyridin-4-yl)piperidine-1-carboxylic acid. MS (ESI) m / z Calculated value C 16 H 23 F2N2O2[M+H] + 313.2, measured value [M+H] + 312.9.

[0187] Step 3: (S and R)-4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine A mixture of 100 mg (0.320 mmol) of 4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-carboxylic acid tert-butyl ester in HCl-dioxane (2 mL) was stirred for 1 h at 20 °C. The solvent was removed under reduced pressure to give the crude product (S and R)-4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine, which was used directly for the next step without post-treatment. MS (ESI) m / z Calculated value C 11 H 15 F2N2[M+H] + 213.0, measured value [M+H] + :212.9.

[0188] Intermediate 3: 4-Iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2 H -Pyran Step 1: 2-(tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-ol At 0 °C, a solution of tetrahydrofuran-3-carboxaldehyde (1.0 g, 9.99 mmol) and but-3-en-1-ol (0.504 g, 6.99 mmol) in DCM (13 mL) was added dropwise with TFA (5.94 mL, 80 mmol). The solution was slowly heated to 20 °C for 12 h. After completion, the reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with DCM (30 mL × 3). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–20% EtOAc / petroleum ether) to give 2-(tetrahydrofuran-3-yl)tetrahydro-2-yl... H -Pyran-4-ol.

[0189] Step 2: 4-Iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2 H -Pyran I₂ (1.77 g, 6.97 mmol) was added to a mixture of 2-(tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-ol (1.0 g, 5.81 mmol) and imidazole (0.514 g, 7.55 mmol), PPh₃ (1.83 g, 6.97 mmol) in DCM (25 mL) at 0 °C. The resulting mixture was gradually heated to 25 °C over 2 h. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (25 mL) and washed with water (10 mL x 3). The organic layer was separated, and the aqueous layer was repeatedly extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ESI) using 10% ethyl acetate / petroleum ether to give 4-iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2H-pyran. m / z Calculated value C9H 16 IO2[M+H] + 283.0, measured value [M+H] + 283.0.

[0190] Intermediate 4: 4-(4,4,5,5-tetraethyl-1,3,2-dioxacyclopentaborane-2-yl)-5,6-dihydro-2H-pyridine 2-anion Step 1: 6-O-3,6-dihydro-2H-pyran-4-yl ester of 4-methylbenzenesulfonic acid In a 50 mL round-bottom flask equipped with a stir bar, dihydro-2H-pyran-2,4(3H)-dione (3.00 g, 26.3 mmol), DCM (10.0 mL), and triethylamine (3.06 g, 4.21 mL, 30.2 mmol) were added. The mixture was cooled to 0 °C. p-Toluenesulfonyl chloride (5.51 g, 4.40 mL, 28.9 mmol) was added. After 30 min, the mixture was washed with water (10 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid chromatography (0-60% EtOAc in hexane) to give 6-oxo-3,6-dihydro-2H-pyran-4-yl ester of 4-methylbenzenesulfonic acid.

[0191] Step 2: 4-(4,4,5,5-Tetraethyl-1,3,2-dioxacyclopentaborane-2-yl)-5,6-dihydro-2H-pyran- 2-keto In a 500 mL round-bottom flask equipped with a stir bar, add 6-oxo-3,6-dihydro-2H-pyran-4-yl ester of 4-methylbenzenesulfonic acid (6.40 g, 23.9 mmol), Pd(dppf)Cl2 (995 mg, 1.36 mmol), potassium acetate (4.68 g, 47.7 mmol), and 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(1,3,2-dioxacycloborane) (13.1 g, 35.8 mmol). Purge the mixture with N2 and add degassed 1,4-dioxane (128 mL). Heat the mixture to 70 °C for 16 h. Cool the mixture to room temperature, filter, and concentrate under reduced pressure. The crude mixture was purified by rapid chromatography (0 to 55% ethyl acetate in hexane) to give 4-(4,4,5,5-tetraethyl-1,3,2-dioxaneborane-2-yl)-5,6-dihydro-2H-pyran-2-one.

[0192] Intermediate 5: Trifluoromethanesulfonic acid (S)-4-(9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazine) [1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester and trifluoromethanesulfonic acid (R)-4-(9-(2,4-difluorophenyl)- 2,3-Dimethyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester Step 1: 5-Bromo-3-(2,4-difluorophenyl)pyrazine-2-amine 3,5-Dibromopyrazin-2-amine (10.0 g, 39.5 mmol), difluorophenylboronic acid (6.24 g, 39.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.28 g, 1.98 mmol), and sodium carbonate (10.5 g, 98.9%) were added to a 500 mL round-bottom flask equipped with a stir bar. The flask was purged with N2, and then toluene (160 mL) and water (5.5 mL) were added. The mixture was stirred for 18 h. The aqueous layer was removed, the organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. Ethyl acetate (60 mL), DCM (60 mL), and hexane (30 mL) were added to the crude mixture. The mixture was stirred at room temperature and then filtered to collect 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine. The mother liquor was collected and concentrated under reduced pressure. To collect the second batch of product, ethyl acetate (20 mL), DCM (20 mL), and hexane (30 mL) were added. The mixture was stirred at room temperature and filtered to collect solid 5-bromo-3-(2,4-difluorophenyl)pyrazine-2-amine. MS (ESI, m / z ): Calculated value C 10 H7BrF2N3[M+H] + 285.9, measured value 285.9.

[0193] Step 2: 7-Bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one In a 40 mL vial equipped with a stir bar, 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine (2.30 g, 8.04 mmol), toluene (46.0 mL), and methanesulfonic acid (3.86 g, 40.2 mmol) were added. Ethyl 2-methyl-3-oxobutyrate (5.80 g, 5.69 mL, 40.2 mmol) was added, and the reaction was heated to 100 °C for 5 h. When SM was consumed, the reactants were cooled to room temperature, and the reaction mixture was poured into 10 mL of H₂O. The layers were separated, and the aqueous layer was extracted with 60 mL of ethyl acetate. The combined organic layers were washed with NaHCO₃, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude residue was dissolved in 20 mL of DCM, and then 20 mL of EA and 10 mL of hexane were added. The solution was filtered and washed with hexane to give 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one. MS (ESI, m / z ): Calculated value C 15 H 11 BrF₂N₃O [M+H] + 366.0, measured value 366.0.

[0194] Step 3: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-oxo-3,6-dihydro-2H-pyran-4-yl)- 4H-pyrazino[1,2-a]pyrimidin-4-one In a 40 mL vial equipped with a stir bar, 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (1.00 g, 2.46 mmol) and XPhos Pd G2 (193 mg, 246 μmol) were added. The mixture was purged with N2, and a solution of 4-(4,4,5,5-tetraethyl-1,3,2-dioxane-2-yl)-5,6-dihydro-2H-pyran-2-one (1.38 g, 4.92 mmol) in 1,4-dioxane (20.0 mL) was added. An aqueous solution of potassium carbonate (2.95 mL, 2.50 M, 7.37 mmol) was added, and the mixture was heated to 70 °C for 18 h. The reaction was cooled to room temperature and filtered. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The crude mixture was purified on silica gel (0-100% ethyl acetate in hexane) to give a crude solid. DCM (5 mL) and hexane (1 mL) were added, and the mixture was stirred for 1 h, then filtered. The solid was washed with hexane and then dried under vacuum by N2 purging to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-oxo-3,6-dihydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one. MS (ESI, m / z ): Calculated value C 20 H 16 F2N3O3[M+H] + 384.0, measured value 384.0.

[0195] Step 4: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazine [1,2-a]pyrimidin-4-one In a 20 mL vial equipped with a stir bar, copper(II) acetate monohydrate (39.3 mg, 197 μmol) and 1,2-bis(diphenylphosphine)benzene (17.56 mg, 39.3 μmol) were added. The mixture was purged with N2, and tert-butanol (564 μL, 5.90 mmol) and toluene (15.1 mL) were added. The mixture was stirred at room temperature for 20 min. PMHS (2.493 g, 2.479 mL, 9.83 mmol) was added. In a 40 mL vial equipped with a stir bar, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-oxo-3,6-dihydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one (754 mg, 1.97 mmol) was added, and the vial was purged with N2. Cu solution was added to the solution, and the mixture was heated to 50 °C overnight. The mixture was cooled to room temperature and water (10 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid chromatography (0-100% EtOAc in hexane) to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one. MS (ESI, m / z ): Calculated value C 20 H 18 F2N3O3[M+H] + 386.0, measured value 386.0.

[0196] Step 5: Trifluoromethanesulfonic acid (S)-4-(9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazine) [1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester and trifluoromethanesulfonic acid (R)-4-(9-(2,4-difluorophenyl)- 2,3-Dimethyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one (300 mg, 778 μmol) was added to a 40 mL vial equipped with a stir bar and purged with N2. THF (4.50 mL) was added and the mixture was cooled to -78 °C. LiHMDS (570.9 μL, 1.50 M in THF, 856 μmol) was added dropwise, and the mixture was stirred at -78 °C for 15 min. Tf2O (157 μL, 934 μmol) was added dropwise, and the mixture was stirred continuously at -78 °C for 15 min, then allowed to warm to room temperature. The mixture was quenched with 15% Na2CO3 aqueous solution and diluted with CH2Cl2. The mixture was filtered through a phase separator and concentrated under reduced pressure. The crude mixture was purified by rapid chromatography (0-100% EtOAc in hexane) to obtain 4-(9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester of trifluoromethanesulfonic acid. The final product was then subjected to chiral SFC separation. Column and specifications: Lux-3, 21x250 mm, 5 μm; UV wavelength: 215 nm; flow rate: 70 ml / min; modifier: 10% MeOH w / 0.1% NH4OH, to obtain Trifluoromethanesulfonic acid (S or R)-4-(9-(2,4-difluorophenyl)-2,3-dimethyl- 4-O-4H-pyrazino[1,2-a]pyrimidin-7-yl)-3,4-dihydro-2H-pyran-6-yl ester SFC peak 1 (required) and Trifluoride Methanesulfonic acid (R or S)-4-(9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-7- 3,4-dihydro-2H-pyran-6-yl ester SFC peak 2 (unnecessary). Analytical data matching for the two enantiomers. MS(ESI, m / z ): Calculated value C 21 H 17 F5N3O5S [M+H] + 518.1, measured value 518.1. 1 H NMR (300 MHz, DMSO-d6)δ 8.53 (s, 1H), 7.73 (td, J = 8.4, 6.7 Hz, 1H), 7.43 (td, J = 9.9, 2.5 Hz, 1H), 7.27 (td, J = 8.4, 2.6 Hz, 1H), 5.26 (d, J = 3.9 Hz, 1H), 4.43-4.24 (m, 2H), 4.01(q, J= 5.2 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 1H), 2.18 (s, 3H), 2.08 (d, J = 15.2Hz, 1H).

[0197] Intermediate 6: 7-((2R,4S)-2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorobenzene) 7-((2S,4R)-2-(1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one Step 1: 7-(2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-di Methyl-4H-pyrazino[1,2-a]pyrimidin-4-one 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one (60 mg, 0.103 mmol) was stirred in a mixture of TFA (1 mL) and DCM (0.200 mL). The mixture was stirred at 60 °C for 1 h. After stirring, the reaction mixture was quenched with an aqueous sodium bicarbonate solution (1 mL) and extracted with DCM (2 mL x 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by prep-TLC (silica gel, ethyl acetate / petroleum ether = 20 mL / 20 mL, v / v) yielded 7-(2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one.

[0198] Step 2: 7-((2R,4S)-2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorobenzene) 7-((2S,4R)-2-(1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one Through chiral-SFC (column DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 μm); conditions: CO2-EtOH (0.1% NH3H2O); start B35, end B35 gradient; time (min): 1; 100% B. Hold time 1; Flow rate (mL / min): 150) 7-(2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one was resolved to give (SFC peak 1): 7-((2R,4S or 2S,4R)-2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (t r= 1.777 min), and (SFC peak 2): 7-((2S,4R or 2R,4S)-2-(1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (t r = 2.118 min).

[0199] SFC Peak 1: MS (ESI) m / z Calculated value C 23 H 24 ClFN5O2[M+H] + : 454.1 / 456.1, measured value 454.1 / 456.1. 1 H NMR (400 MHz, CDCl3-d) δ ppm 8.59 (s, 1 H), 7.65 - 7.76 (m, 1 H),7.60 (t, J =7.87 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 7.23 - 7.26 (m, 1 H), 4.60 -4.67 (m, 1 H), 4.26 - 4.34 (m, 1 H), 3.76 - 3.86 (m, 1 H), 3.17 - 3.29 (m, 1H), 2.45 (s, 4H), 2.29 (s, 3H), 2.00 - 2.07 (m, 2H).

[0200] SFC Peak 2: MS (ESI) m / z Calculated value C 23 H 24 ClFN5O2[M+H] + : 454.1 / 456.1, measured value 454.1 / 456.1. 1 H NMR (400 MHz, CDCl3-d) δ ppm 8.58 (s, 1 H), 7.57 - 7.69 (m, 3 H), 7.28 - 7.33 (m, 1 H), 7.23 - 7.26 (m, 1 H), 4.62 (br d, J =11.21 Hz, 1 H), 4.28 (br d, J=11.44 Hz, 1 H), 3.76 - 3.87 (m, 1 H), 3.17 - 3.27 (m, 1 H), 2.45 (s, 3 H), 2.30 - 2.36 (m, 1 H), 2.29 (s, 3 H), 2.17 - 2.23 (m, 1 H), 2.01 - 2.07 (m, 2 H), 1.92 - 2.00 (m, 1 H).

[0201] Intermediate 7: 4-Methyl-N-(2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)ethyl)benzenesulfonamide Step 1: 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole NaH (4.08 g, 102 mmol, 60% W) was added to a mixture of 4-bromo-1H-pyrazole (10 g, 68.0 mmol) in THF (120 mL) at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was then treated with (2-(chloromethoxy)ethyl)trimethylsilane (14.4 mL, 82 mmol) at 0 °C. The resulting mixture was then subjected to a temperature range of 0–25 °C. o The mixture was stirred at C for 2 h. The reaction mixture was quenched with water (125 mL) and extracted with EtOAc (120 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-bromo-1-((2-(trimethylsilanealkyl)ethoxy)methyl)-1H-pyrazole. MS (ESI) m / z Calculated value C9H 17 BrN2OSi [M+H] + : 277.0 / 279.0, measured value 277.0 / 279.0.

[0202] Step 2: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl-1-one A mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (30 g, 108 mmol), 1,3-bis(diphenylphosphine)propane (4.46 g, 10.8 mmol), (butoxy)ethylene (70.0 mL, 541 mmol), palladium(II) acetate (1.21 g, 5.41 mmol), and K₂CO₃ (17.9 g, 130 mmol) in DMF (200 mL) and water (40 mL) was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (1000 mL x 3). The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a gradient of 60% ethyl acetate / petroleum ether) to give 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl-1-one. 1 H NMR (400 MHz, CDCl3-d) δ 8.05(s, 1H), 7.94 (s, 1H), 5.44 (s, 2H), 3.55-3.61 (m, 2H), 2.45 (s, 3H), 0.89-0.94 (m, 2H), 0.00 (s, 9H). MS(ESI) m / z Calculated value C 11 H 20 N₂O₂Si [M+H] + : 241.1, measured value 183.1.

[0203] Step 3: 2-Bromo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl-1-one A mixture of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)ethyl-1-one (2.00 g, 8.32 mmol), 2-pyrrolidone (1.41 g, 16.6 mmol), and pyrrolidone tribromide (5.42 g, 16.6 mmol) in THF (20 mL) was stirred at 70 °C for 1 h. The mixture was filtered, and diethylphosphonate (2.30 g, 16.6 mmol) and DIPEA (2.91 mL, 16.6 mmol) were added to the filtrate, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a gradient of 30% ethyl acetate / petroleum ether) to give 2-bromo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl-1-one. 1 H NMR (400 MHz, CDCl3-d) δ 8.17 (s, 1H), 8.02 (s, 1H), 5.47 (s, 2H), 4.20 (s, 2H), 3.59-3.64 (m, 2H), 0.91-0.96 (m, 2H), 0.00 (s, 9H). MS(ESI) m / z Calculated value C 11 H 19 BrN2O2Si [M+H] + 319.0 / 321.0, measured value [M+H-58] + :261.0 / 263.0.

[0204] Step 4: 4-Methyl-N-(2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- ethylbenzenesulfonamide Add benzaldehyde-p-toluenesulfonylhydrazone (0.945 g, 3.45 mmol) to a solution of 2-bromo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl-1-one (1 g, 3.13 mmol) and Cs₂CO₃ (1.12 g, 3.45 mmol) in acetonitrile (10 mL). Stir the mixture at 20 °C for 10 min. Quench the reaction mixture with water (20 mL) and extract with EtOAc (30 mL x 3). Wash the combined organic phases with brine (20 mL), dry with anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a 100% ethyl acetate gradient) to obtain 4-methyl-N-(2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl)benzenesulfonamide. 1 H NMR (400 MHz, CDCl3-d) δ 8.07 (s, 1H), 7.91 (s, 1H), 7.75-7.80 (m,2H), 7.30 (d, J = 7.99 Hz, 2H), 5.51-5.58 (m, 1H), 5.43 (s, 2H), 4.23 (d, J =4.65 Hz, 2H), 3.53-3.62 (m, 2H), 2.41 (s, 3H), 0.88-0.95 (m, 2H), 0.00 (s, 9H). MS(ESI) m / z Calculated value C 18 H 27 N3O4SSi [M+H] + 410.1, measured value [M+H-58] + :352.1.

[0205] Step 5: (S)-N-(2-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl) Ethyl)-4-methylbenzenesulfonamide Under a nitrogen atmosphere at 25 °C, BH3·S(CH3)2 (0.366 mL, 3.66 mmol) was added dropwise to a solution of (S)-(-)-2-methyl-cbs-oxazolborane (1015 mg, 3.66 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at 25 °C for 20 minutes. Then, 4-methyl-N-(2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)ethyl)benzenesulfonamide (500 mg, 1.22 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 4 h. The mixture was quenched with water (10 mL), extracted with DCM (20 mL x 3), washed with brine (20 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated to give crude (S)-N-(2-hydroxy-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl)-4-methylbenzenesulfonamide (ee% = 92.78%). MS (ESI) m / z Calculated value C 18 H 29 N3O4SSi [M+H] + : 412.2, measured value 412.1.

[0206] Step 6: (S)-4-p-Toluenesulfonyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)morpholine Triethylamine (0.456 mL, 3.28 mmol) was added to a solution of (S)-N-(2-hydroxy-2-(1-((2-(trimethylsilanealkyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl)-4-methylbenzenesulfonamide (450 mg, 1.09 mmol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (396 mg, 1.09 mmol) in DCM (5 mL). The mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a gradient of 40% ethyl acetate / petroleum ether) to give (S)-4-p-toluenesulfonyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholine. 1 H NMR (400 MHz, CDCl3-d) δ7.63 (d, J = 8.34 Hz, 2H), 7.51 (s, 1H), 7.47 (s, 1H), 7.34 (d,J = 7.99 Hz, 2H),5.37 (s, 2H), 4.58-4.66 (m, 1H), 3.94-4.01 (m, 1H), 3.75-3.85 (m, 1H), 3.66-3.72 (m, 1H), 3.49-3.58 (m, 3H), 2.53 (dt, J = 3.34, 11.27 Hz, 1H), 2.44 (s,3H), 2.38 (dd, J = 10.01, 11.44 Hz, 1H), 0.84-0.92 (m, 2H), 0.00 (s, 9H). MS(ESI) m / z Calculated value C 20 H 31 N3O4SSi [M+H] + : 438.2, measured value 438.2.

[0207] Step 7: (S)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholine Magnesium (117 mg, 4.80 mmol) was added to a solution of (S)-4-p-toluenesulfonyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholine (300 mg, 0.686 mmol) in MeOH (15 mL) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column (50% MeCN / water gradient eluent) to give (S)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholine. 1 H NMR (400 MHz, CDCl3-d) δ 9.71-10.14 (m, 2H), 7.59 (s,1H), 7.54 (s, 1H), 5.40 (s, 2H), 4.84-4.92 (m, 1H), 4.00-4.20 (m, 2H), 3.50-3.59 (m, 2H), 3.42 (d, J =12.40 Hz, 1H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.02-3.11 (m, 1H), 0.84-0.94 (m, 2H), 0.06 (s, 9H). MS(ESI) m / z Calculated value C 13 H 25 N3O2Si [M+H] +: 284.2, measured value 284.2.

[0208] Intermediate 8: (S)-3-(2-(1H-pyrazol-4-yl)morpholino)-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridine [3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one Step 1: (S)-1-(4-chloro-2-fluorophenyl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one A solution of 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one (1.3 g, 3.71 mmol) in dioxane (18.56 mL) was supplemented with (S)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholine (1.37 g, 4.83 mmol), Cs₂CO₃ (3.63 g, 11.1 mmol), and rac-BINAP Pd G₄ (0.747 g, 0.742 mmol). The resulting mixture was stirred at 80 °C for 12 h under N₂ protection. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed and dried over Na₂SO₄. The mixture was then filtered and concentrated. The residue was purified by rapid silica gel chromatography (eluting with a gradient of 0–50% ethyl acetate / petroleum ether) to give (S)-1-(4-chloro-2-fluorophenyl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholino)-8,9-dihydropyridino[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z Calculated value C 29 H 35 ClFN6O3Si [M+H] + : 597.2 / 599.2, measured value 597.1 / 599.2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.63 (d, J =8.34 Hz, 2 H), 7.53 - 7.57 (m, 1 H), 7.37 (s, 1 H),7.24 (br d, J =1.67 Hz, 1 H), 7.20 (dd, J =9.54, 1.91 Hz, 1 H), 5.42 (s, 2 H), 4.68 (dd, J =10.25, 2.50 Hz, 1 H), 4.39 (br d, J=12.28 Hz, 1 H), 4.12 - 4.20 (m,4 H), 3.84 - 3.91 (m, 1 H), 3.55 - 3.61 (m, 2 H), 3.15 - 3.22 (m, 1 H), 3.05- 3.13 (m, 3 H), 2.22 - 2.30 (m, 2 H), 0.89 - 0.95 (m, 2 H), -0.01 (s, 9 H).

[0209] Step 2: (S)-3-(2-(1H-pyrazol-4-yl)morpholino)-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridine [3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one A mixture of (S)-1-(4-chloro-2-fluorophenyl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one (1.7 g, 2.85 mmol) in TFA (4.17 mL) and DCM (20.8 mL) was stirred for 2 h at 60 °C. The reaction mixture was quenched with an aqueous sodium bicarbonate solution (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (30% MeCN / H2O, TFA-free) to give (S)-3-(2-(1H-pyrazol-4-yl)morpholino)-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z Calculated value C 23 H 21 ClFN6O2[M+H] + : 467.1 / 469.1, measured value 467.0 / 469.0. 1 HNMR (400 MHz, CDCl3) δ ppm 7.73 (s, 2 H), 7.52 - 7.57 (m, 1 H), 7.38 (s, 1H), 7.18 - 7.26 (m, 2 H), 4.73 (dd, J =10.13, 2.74 Hz, 1 H), 4.41 (br d, J =13.11Hz, 1 H), 4.17 (br d, J=7.27 Hz, 3 H), 3.86 - 3.93 (m, 1 H), 3.19 - 3.24 (m, 1H), 3.06 - 3.15 (m, 4 H), 2.23 - 2.29 (m, 2 H).

[0210] Intermediate 9: 3-chloro-1-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-8,9-dihydropyrido[3,4-d] Pyrrolo[1,2-a]pyrimidin-5(7H)-one Step 1: In a glove box, add 1,2-dibromoethane (3.29 µl, 0.038 mmol) to a suspension of magnesium (10.2 mg, 0.420 mmol) in THF (2 mL). Stir the suspension at 25 °C for 30 min. Add 1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (100 mg, 0.382 mmol) from THF (2 mL) dropwise to the suspension. Heat the resulting mixture to 75 °C and stir for 1 h. Add the resulting solution to another vial loaded with zinc chloride (0.210 mL, 0.420 mmol) in 2-methyltetrahydrofuran and stir at 25 °C for 1 h. Use the solution directly for the next step. Step 2: In a glove box, add bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.42 mg, 7.63 µmol) to a solution of 1,3-dichloro-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one (20.5 mg, 0.080 mmol) in THF (2 mL). Add the solution from Step 1 dropwise to the second solution. Stir the reaction at 45 °C for 1 h. Concentrate the mixture under vacuum to obtain a residue. Add water (5 mL). Extract the mixture with EtOAc (10 mL x 3). Wash the combined organic layers with brine (10 mL), dry with anhydrous Na2SO4, filter, and concentrate the filtrate. The residue was purified by Prep-HPLC (water (0.1% TFA)-ACN) to give 3-chloro-1-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z Calculated value C 16 H 14 ClF3N3O [M+H] + : 356.0 / 358.0, actual value 355.9.

[0211] Intermediate 10: 3-chloro-1-(4,4-difluorocyclohexyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine 5(7H)-one A solution of nickel(II) bromide ethylene glycol dimethyl ether complex (48.2 mg, 0.156 mmol) and 4,4'-di-tert-butyl-N-cyano-[2,2'-bipyridine]-6-formamidinium (52.4 mg, 0.156 mmol) in DMA (4 mL) was stirred for 1 h at 25 °C. Zinc (153 mg, 2.34 mmol), TBAI (288 mg, 0.781 mmol), 4-bromo-1,1-difluorocyclohexane (233 mg, 1.17 mmol), and 1,3-dichloro-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one (200 mg, 0.781 mmol) were then added, and the resulting mixture was stirred at 40 °C for 2 h. The mixture was cooled, quenched with water (10 mL), and extracted with EtOAc (5 mL x 3). The combined organic fractions were washed with brine (10 mL x 3), dried over Na₂SO₄, and filtered. The organic layer was concentrated under vacuum and purified by prep. HPLC (water (0.1% TFA)-ACN) to give 3-chloro-1-(4,4-difluorocyclohexyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z Calculated value C 16 H 17 ClF2N3O [M+H] + : 340.0 / 342.0, measured values ​​339.9 / 341.9.

[0212] The examples shown in Table I-1 below were prepared using appropriate initial raw materials according to a procedure similar to that of intermediate 10 described above.

[0213] Table I-1 Intermediate 12: 4,4,5,5-Tetraethyl-2-(6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)- 1,3,2-Dioxanepentylborane ring Step 1: Synthesis of 6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate At 0 °C, butyryl-1-ol (1.050 g, 14.98 mmol) was added dropwise to a solution of tetrahydrofuran-3-carboxaldehyde (1 g, 9.99 mmol) in DCM (20 mL) under N2 in a three-necked flask, followed by the dropwise addition of trifluoromethanesulfonic acid (2.396 mL, 30.0 mmol). The mixture was stirred at 25 °C for 16 h. After stirring, the mixture was quenched with saturated NaHCO3 aqueous solution (200 mL) and extracted with DCM (100 mL x 3). The combined organic fractions were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography (eluent 0-40% ethyl acetate / petroleum gradient) to give the desired product 6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate. MS (ESI) m / z Calculated value C 10 H 14 F3O5S [M+H] + : 303.1, measured value 303.1.

[0214] Step 2: 4,4,5,5-Tetraethyl-2-(6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-1,3, Synthesis of 2-dioxacyclopentaborane To a solution of 6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (1 g, 3.31 mmol) in 1,4-dioxane (8 ml), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.242 g, 0.331 mmol), 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(1,3,2-dioxacyclopentaborane) (1.454 g, 3.97 mmol), and potassium acetate (0.649 g, 6.62 mmol) were added. The mixture was then purged three times with N2 and stirred at 80 °C for 1 h. After completion, the mixture was filtered and the filtrate was concentrated. The crude product was purified by rapid silica gel chromatography (eluent gradient of 0-40% EtOAc / petroleum ether) to obtain the desired product, 4,4,5,5-tetraethyl-2-(6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxane. MS (ESI) m / z Calculated value C 19 H 34 BO4[M+H] + : 337.1, measured value 337.1.

[0215] Intermediate 13: (cis)-2-methyl-6-(2-methylpyridin-4-yl)morpholine Step 1: Synthesis of 4-(1-ethoxyvinyl)-2-methylpyridine 4-Bromo-2-methylpyridine (2.4 kg, 13.95 mol) was stirred in 1,4-dioxane (26.4 L), and tributyl(1-ethoxyvinyl)tin (5.78 kg, 16.00 mol, 1.15 equiv) was added to obtain a mixture, which was degassed with argon, followed by the addition of tetrakis(triphenylphosphine)palladium (800.0 g, 692.28 mmol, 0.05 equiv). The resulting mixture was heated to 110 °C for 6 hours, then filtered and washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure to obtain crude 4-(1-ethoxyvinyl)-2-methylpyridine. The crude feedstock was used directly in the next step without purification.

[0216] Step 2: Synthesis of 1-(2-methylpyridin-4-yl)ethyl-1-one At 0 °C, HCl (26 L, 2 V, 6 M) was added to 13 kg of crude 4-(1-ethoxyvinyl)-2-methylpyridine under stirring, and the resulting solution was stirred at 25 °C for 2 h. The reaction mixture was quenched with sodium bicarbonate solution and extracted 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 product was purified by rapid silica gel chromatography (eluent 0-30% ethyl acetate / petroleum ether) to give the desired product 1-(2-methylpyridin-4-yl)ethyl-1-one.

[0217] Step 3: Synthesis of 2-bromo-1-(2-methylpyridin-4-yl)ethyl-1-one A mixture of 1-(2-methylpyridin-4-yl)ethyl-1-one (450 g, 3.33 mol), DIPEA (538 g, 4.16 mol), and TMSOTf (888 g, 3.99 mol) in DCM (4.5 L, 10 V) was stirred for 0.5 h at 0–5 °C, followed by the addition of NBS (711 g, 3.99 mol), and stirring was continued at 0–5 °C for another 0.5 h. The reaction was quenched using an aqueous solution of NaHCO3 (8%, 10 V, 4.5 L). The separated organic layer was concentrated under vacuum and used directly in the next step.

[0218] Step 4: Synthesis of 2-(benzyl(2-hydroxypropyl)amino)-1-(2-methylpyridin-4-yl)ethyl-1-one At 10 °C, a mixture of 2-bromo-1-(2-methylpyridin-4-yl)ethyl-1-one hydrobromide (4) (712 g, 3.33 mol), 1-(benzylamino)prop-2-ol (550 g, 3.33 mol), and N,N-diisopropylethylamine (645 g, 4.99 mol) in THF (4500 mL) was stirred for 1 h. After completion, the reaction mixture was quenched with water (4500 mL) and treated with EtOAc (2000 mL). 3) Extraction. The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography (eluting with a gradient of 100% ethyl acetate / petroleum ether) to obtain the desired product 2-(benzyl(2-hydroxypropyl)amino)-1-(2-methylpyridin-4-yl)ethyl-1-one.

[0219] Step 5: Synthesis of 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2H-1,4-oxazine At 0 °C, TMSOTf (1.25 kg, 5.63 mol) was added to 2-(benzyl(2-hydroxypropyl)amino)-1-(2-methylpyridin-4-yl)ethyl-1-one (5) (560 g, 1.88 mol) and DCE (11.2 L, 20 V). The resulting mixture was heated to 90 °C for 16 h, then quenched with sodium bicarbonate (8%, 5.6 L, 10 V) and extracted with 10% methanol in dichloromethane. The organic layer was washed with brine (10%, 5.6 L, 10 V), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2H-1,4-oxazine, which was used directly for the next step without further purification.

[0220] Step 6: Synthesis of (cis)-2-methyl-6-(2-methylpyridin-4-yl)morpholine Pd(OH)₂ (240 g, 40% wt) and ammonium formate (675 g, 10.7 mol) were added to a solution of 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2H-1,4-oxazine (6) (600 g, 2.14 mol) in MeOH (6 L). The mixture was stirred at 85 °C for 1 h under a N₂ atmosphere. After completion, the reaction was filtered and the filtrate was concentrated under vacuum and then purified by prep HPLC (MeCN / water, using 0.04% NH₃H₂O + 10 mM NH₄HCO₃) to give the desired product (cis)-2-methyl-6-(2-methylpyridin-4-yl)morpholine. MS (ESI) m / z Calculated value C 11 H 17 IN2O [M+H] + 193, measured value 193.

[0221] Intermediate 14: 4-(4-bromotetrahydro-2-) H -pyran-2-yl)-1-cyclopropyl-1 H -Pyrazole Three identical-scale reactions were performed in parallel. DCM (12 mL) was added to a 40 mL vial containing 1-cyclopropylpyrazole-4-carboxaldehyde (1.00 g, 7.3 mmol) and but-3-en-1-ol (583 mg, 0.70 mL, 8.08 mmol). The reaction was cooled to 0 °C. o C, then add HBr (3.9 mL, 33% wt, 22.0 mmol) from acetic acid. Stir the reaction mixture at room temperature for 0.5 h. Combine the three reaction mixtures, dilute with DCM (20 mL) and carefully quench with saturated NaHCO3 aqueous solution until the solution becomes weakly alkaline. Then extract the mixture with 2 x 50 mL DCM. Combine and concentrate the organic extracts. Purify the crude residue by column chromatography on silica gel using elution with 10% to 25% to 40% EtOAc in hexane to give the desired product 4-(4-bromotetrahydro-2-oxo ... H -pyran-2-yl)-1-cyclopropyl-1 H -Pyrazole. The product was purified by SFC under the following conditions to obtain isomers of peak 1 at 3.76 min, peak 2 at 4.36 min, and peak 3 at 5.03 min (a mixture of the two isomers). The mixture of peaks 3 was further separated by SFC.

[0222] SFC Conditions (Sepiatec 3): Column and Specifications: IG, 21x250 mm, 5 μm; UV Wavelength: 215 nm; Flow Rate: 90 ml / min; Modifier: 20% MeOH w / 0.1% NH4OH; Outlet Pressure: 100 bar; Sample Volume: 5800 mg; Diluent: 1:1 MeOH / CH3CN; Dilution Volume: 40 ml; Injection Volume: 0.3 ml; Instrument: Sepiatec 3 The mixture sample of the above peak 3 was separated by a second SFC run to produce one of the isomers of peak 3-1 at 2.7 min and intermediate 14 (peak 3-2) at 3.3 min.

[0223] SFC Conditions 2: Column and Specifications: IB-N, 21x250 mm, 5 μm; UV Wavelength: 215 nm; Flow Rate: 70 ml / min; Modifier: 15% MeOH w / 0.1% NH4OH; Outlet Pressure: 100 bar; Instrument: Sepiatec 2 The examples shown in Table I-2 below were prepared using appropriate initial raw materials according to a procedure similar to that described in I-14 above.

[0224] Table I-2 Intermediate 21: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxane) Pentylborane-2-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one To 250 mL of RBF, add 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (10.0 g, 27.3 mmol), potassium acetate (8.04 g, 81.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (10.4 g, 40.9 mmol), and Pd(dppf)Cl2 (1.99 g, 2.731 mmol). Add 1,4-dioxane (200 mL) and purge the reaction mixture with nitrogen bubbling for 5 min. Equip the mixture with a reflux condenser and maintain it under N2. Heat the reaction to 80 °C while stirring at 900 rpm. The mixture was cooled and filtered through activated carbon (G60) and a diatomaceous earth pad. It was washed with dioxane by displacement until no more colored filtrate was observed leaving the filter. The filtrate was concentrated to dryness by rotary evaporation. The solid was dissolved as a suspension in diethyl ether (50 mL) and heptane (100 mL) and concentrated to dryness. This process was repeated using 100 mL of heptane. Next, 550 mL of a 1:1 MeCN / water solution was added, and the mixture was stirred at room temperature (top-mounted stirrer; 385 rpm) and aged overnight with stirring. The mixture was filtered, and the wet filter cake was washed with heptane to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z C 15 H 13 B2N3O3[M+H]+, calculated value 332.1, measured value 332.1.

[0225] Intermediate 22: 4-Methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-ylidene)benzenesulfonylhydrazine Step 1: (6-Methylpyrimidin-4-yl)methanol Under N2 protection, at 0 °C, NaBH4 (6.89 g, 182 mmol) was added to a mixture of ethyl 6-methylpyrimidin-4-carboxylate (25.0 g, 150 mmol) in EtOH (300 mL). The resulting mixture was stirred at 20 °C for 1 h. At 0 °C, 2N HCl-MeOH (200 mL) was added to the mixture to adjust the pH to ~4. The mixture was stirred at 20 °C for 0.5 h. The resulting mixture was concentrated under vacuum to obtain the residue. The residue was purified by rapid silica gel chromatography (20% MeCN / H2O) to give (6-methylpyrimidin-4-yl)methanol. MS (ESI) m / z Calculated value: C6H9N2O [M+H] + : 125.1, measured value 125.0.

[0226] Step 2: 6-Methylpyrimidine-4-carboxaldehyde A mixture of (6-methylpyrimidin-4-yl)methanol (11.0 g, 89 mmol) and IBX (49.6 g, 177 mmol) in a DCE (100 mL) was stirred for 2 h at 80 °C. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give crude 6-methylpyrimidin-4-carboxaldehyde, which required no further purification. MS (ESI) m / z Calculated value: C6H7N2O [M+H] + : 123.0, measured value 123.0.

[0227] Step 3: 2-(6-methylpyrimidin-4-yl)-2,3-dihydro-4H-pyran-4-one ZnCl2 (2.04 mL, 4.09 mmol) was added to a solution of 6-methylpyrimidin-4-carboxaldehyde (5 g, 40.9 mmol) and 1-methoxy-3-trimethylsiloxy-1,3-butadiene (7.05 g, 40.9 mmol) in toluene (50 mL) at 25 °C. The mixture was stirred at 80 °C for 12 h. TFA (3.15 mL, 40.9 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography (60% ethyl acetate / petroleum ether gradient eluent) to give 2-(6-methylpyrimidin-4-yl)-2,3-dihydro-4H-pyran-4-one. MS (ESI) m / z Calculated value C 10 H 11 N₂O₂[M+H] + : 191.1, measured value 191.0.

[0228] Step 4: 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one Under a nitrogen atmosphere, Pd-C (0.492 g, 0.463 mmol) was added to a solution of 2-(6-methylpyrimidin-4-yl)-2,3-dihydro-4H-pyran-4-one (2.2 g, 11.5 mmol) in EtOAc (30 mL). The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 25 °C under H2 (pressure: 15 psi) for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one, which was used directly for the next step. MS (ESI) m / z Calculated value C 10 H 13 N₂O₂[M+H] + : 193.1, measured value 193.0.

[0229] Step 5: 4-Methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-ylidene)benzenesulfonylhydrazine 4-Methylbenzenesulfonylhydrazine (1.93 g, 10.40 mmol) was added to a solution of 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one (2.0 g, 10.4 mmol) in MeOH (40 mL), and the resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (60% ethyl acetate / petroleum ether gradient eluent) to give 4-methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-yl)benzenesulfonylhydrazine. MS (ESI) m / z Calculated value C 17 H 21 N4O3S [M+H] + 361.1, measured value 361.0.

[0230] Intermediate 23: 2-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-4,4,5, 5-Tetraethyl-1,3,2-dioxacyclopentaborane Step 1: 5,5-Dimethyltetrahydrofuran-3-carboxaldehyde A solution of (5,5-dimethyltetrahydrofuran-3-yl)methanol (3.0 g, 23.0 mmol) and 1-hydroxy-1-oxo-115-benzo[d][1,2]iodocyclopentan-3(1H)-one (12.9 g, 46.1 mmol) in EtOAc (115 mL) was stirred for 3 h at 70 °C. The reaction solution was filtered and concentrated under vacuum to obtain crude 5,5-dimethyltetrahydrofuran-3-carboxaldehyde, which was used directly in the next step without further purification.

[0231] Step 2: 4-Bromo-6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran HBr (6.42 ml, 39.0 mmol) was added to a solution of 5,5-dimethyltetrahydrofuran-3-carboxaldehyde (2.5 g, 19.5 mmol) and but-3-yn-1-ol (2.05 g, 29.3 mmol) in DCM (20 ml) for 10 min at 0 °C. The resulting mixture was stirred for 3 h. The reaction mixture was quenched with water (10 mL) and the pH was adjusted to >8 with saturated NaHCO3, followed by extraction with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep. HPLC (conditions MeCN / water (0.1% TFA)) to give 4-bromo-6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran. MS (ESI) m / z Calculated value C 11 H 17 BrO2[M+H] + : 261.0 / 263.0, measured value 261.2 / 263.2.

[0232] Step 3: 2-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- Tetraethyl-1,3,2-dioxacyclopentaborane Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44.8 mg, 0.061 mmol), 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bis(1,3,2-dioxane) (224 mg, 0.613 mmol), and potassium acetate (120 mg, 1.225 mmol) to a solution of 4-bromo-6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran (160 mg, 0.613 mmol), and potassium acetate (120 mg, 1.225 mmol) to the solution of 1,4-dioxane (5 ml). The mixture was then purged three times with N2 and stirred at 80 °C for 2 h. The mixture was filtered and concentrated. The residue was purified by rapid silica gel chromatography to give 2-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetraethyl-1,3,2-dioxacyclopentaborane. MS (ESI) m / z Calculated value C 21 H 37 BO4[M+H] + : 365.2, measured value 364.9.

[0233] Intermediate 24: 3-Methyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)- 1,3-Dihydro-10H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one Step 1: Methyl 5-methyl-4-oxotetrahydrofuran-3-carboxylic acid ester A suspension of NaH (16.1 g, 403 mmol) in THF (500 mL) was stirred for 10 min, followed by dropwise addition of a solution of methyl 2-hydroxypropionate (40.0 g, 384 mmol) in THF (100 mL) over 15 min. DMSO (100 mL) was added, and a solution of methyl acrylate (40.6 g, 471 mmol) in DMSO (100 mL) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. The pH was adjusted to approximately 3–4 using 2 M HCl. The reaction mixture was quenched with H₂O (250 mL) and extracted with EtOAc (250 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a gradient of [0-30]% ethyl acetate / petroleum ether) to obtain methyl 5-methyl-4-oxotetrahydrofuran-3-carboxylic acid. 1 H NMR (400 MHz, CDCl3) δ ppm 4.47 - 4.56 (m, 1 H), 4.23 - 4.30 (m, 1 H), 3.84 - 3.97 (m, 1 H), 3.75 (s, 3 H), 3.48 -3.55 (m, 1 H), 1.31 (dd, J =6.85, 1.01 Hz, 3 H).

[0234] Step 2: 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2,5-dihydrofuran-3-carboxylic acid methyl ester A mixture of 5-bromo-3-(methylthio)pyrazin-2-amine (1.00 g, 4.54 mmol), AcOH (0.520 ml, 9.09 mmol), MgSO4 (5.47 g, 45.4 mmol), and methyl 5-methyl-4-oxotetrahydrofuran-3-carboxylic acid (0.719 g, 4.54 mmol) in MeOH (10 ml) was stirred for 16 h at 80 °C. The reaction was performed ten times in parallel. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with [0–30]% ethyl acetate / EtOH and diethyl ether gradient) to give methyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2,5-dihydrofuran-3-carboxylic acid. MS (ESI) m / z: Calculated value C 12 H 15 BrN3O3S [M+H] + : 327.9 / 329.9, measured value 327.8 / 329.8.

[0235] Step 3: 7-Bromo-3-methyl-5-(methylthio)-1,3-dihydro-10H-furano[3,4-d]pyrazino[1,2-a] Pyrimidin-10-one A mixture of methyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2,5-dihydrofuran-3-carboxylic acid (2.8 g, 7.77 mmol) in diphenyl ether (25 ml) was stirred for 4 h in a sand bath at 280 °C. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:3) to give 7-bromo-3-methyl-5-(methylthio)-1,3-dihydro-10H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z Calculated value C 11 H 11 BrN3O2S [M+H] + : 327.9 / 329.9, measured value 327.9 / 329.9. 1 H NMR (400 MHz, CDCl3) δ ppm 8.62 (s, 1 H), 5.25 - 5.30 (m, 1 H), 5.10 - 5.22 (m, 2 H), 2.62 (s, 3 H), 1.57 (d, J =6.56 Hz, 3 H).

[0236] Step 4: 3-Methyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-1,3- Dihydro-10H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one In a glove box, at 25 °C, a mixture of NiCl2-DME (26.8 mg, 0.122 mmol) and pyridine-2-formamidin hydrochloride (19.2 mg, 0.122 mmol) in DMA (5 ml) was stirred for 0.5 h. Then, zinc (159 mg, 2.438 mmol), tetrabutylammonium iodide (338 mg, 0.914 mmol), 7-bromo-3-methyl-5-(methylthio)-1,3-dihydro-10H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one (200 mg, 0.609 mmol), and 4-(4-bromotetrahydro-2H-pyrano-2-yl)-2-methylpyridine (203 mg, 0.792 mmol) were added. The mixture was then heated at 40 °C. oStirred at C for 2 h. Three reactions were performed in parallel. The reaction mixture was quenched with an aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography (eluting with a gradient of 0-40% ethyl acetate / petroleum ether) to give 3-methyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-1,3-dihydro-10H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z Calculated value C 22 H 24 N4O3S [M+H] + : 425.1, measured value 425.2.

[0237] Intermediate 25: 2,4-Dichloro-7,8-dihydropyrimidino[4,5-f]indazine-10(6H)-one Step 1: Methyl 5-iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate Iodine (2.69 g, 10.5 mmol) and periodic acid (7.24 g, 31.7 mmol) were added to a solution of orotate (9.0 g, 52.9 mmol) in MeOH (100 mL), and the resulting mixture was stirred at 70 °C for 16 h. The reaction solution was filtered and concentrated under vacuum, then washed with water and filtered to obtain crude methyl 5-iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, which was used directly for the next step without further purification. MS (ESI) m / z Calculated value: C6H5IN2O4[M+H] + : 296.9, measured value 296.7.

[0238] Step 2: Methyl 5-iodo-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid Methyl 5-iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid was slowly added to a solution of 5-iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ester (13 g, 43.9 mmol) and Na₂CO₃ (13.0 g, 123 mmol) in DMF (100 mL), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was treated with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic fractions were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (eluent 25% ethyl acetate / petroleum ether gradient) to give methyl 5-iodo-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ester. MS (ESI) m / z Calculated value C 22 H 21 IN₂O₆[M+H] + : 537.0, measured value 536.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.25 - 7.25(m, 1 H), 7.25 (d, J =8.58 Hz, 1 H), 7.16 (d, J =8.70 Hz, 2 H), 6.89 (t, J =8.76Hz, 4 H), 4.99 (s, 2 H), 4.90 (s, 2 H), 3.78 - 3.83 (m, 3 H), 3.73 (d, J =4.29Hz, 6 H).

[0239] Step 3: 5-(5-((tert-Butoxycarbonyl)amino)pent-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6- Methyl dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate TEA (5.20 mL, 37.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.31 g, 1.86 mmol), copper(I) iodide (0.710 g, 3.73 mmol), and tert-butyl pentan-4-yn-1-ylcarbamate (4.10 g, 22.3 mmol) were added to a solution of methyl 5-iodo-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carboxylic acid (93 mL). The resulting mixture was stirred at 80 °C for 12 h under nitrogen protection. The reaction solution was filtered and concentrated under vacuum, then purified by rapid silica gel chromatography (eluting with a gradient of 0-35% ethyl acetate / petroleum ether) to give methyl 5-(5-((tert-butoxycarbonyl)amino)pent-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid. MS (ESI) m / z Calculated value C 32 H 37 N3O8[M+H] + : 592.2, measured value 592.2.

[0240] Step 4: 5-(5-aminopent-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6- Tetrahydropyrimidine-4-carboxylic acid methyl ester A solution of methyl 5-(5-((tert-butoxycarbonyl)amino)pentan-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (5.50 g, 9.30 mmol) in MeOH (50 ml) / hydrochloric acid, 37% (5.00 ml) was stirred for 6 h at 25 °C. The reaction solution was filtered and concentrated under vacuum to give crude methyl 5-(5-aminopentan-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, which was used directly for the next step without further purification. MS (ESI) m / z Calculated value C 27 H 29 N3O6[M+H] + : 492.2, measured value 492.1.

[0241] Step 5: 1,3-bis(4-methoxybenzyl)-1,6,7,8-tetrahydropyrimidino[4,5-f]indazine-2,4,10(3H)- Triketones Cs₂CO₃ (11.93 g, 36.6 mmol) was added to a solution of methyl 5-(5-aminopent-1-yn-1-yl)-1,3-bis(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carboxylic acid (4.5 g, 9.15 mmol) in DMF (45.8 mL), and the resulting mixture was stirred at 80 °C for 6 h. The reaction solution was filtered and concentrated under vacuum. The mixture was purified by reverse-phase column chromatography (60% MeCN / H₂O, TFA modifier) ​​to give 1,3-bis(4-methoxybenzyl)-1,6,7,8-tetrahydropyrimidino[4,5-f]indazine-2,4,10(3H)-trione. MS (ESI) m / z Calculated value C 26 H 25 N3O5[M+H] + : 460.1, measured value 460.0.

[0242] Step 6: 1,6,7,8-Tetrahydropyrimido[4,5-f]indazine-2,4,10(3H)-trione Trifluoromethanesulfonic acid (1.79 mg, 0.012 mmol) was added to a solution of 1,3-bis(4-methoxybenzyl)-1,6,7,8-tetrahydropyrimido[4,5-f]indazine-2,4,10(3H)-trione (550 mg, 1.19 mmol) in TFA (2 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was purified by reverse-phase column chromatography (80% MeCN / H2O) to give 1,6,7,8-tetrahydropyrimido[4,5-f]indazine-2,4,10(3H)-trione. MS (ESI) m / z Calculated value C 10 H9N3O3[M+H] + : 220.0, measured value 220.0.

[0243] Step 7: 2,4-Dichloro-7,8-dihydropyrimidino[4,5-f]indazine-10(6H)-one At 0 °C, DIPEA (0.359 mL, 2.05 mmol) and POCl3 (1.14 mL, 12.2 mmol) were added to a solution of 1,6,7,8-tetrahydropyrimidino[4,5-f]indazine-2,4,10(3H)-trione (450 mg, 2.05 mmol) in MeCN (10 mL), and the mixture was stirred at 25 °C for 15 min. The resulting mixture was then stirred at 100 °C for 2 h. Lithium chloride (174 mg, 4.11 mmol) was then added, and the mixture was stirred at 100 °C for 2 h. The mixture was quenched with saturated NaHCO3 aqueous solution (8 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a 100% ethyl acetate gradient) to give 2,4-dichloro-7,8-dihydropyrimidino[4,5-f]indazine-10(6H)-one. MS (ESI) m / z Calculated value C 10 H7Cl2N3O [M+H] + : 256.0, measured value 255.9. 1 H NMR (400 MHz, CDCl3) δ ppm 6.67 (s, 1H), 4.28 - 4.33 (m, 2 H), 3.24 (td, J =7.72, 1.25 Hz, 2 H), 2.31 (quin, J =7.48Hz, 2 H).

[0244] Synthesis of example compounds Example 1-1: ( S )-1-(4-chloro-2-fluorophenyl)-3-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-8,9-dihydropyridine and [3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Step 1: 1,3-Dichloro-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone A suspension of 3-amino-2,6-dichloroisonicotinic acid (500 mg, 2.415 mmol) and pyrrolidone-2-one (226 mg, 2.66 mmol) was prepared by adding toluene (5 mL). Then, POCl3 (1.351 mL, 14.49 mmol) was slowly added. The reaction was then placed under nitrogen and stirred for 15 min. The reaction mixture was then stirred at 90 °C for 2 h under nitrogen. After LCMS showed the reaction was complete, the reaction mixture was slowly transferred to a flask containing 50 mL of saturated sodium hydroxide. The mixture was extracted with EtOAc (30 mL × 3). The organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by rapid silica gel chromatography (0-100% hexane: EtOAc eluent) to provide 1,3-dichloro-8,9-dihydropyridinol[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z C 10 H8Cl2N3O [M+H] + Calculated value: 255.9, measured value: 256.0.

[0245] Step 2: 3-Chloro-1-(4-Chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5 (7 H )-ketone Add 1,3-dichloro-8,9-dihydropyridine[3,4-] to the vial d ]pyrrolo[1,2-a]pyrimidine-5(7 H The reaction mixture consisted of 1,4-dioxane (0.95 g, 3.7 mmol), (4-chloro-2-fluorophenyl)boronic acid (0.65 g, 3.7 mmol), potassium carbonate (1.5 g, 11 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.30 g, 0.37 mmol) in combination with dichloromethane. 1,4-Dioxane (13 mL) and water (1.3 mL) were then added, and the reaction mixture was purged with nitrogen for 15 min. The reaction was then heated to 40 °C for 2 h, followed by cooling to room temperature and concentration. The residue was dissolved in 5 mL of water and 5 mL of DCM. The organic layer was passed through a phase separator, the aqueous layer was washed with DCM (3 x 5 mL), and the combined organic layers were concentrated. The crude residue was purified by rapid silica gel chromatography (0-100% EtOAc / hexane) to provide 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridino[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z C 16 H 11 Cl2FN3O [M+H]+ Calculated value: 350.0, measured value: 350.0.

[0246] Step 3: ( S )-1-(4-chloro-2-fluorophenyl)-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8,9-di Hydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Add RuPhos Pd G3 (8.55 mg, 10.2 μmol), potassium phosphate (65.1 mg, 307 μmol), and 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridino[3,4-] to a vial. d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-keto (35.8 mg, 102 μmol) and ( S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine (34.2 mg, 204 μmol). Then 1,4-dioxane (2.04 mL) was added, the solution was purged with nitrogen for 15 min, and the reaction was then carried out at 65 °C. o Heating at C for 2 h. The reaction was filtered and concentrated, and then the crude substance was purified by rapid silica gel chromatography (0-100% EtOAc / hexane gradient), which provides ( S )-1-(4-chloro-2-fluorophenyl)-3-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone.

[0247] MS (ESI) m / z C 24 H 23 ClFN6O2[M+H] + Calculated value: 481.1, measured value: 481.0. 1 H NMR (499 MHz, DMSO) δ 7.74 (s, 1H), 7.58 – 7.48 (m, 2H), 7.46 (s, 1H), 7.39 (dd, J = 8.2, 2.0Hz, 1H), 7.36 (s, 1H), 4.56 (dd, J = 10.4, 2.6 Hz, 1H), 4.29 (d, J = 11.7 Hz, 1H), 4.13 (d, J= 12.5 Hz, 1H), 4.06 – 3.98 (m, 3H), 3.81 (s, 3H), 3.75 – 3.66(m, 1H), 3.01 (td, J = 12.5, 3.5 Hz, 1H), 2.98 – 2.87 (m, 3H), 2.13 (p, J = 7.7Hz, 2H).

[0248] Examples 1-2 and 1-3: 1-(4-chloro-2-fluorophenyl)-3-[(2 R 4 S )-2-(2-methylpyridin-4-yl)oxacyclohexane-4-yl]-8,9- Dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone and 1-(4-chloro-2-fluorophenyl)-3-[(2 S 4 R )-2- (2-Methylpyridin-4-yl)oxacyclohexane-4-yl]-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5 (7 H )-ketone At 20 °C, 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridino[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-keto (20 mg, 0.057 mmol), 4-(4-bromotetrahydro-2-) H A mixture of pyran-2-yl)-2-methylpyridine (29.3 mg, 0.114 mmol), nickel(II) glycol dimethyl ether complex (1.255 mg, 5.71 µmol), zinc (7.47 mg, 0.114 mmol), sodium iodide (2.140 mg, 0.014 mmol), and pyridine-2-methylamidine hydrochloride (0.900 mg, 5.71 µmol) in DMA (5 ml) was added to TFA (0.440 µl, 5.71 µmol), and the mixture was stirred at 60 °C for 16 h under N2 atmosphere. LCMS showed that the reaction was complete. After filtration and concentration, the mixture was purified by pre-HPLC (water / MeCN, containing TFA modifier) ​​to obtain rac- 1-(4-chloro-2-fluorophenyl)-3-((2 R 4 S and 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketones. Separation of 1-(4-chloro-2-fluorophenyl)-3-(2-(2-methylpyridin-4-yl)tetrahydro-2- ketones by chiral SFC. H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone (35 mg, 0.071 mmol) was obtained by lyophilization to give 1-(4-chloro-2-fluorophenyl)-3-((2-)-ketone (35 mg, 0.071 mmol) and lyophilized ... S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-keto (Rt = 1.104 min, ee > 99.99%) 1-2,1-(4-chloro-2-fluorophenyl)-3-((2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone (Rt = 2.021 min, ee > 99.99%) 1-3.

[0249] Example 1-2-Peak 1: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone: 1 H NMR (CDCl3- d ,400 MHz) δ = 8.79 (d, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.68 - 7.65 (m, 1H), 7.64- 7.61 (m, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.23 (dd, J =1.8, 9.4 Hz, 1H), 4.72 (br d, J = 11.2 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.23 (t, J=7.3 Hz, 2H), 3.93 - 3.79 (m, 1H), 3.45 - 3.35 (m, 1H), 3.15 (t, J = 8.0 Hz,2H), 2.85 (s, 3H), 2.43 - 2.37 (m, 1H), 2.34 - 2.26 (m, 2H), 2.15 - 2.06 (m,2H), 1.85 - 1.73 (m, 1H). MS(ESI) m / z: Calculated value C 27 H 24 ClFN4O2 + [M+H] + 490.9, measured value [M+H] + 491.1 Example 1-3-Peak 2: 1-(4-chloro-2-fluorophenyl)-3-((2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone: 1 H NMR (CDCl3- d ,400 MHz) δ = 8.70 (d, J = 6.0 Hz, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 7.55 (br d, J = 5.7 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.14 (dd, J =1.8, 9.5 Hz, 1H), 4.63 (br d, J = 10.0 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.14 (t, J =7.3 Hz, 2H), 3.80 - 3.71 (m, 1H), 3.35 - 3.29 (m, 1H), 3.06 (t, J = 7.9 Hz,2H), 2.77 (s, 3H), 2.30 (br d, J = 13.5 Hz, 1H), 2.21 (td, J= 7.6, 14.9 Hz, 2H), 2.05 - 1.97 (m, 2H), 1.76 - 1.64 (m, 1H). MS(ESI) m / z Calculated value C 27 H 24 ClFN4O2 + [M+H]+: 490.9, measured value [M+H] + 491.1 The examples shown in Table 1-1 below were prepared using suitable initial raw materials according to a procedure similar to that outlined in Examples 1-1 to 1-3 above.

[0250] Table 1-1: Examples 1-4 to 1-23 Example 24-24: ( R )-1-(4-chloro-2-fluorophenyl)-3-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)-8,9-dihydropyridine [3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Step 1: ( S )-1-(4-chloro-2-fluorophenyl)-3-(3-hydroxypyrrolidone-1-yl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Add (to a 20 mL vial) S )-Pyrrolidine-3-ol, HCl (123 mg, 1.00 mmol), 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H A solution of 1,4-dioxane (350 mg, 1.00 mmol), RuPhos G3 (20.9 mg, 25.0 μmol), and cesium carbonate (716 mg, 2.20 mmol) was prepared in anhydrous 1,4-dioxane (10 mL). The mixture was purged with bubbling N2 for 5 min, sealed, and heated to 80 °C for 5 h. The mixture was cooled, filtered, concentrated, and loaded onto a silica gel column for purification (50-100% EtOAc in hexane). The fractions were collected and concentrated to obtain ( S )-1-(4-chloro-2-fluorophenyl)-3-(3-hydroxypyrrolidone-1-yl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / zCalculated value C 20 H 19 ClFN4O2[M+H] + 401.0, measured value [M+H] + :401.0.

[0251] Step 2: ( R )-1-(4-chloro-2-fluorophenyl)-3-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)-8,9-dihydro Pyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Add the solution dissolved in anhydrous THF (582 μL) to a 2-dram vial. S )-1-(4-chloro-2-fluorophenyl)-3-(3-hydroxypyrrolidone-1-yl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone (14.0 mg, 34.9 μmol), triphenylphosphine (18.3 mg, 69.9 μmol), and pyridin-4-ol (4.15 mg, 43.7 μmol). 200 μL of DCM was added to improve dissolution. Finally, DIAD (13.6 μL, 69.9 μmol) was added in a single addition at room temperature, and the resulting mixture was stirred for 3 h. The solvent was evaporated and dissolved in MeOH, filtered, and purified by reverse-phase reaction: (MeCN / water, containing 0.1% TFA modifier) ​​to obtain ( R )-1-(4-chloro-2-fluorophenyl)-3-(3-(pyridin-4-yloxy)pyrrolidine-1-yl)-8,9-dihydropyrido[3,4- d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z Calculated value C 25 H 22 ClFN5O2[M+H] + 478.1, measured value [M+H] + :478.1. 1 H NMR (499 MHz, DMSO) δ 8.68 (d, J = 6.8 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H), 7.56 – 7.47 (m, 3H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 5.55 (s, 1H), 4.10 (d, J = 7.5 Hz, 1H), 4.07 –4.01 (m, 2H), 3.92 (dd,J = 12.5, 4.2 Hz, 1H), 3.76 (dd, J = 19.2, 10.7 Hz, 2H), 3.60 (d, J = 7.1 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 2.13 (dt, J = 15.1, 7.9 Hz, 2H).

[0252] Examples 1-25 and 1-26: ( R or S )-3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8, 9-Dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone and ( S or R )-3-(4,4-difluoro-3-(2-methylpyridine) (Pyridine-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-] d ]pyrrolo[1,2-a]pyrimidine-5 (7 H )-ketone Step 1: 3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8,9- Dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone To 3-chloro-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H A solution of 4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine (60 mg, 0.283 mmol), Cs₂CO₃ (234 mg, 0.719 mmol), and rac-BINAP Pd G₄ (18.09 mg, 0.018 mmol) in dioxane (3 mL) was added, and the resulting mixture was stirred at 100 °C for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in water (20 mL). The aqueous layer was repeatedly extracted with EtOAc (20 mL × 3), and the combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-MeCN) to give 3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone. The compound was resolved by chiral SFC [DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); conditions: CO2-EtOH (0.1% NH3·H2O)] to give 1–25 (SFC peak 1): ( S or R)-3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone and 1-26 (SFC peak 2): ( R or S )-3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-1-yl)-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone.

[0253] Ex 1-25 (SFC peak 1): MS (ESI) m / z: calculated value C 27 H 24 F4N5O [M+H] + 510.2, measured value [M+H] + :510.2. 1 H NMR (400MHz, CDCl3)δ = 8.48 (d, J = 3.6 Hz, 1H), 7.61 - 7.54 (m, 1H),7.45 (s, 1H), 7.16 (s, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.99 (dt, J = 1.9, 8.2 Hz, 1H), 6.92 (dt, J = 2.4, 9.5 Hz, 1H), 4.62 - 4.53 (m, 2H), 4.18 (t, J = 7.2 Hz, 2H), 3.52 (t, J = 12.6 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.24 - 3.12 (m, 1H), 3.09(t, J = 7.9 Hz, 2H), 2.58 (s, 3H), 2.28 - 2.24 (m, 2H), 2.22 - 1.99 (m, 2H).

[0254] Ex 1-26 (SFC Peak 2): MS (ESI) m / z Calculated value C 27 H 24 F4N5O [M+H] + 510.2, measured value [M+H] + :510.2.1 H NMR (400MHz, CDCl3)δ = 8.55 - 8.41 (m, 1H), 7.61 - 7.54 (m, 1H), 7.45(s, 1H), 7.17 (s, 1H), 7.12 (d, J = 4.6 Hz, 1H), 6.99 (dt, J = 2.1, 8.3 Hz, 1H), 6.92 (dt, J = 2.3, 9.5 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.18 (t, J = 7.3 Hz, 2H), 3.52 (t, J = 12.5 Hz, 1H), 3.45 - 3.36 (m, 1H), 3.23 - 3.12 (m, 1H), 3.09 (t, J =7.9 Hz, 2H), 2.58 (s, 3H), 2.28 - 2.24 (m, 2H), 2.22 - 1.99 (m, 2H).

[0255] Examples 1-27, 1-28, 1-29 and 1-30: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H - pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone, 1-(4-chloro-2-fluorophenyl)- 3-((2 S 4 R or 2 R 4 S )-2-(( R or S )-Tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyridine [3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone, 1-(4-chloro-2-fluorophenyl)-3-((2 R 4 S or 2 S 4 R )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5 (7 H )-ketone and 1-(4-chloro-2-fluorophenyl)-3-((2 R 4 S or 2 S 4 R )-2-(( R or S )-Tetrahydrofuran-3-yl)tetrahydro-2 H - pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone.

[0256] Step 1: 1-(4-chloro-2-fluorophenyl)-3-(2-(tetrahydrofuran-3-yl)tetrahydro-2-yl) H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Add 3-chloro-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) to a vial containing 4-bromo-2-(tetrahydrofuran-3-yl)tetrahydro-2H-pyran (101 mg, 428 μmol) in DMA (3.57 mL). HThe reaction mixture was prepared by purging N2 for 15 min with 10.5 mg of 2,6-bis(formamidinium) dihydrochloride (13.5 mg, 57.1 μmol) and nickel(II) chloride DME adduct (12.5 mg, 57.1 μmol) and 10.7 mg of sodium iodide (10.7 mg, 71.4 μmol), zinc powder (74.7 mg, 1.14 mmol), pyridine-2,6-bis(formamidinium) dihydrochloride (13.5 mg, 57.1 μmol), and then heating at 60 °C for 1 h with N2. The reaction mixture was quenched with water (10 mL) and extracted with EtOAC (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase prep-HPLC (MeCN / water, containing 0.1% NH3OH modifier) ​​to obtain 1-(4-chloro-2-fluorophenyl)-3-(2-(tetrahydrofuran-3-yl)tetrahydro-2-yl) as a mixture of isomers. H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z Calculated value C 25 H 26 ClFN3O3[M+H] + 470.2, measured value [M+H] + 470.2.

[0257] Isomers were separated by chiral SFC using a chiral IH column (21 x 250 mm, 5 μm); modifier: 20% MeOHw / 0.1% NH4OH, to obtain SFC peak 1-27: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone, 1-28 SFC peak 2: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7H )-ketone, 1-29SFC peak 3: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone, 1-30 SFC peak 4: 1-(4-chloro-2-fluorophenyl)-3-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone.

[0258] Ex 1-27, SFC peak 1: MS (ESI) m / z Calculated value C 25 H 26 ClFN3O3[M+H] + 470.2, measured value [M+H] + 470.2. 1 H NMR (499 MHz, DMSO) δ 7.91 (s, 1H), 7.60 – 7.53 (m, 2H), 7.44 (dd, J =8.3, 2.0 Hz, 1H), 4.12 – 4.06 (m, 2H), 4.02 (dd, J = 11.3, 3.3 Hz, 1H), 3.77(t, J = 8.0 Hz, 1H), 3.71 (td, J = 8.2, 4.4 Hz, 1H), 3.63 – 3.48 (m, 3H), 3.18(t, J = 11.9 Hz, 1H), 3.03 (t, J = 8.0 Hz, 2H), 2.27 – 2.18 (m, 1H), 2.15 (d, J=7.2 Hz, 2H), 2.04 – 2.00 (m, 2H), 1.91 – 1.84 (m, 1H), 1.81 – 1.73 (m, 1H), 1.61 – 1.38 (m, 3H).

[0259] Ex 1-28, SFC peak 2: MS (ESI) m / z Calculated value C 25 H 26 ClFN3O3[M+H] + 470.2, measured value [M+H] + 470.2. 1H NMR (499 MHz, DMSO) δ 7.91 (s, 1H), 7.56 (s, 2H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 4.12 – 3.99 (m, 2H), 3.75 – 3.66 (m, 2H), 3.61 (q, J = 7.5 Hz,1H), 3.57 – 3.50 (m, 1H), 3.43 (dd, J = 15.9, 8.4 Hz, 2H), 3.21 – 3.12 (m,1H), 3.03 (t, J = 7.9 Hz, 2H), 2.34 – 2.21 (m, 1H), 2.16 (p, J = 7.9 Hz, 2H), 1.97 – 1.69 (m, 2H), 1.51 (q, J = 12.2 Hz, 2H), 1.42 – 1.31 (m, 3H).

[0260] Ex 1-29, SFC peak 3: MS (ESI) m / z Calculated value C 25 H 26 ClFN3O3[M+H] + 470.2, measured value [M+H] + 470.2. 1 H NMR (499 MHz, DMSO) δ 7.91 (s, 1H), 7.60 – 7.53 (m, 2H), 7.44 (dd, J =8.3, 2.0 Hz, 1H), 4.12 – 4.06 (m, 2H), 4.02 (dd, J = 11.3, 3.3 Hz, 1H), 3.77(t, J = 8.0 Hz, 1H), 3.71 (td, J= 8.2, 4.4 Hz, 1H), 3.63 – 3.48 (m, 3H), 3.18(t, J = 11.9 Hz, 1H), 3.03 (t, J = 8.0 Hz, 2H), 2.27 – 2.18 (m, 1H), 2.15 (d, J =7.2 Hz, 2H), 2.04 – 2.00 (m, 2H), 1.91 – 1.84 (m, 1H), 1.81 – 1.73 (m, 1H), 1.61 – 1.38 (m, 3H).

[0261] Ex 1-30, SFC peak 4: MS (ESI) m / z Calculated value C 25 H 26 ClFN3O3[M+H] + 470.2, measured value [M+H] + 470.2. 1 H NMR (499 MHz, DMSO) δ 7.91 (s, 1H), 7.56 (s, 2H), 7.44 (dd, J = 8.3,2.0 Hz, 1H), 4.12 – 3.99 (m, 2H), 3.75 – 3.66 (m, 2H), 3.61 (q, J = 7.5 Hz,1H), 3.57 – 3.50 (m, 1H), 3.43 (dd, J = 15.9, 8.4 Hz, 2H), 3.21 – 3.12 (m, 1H), 3.03 (t, J = 7.9 Hz, 2H), 2.34 – 2.21 (m, 1H), 2.16 (p, J = 7.9 Hz, 2H), 1.97 –1.69 (m, 2H), 1.51 (q, J = 12.2 Hz, 2H), 1.42 – 1.31 (m, 3H).

[0262] The examples shown in Table 1-2 below were prepared using suitable initial raw materials, following a procedure similar to that outlined in Examples 1-1 to 1-3 and 1-23 to 1-30 above.

[0263] Table 1-2: Examples 1-31 to 1-57 Examples 1-58: 1-(4-chloro-2-fluorophenyl)-3-((2 S )-2-(1-(( R and S )-2,2-Difluorocyclopropyl)-1 H -pyrazole-4-yl) Morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone Fill the small bottle with ( S )-3-(2-(1 H -pyrazol-4-yl)morpholino)-1-(4-chloro-2-fluorophenyl)-8,9-dihydropyridino[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-ketone (10.0 mg, 21.4 μmol), 2-bromo-1,1-difluorocyclopropane (5.3 μL, 64.25 μmol), and cesium carbonate (20.9 mg, 64.2 μmol). DMF (428 μL) was added, and the reaction was stirred and heated to 80°C. o The reaction was carried out at C for 16 h. The reaction was cooled, filtered, and purified by reverse-phase reaction (MeCN / H2O+NH4OH) to provide 1-(4-chloro-2-fluorophenyl)-3-((2 S )-2-(1-(( R and S )-2,2-Difluorocyclopropyl)-1 H -pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z Calculated value C 26 H 23 ClF3N6O2[M+H] + 543.1, measured value 543.1. 1 H NMR (499 MHz, DMSO) δ 7.97 (s, 1H), 7.61 (s, 1H), 7.58 – 7.48 (m, 2H), 7.41 – 7.33 (m, 2H), 4.59 (d, J = 10.4 Hz, 1H), 4.56 –4.46 (m, 1H), 4.32 (d, J = 12.3 Hz, 1H), 4.15 (s, 1H), 4.04 (q, J= 6.9 Hz, 3H), 3.78 – 3.64 (m, 1H), 3.01 (s, 1H), 2.96 (t, J = 7.9 Hz, 3H), 2.35 – 2.25 (m,1H), 2.19 – 2.07 (m, 2H).

[0264] Examples 1-59: 7-(( S )-2-(1-Cyclopropyl-1 H -pyrazol-4-yl)morpholino)-5-(2,4-difluorophenyl)-6-fluoro-2,3-di Hydropyrrolo[2,1-b]quinazoline-9(1) H )-ketone Step 1: Methyl 2-amino-3,5-dibromo-4-fluorobenzoate NBS (51.3 g, 288 mmol) was added to a solution of methyl 2-amino-4-fluorobenzoate (19.5 g, 115 mmol) in anhydrous DMF (389 mL) at 0 °C. The resulting mixture was stirred at 0–25 °C for 2 h. The mixture was concentrated under reduced pressure. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography ([0–30]% ethyl acetate / petroleum ether gradient eluent) to give methyl 2-amino-3,5-dibromo-4-fluorobenzoate. MS (ESI) m / z Calculated value: C8H7Br2FNO2[M+H] + : 325.8 / 327.8, measured value 325.9 / 327.9. 1 H NMR (400 MHz, CDCl3) δ ppm 8.05 (d, J =7.63 Hz, 1 H), 3.87 (s, 3 H).

[0265] Step 2: 2-Amino-3,5-dibromo-4-fluorobenzoic acid A solution of methyl 2-amino-3,5-dibromo-4-fluorobenzoate (10 g, 30.6 mmol) and lithium hydroxide hydrate (5.13 g, 122 mmol) in THF (50 mL) and water (50.0 mL) was stirred at 40 °C for 16 h. The pH was adjusted to approximately 3–4 with 2 M HCl. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-amino-3,5-dibromo-4-fluorobenzoic acid, which was not further purified. MS (ESI) m / zCalculated value: C7H5Br2FNO2[M+H] + 311.9 / 313.9 / 315.9, measured values ​​312.0 / 314.1 / 316.0.

[0266] Step 3: 5,7-Dibromo-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1 H )-ketone At 0 °C, POCl3 (7.15 mL, 77 mmol) was added to a solution of 2-amino-3,5-dibromo-4-fluorobenzoic acid (8.0 g, 25.6 mmol) in toluene (100 mL), and the mixture was stirred for 20 min. Then, pyrrolidone-2-one (4.35 g, 51.1 mmol) was added, and the resulting mixture was stirred at 80 °C under N2 for 16 h. The reaction solution was concentrated under vacuum. The mixture was treated with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic fractions were concentrated under reduced pressure. Then, 3 mL of EtOAc was added and the mixture was stirred for 30 min. The mixture was filtered, and the solid was concentrated under reduced pressure to give crude 5,7-dibromo-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1 H )-ketones, which were not further purified. MS (ESI) m / z Calculated value C 11 H7Br2FN2O [M+H] + 360.9 / 362.9 / 364.9, measured values ​​are 360.9 / 362.9 / 364.9.

[0267] Step 4: ( S )-5-bromo-7-(2-(1-cyclopropyl-1 H -pyrazol-4-yl)morpholino)-6-fluoro-2,3-dihydropyrrole [2,1-b]quinazoline-9(1) H )-ketone To 5,7-dibromo-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1 H A solution of 300 mg (0.829 mmol) of ketone in dioxane (10 mL) was added. S )-2-(1-Cyclopropyl-1 H -pyrazol-4-yl)morpholine (320 mg, 1.65 mmol), Cs2CO3 (810 mg, 2.486 mmol), rac-BINAP Pd G4 (83 mg, 0.083 mmol) and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography ([0-30]% ethyl acetate / petroleum ether gradient eluent) to give ( S)-5-bromo-7-(2-(1-cyclopropyl-1 H -pyrazol-4-yl)morpholino)-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolino-9(1 H )-Ketone. MS (ESI) m / z Calculated value C 21 H 22 BrFN5O2[M+H] + 474.0 / 476.0, measured values ​​474.1 / 476.1.

[0268] Step 5: 7-(( S )-2-(1-Cyclopropyl-1 H -pyrazol-4-yl)morpholino)-5-(2,4-difluorophenyl)-6-fluoro- 2,3-Dihydropyrrolo[2,1-b]quinazoline-9(1 H )-ketone Will( S )-5-bromo-7-(2-(1-cyclopropyl-1 H -pyrazol-4-yl)morpholino)-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolino-9(1 H A mixture of 2,4-difluorophenyl)boronic acid (14.9 mg, 0.095 mmol), Pd(PPh3)4 (7.31 mg, 6.32 µmol), and Na2CO3 (20.1 mg, 0.190 mmol) in dioxane (1 mL) and water (0.333 mL) was degassed and backfilled with N2 (x3). The mixture was heated to 60 °C. o C was maintained for 16 h. After cooling to room temperature, the reaction mixture was poured into water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN) to obtain 7-(( S )-2-(1-Cyclopropyl-1 H -pyrazol-4-yl)morpholino)-5-(2,4-difluorophenyl)-6-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolino-9(1 H )-Ketone. MS (ESI) m / z Calculated value C 27 H 25 F3N5O2[M+H] + 507.0, measured value 507.1. 1 H NMR (400 MHz, CDCl3) δ ppm 7.83 - 7.87 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.31 -7.39 (m, 1 H), 6.92 - 7.04 (m, 2 H), 4.76 (d,J =8.20 Hz, 1 H), 4.16 - 4.22 (m,2 H), 4.06 - 4.13 (m, 1 H), 3.94 - 4.04 (m, 1 H), 3.49 - 3.62 (m, 2 H), 3.35- 3.46 (m, 1 H), 2.94 - 3.15 (m, 4 H), 2.20 - 2.29 (m, 2 H), 1.08 - 1.16 (m, 2 H), 0.98 - 1.06 (m, 2 H).

[0269] Examples 1-60: 1-(4-chloro-2-fluorophenyl)-8-cyclopropyl-3-( S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-8,9- Dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone Step 1: 3-Chloro-1-(4-Chloro-2-fluorophenyl)-8-cyclopropyl-8,9-dihydropyridino[3,4-d]pyrrolo[1, 2-a]pyrimidine-5(7 H )-ketone Synthesis by library preparation: A solution of POCl3 (240 μmol, 4.00 eq.) in 1 mL toluene was added to a microwave-safe vial containing a monomeric lactam (180 μmol, 3.00 eq.). Then, a solution of the core 3-amino-6-chloro-2-(4-chloro-2-fluorophenyl)isonicotinic acid (60.0 μmol, 1.00 eq.) in 1 mL toluene was added. The mixture was stirred in a microwave at 100 °C for 2 h. The mixture was concentrated, and the residue was purified by preparative TLC to obtain a pure intermediate, which was used in the next step without further purification.

[0270] Step 2: 1-(4-chloro-2-fluorophenyl)-8-cyclopropyl-3-(( S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine 8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7) H )-ketone Towards( S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine, 3-chloro-1-(4-chloro-2-fluorophenyl)-8-cyclopropyl-8,9-dihydropyridino[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H A solution of 1-(4-chloro-2-fluorophenyl)-8-cyclopropyl-3-( S )-2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[1,2-a]pyrimidine-5(7 H )-Ketone. MS (ESI) m / z Calculated value C 26 H 27 ClFN6O2[M+H] + 509.2, measured value 509.2.

[0271] The examples shown in Tables 1-3 below were prepared using suitable initial raw materials according to procedures similar to those outlined in Examples 1-1 to 1-3, 1-23 to 1-30, and 1-58 to 1-60 above.

[0272] Table 1-3: Examples 1-61 to 1-259 Example 2-1 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2 S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine-4- [Base]-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: PPA (5 mL) was added to a solution of 5-bromo-3-(methylthio)pyrazin-2-amine (500 mg, 2.272 mmol) and ethyl 2-methyl-3-oxobutyrate (1638 mg, 11.36 mmol) at 20 °C. The resulting mixture was stirred at 100 °C for 1 h. LCMS showed the reaction was complete. The mixture was added to water (100 mL). The pH was adjusted to 7 by gradually adding solid NaHCO3. The reaction mixture was extracted with EtOAc (100 mL x 3). The organic phase was concentrated to 50 mL, filtered, and the filter cake was dried. The crude product was used for the next step without purification.

[0273] Step 2: To crude 7-bromo-2,3-dimethyl-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (800 mg, 2.67 mmol) in dioxane (16 mL) was added. S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine (560 mg, 3.35 mmol), Cs2CO3 (2605 mg, 8.00 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (273 mg, 0.533 mmol) were added, and the resulting mixture was stirred at 60 °C for 1 h. LCMS showed that the initial starting material was consumed and the desired compound was found. The mixture was added to water (10 mL) and treated with EtOAc (20 mL). 3) Extraction. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (0-100% EtOAc / petroleum ether gradient eluent @ 30 mL / min) to obtain ( S )-2,3-dimethyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z Calculated value C 18 H 23 N6O2S + [M+H] + 387.1, measured value [M+H] + 386.9 Step 3: In the glove box, to ( S )-2,3-dimethyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (400 mg, 1.035 mmol) in THF (8 mL) was supplemented with copper(I) thiophene-2-carboxylate (592 mg, 3.10 mmol), Pd(Ph3P)4 (120 mg, 0.103 mmol), and (4-chloro-2-fluorophenyl)boronic acid (180 mg, 1.035 mmol). The reaction was heated to 60 °C and stirred for 1 h. The mixture was cooled to room temperature, dissolved in DCM (10 mL), and filtered. The filtrate was washed with saturated NaHCO3 solution. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the resulting crude product was purified by preparative HPLC (water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN) to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0274] MS (ESI) m / z Calculated value C 23 H 23 ClFN6O2 + [M+H] + 469.2, measured value [M+H] + :469.1. 1H NMR (CDCl3-d, 400 MHz) δ 8.10 (s, 1H), 7.65 (t, 1H, J = 7.9 Hz), 7.56 (s, 1H), 7.46(s, 1H), 7.32 (d, 1H, J = 1.8 Hz), 7.26 (dd, 1H, J = 1.8, 9.8 Hz), 4.72 (dd, 1H, J = 2.7, 10.3 Hz), 4.1-4.2 (m, 2H), 3.9-4.0 (m, 1H), 3.93 (s, 3H), 3.91 (s,1H), 3.1-3.2 (m, 1H), 3.0-3.1 (m, 1H), 2.45 (s, 3H), 2.30 (s, 3H) Examples 2-2, 2-3 & 2-4: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyr AN-4-base)-4 H -Pyrazino[1,2-a]pyrimidin-4-one, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 S 4 R )-2- (2-Methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorobenzene) 2,3-dimethyl-7-((2) S 4 S and 2 R 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -pyr Azino[1,2-a]pyrimidin-4-one Step 1: At 20 °C, 7-bromo-2,3-dimethyl-9-(methylthio)-4 H 4-(4-bromotetrahydro-2-oxazino[1,2-a]pyrimidin-4-one (220 mg, 0.733 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (16.10 mg, 0.073 mmol), zinc (144 mg, 2.199 mmol), TBAI (271 mg, 0.733 mmol), and benzamide hydrochloride (23.10 mg, 0.147 mmol) were added to a mixture of DMA (3 mL) and 4-(4-bromotetrahydro-2-oxazino[1,2-a]pyrimidin-4-one (220 mg, 0.733 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (16.10 mg, 0.073 mmol), zinc (144 mg, 2.199 mmol), TBAI (271 mg, 0.733 mmol), and benzamide hydrochloride (23.10 mg, 0.147 mmol) in DMA (3 mL). H 2,3-Dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2-pyridine (225 mg, 0.879 mmol) was mixed and stirred at 60 °C for 16 h under N2 atmosphere. LCMS showed that the reaction was complete. After filtration and concentration, the mixture was purified by pre-HPLC (water / MeCN, with TFA modifier) ​​to give a mixture of four diastereomers of 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2-pyridine. H -pyran-4-yl)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 21 H 24 N4O2S+ Calculated value [M+H] + 396.5, measured value [M+H] + 396.9 Step 2: In the glove box, add 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2- H -pyran-4-yl)-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (60 mg, 0.151 mmol) in THF (1.5 mL) was supplemented with (4-chloro-2-fluorophenyl)boronic acid (39.6 mg, 0.227 mmol), Pd(PPh3)4 (5.25 mg, 4.54 µmol), and CuTC (86.3 mg, 0.453 mmol). The reaction mixture was heated to 60 °C and stirred for 1 h. The reaction mixture was then poured into water (10 mL) and treated with EtOAc (15 mL). 3) Extraction. The organic layer was dried over anhydrous Na₂SO₄. After filtration and concentration, the crude product was purified by preparative HPLC (water / MeCN, using TFA modifier) ​​to obtain a mixture of four diastereomers of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(-2-(2-methylpyridin-4-yl)tetrahydro-2 ... H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. Via SFC (column: Chiralcel OD-3 150) 4.6 mm ID, 3 μm, mobile phase: 40% methanol (0.05% DEA) in CO2, flow rate: 2.5 mL / min, column temperature: 35 ℃, ABPR: 1500 psi) to separate substances to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R 4 R and 2 S 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -pyrazino[1,2-a]pyrimidin-4-one (Rt. = 2.522 and 2.814), 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H-pyrazino[1,2-a]pyrimidin-4-one (Rt. = 3.137) and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one (Rt. = 3.752).

[0275] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R 4 R and 2 S 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one: 1 H NMR (CDCl3- d , 400 MHz) δ = 8.70(d, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.52(d, J = 5.8 Hz, 1H), 7.30 - 7.20 (m, 2H), 4.96 (dd, J = 2.3, 10.0 Hz, 1H), 4.02 -3.91 (m, 2H), 3.45 - 3.36 (m, 1H), 2.77 (s, 3H), 2.53 (d, J = 13.7 Hz, 1H), 2.41 (s, 3H), 2.27 - 2.19 (m, 4H), 2.19 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H); MS (ESI) m / z :C 26 H 24 ClFN4O2 + Calculated value [M+H] + 479.0, measured value [M+H] + 479.1 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H-pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one: 1 H NMR (CDCl3- d , 400 MHz) δ = 8.80 (d, J =6.0 Hz, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.58 (t, J =7.8 Hz, 1H), 7.31 (dd, J = 1.7, 8.3 Hz, 1H), 7.26 (dd, J = 1.9, 9.7 Hz, 1H), 4.72(dd, J = 1.7, 11.3 Hz, 1H), 4.43 (d, J = 3.0, 11.2 Hz, 1H), 3.91 - 3.80 (m, 1H), 3.39 - 3.24 (m, 1H), 2.85 (s, 3H), 2.46 (s, 3H), 2.38 (d, J = 13.2 Hz, 1H),2.30 (s, 3H), 2.13 - 2.06 (m, 2H), 1.78 (q, J = 12.0 Hz, 1H); MS (ESI) m / z :C 26 H 24 ClFN4O2 + Calculated value [M+H] + 479.0, measured value [M+H] + 479.1 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one: 1 H NMR (CDCl3- d , 400 MHz) δ = 8.80 (d, J =6.0 Hz, 1H), 8.59 (s, 1H), 7.65 (s, 1H), 7.62 (d, J = 5.8 Hz, 1H), 7.58 (t,J =7.8 Hz, 1H), 7.31 (dd, J = 1.8, 8.3 Hz, 1H), 7.26 (dd, J = 1.9, 9.7 Hz, 1H), 4.75- 4.69 (m, 1H), 4.46 - 4.39 (m, 1H), 3.93 - 3.79 (m, 1H), 3.38 - 3.25 (m,1H), 2.85 (s, 3H), 2.46 (s, 3H), 2.38 (d, J = 13.0 Hz, 1H), 2.30 (s, 3H), 2.14- 2.06 (m, 2H), 1.83 - 1.72 (m, 1H); MS (ESI) m / z :C 26 H 24 ClFN4O2 + Calculated value [M+H] + 479.0, measured value [M+H] + 479.1 Examples 2-5: 9-(4-cyclopropyl-2-fluorophenyl)-2,3-dimethyl-7-[(2 S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine- 4-base]-4 H -Pyrazino[1,2-a]pyrimidin-4-one Towards( S )-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (50 mg, 0.107 mmol) in dioxane (1 mL) and H₂O (0.1 mL) was supplemented with Cs₂CO₃ (104 mg, 0.320 mmol), chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (7.13 mg, 10.66 µmol), and cyclopropyl difluoromethyl borohydride (77 mg, 0.533 mmol), and the resulting mixture was stirred at 80 °C for 1 hour under N₂. LCMS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was dried over Na₂SO₄. After filtration and concentration, the crude product was purified by pre-HPLC (water / MeCN, with TFA modifier) ​​to give ( S )-9-(4-cyclopropyl-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0276] 1 H NMR (CDCl3- d , 400 MHz) δ = 8.00 (s, 1H), 7.55 - 7.46 (m, 2H), 7.39(s, 1H), 6.92 (br d, J = 8.0 Hz, 1H), 6.80 (br d, J = 11.8 Hz, 1H), 4.63 (dd, J =2.4, 10.0 Hz, 1H), 4.15 - 4.03 (m, 2H), 3.86 (s, 3H), 3.85 - 3.79 (m, 2H), 3.04 (dt, J = 3.4, 12.1 Hz, 1H), 2.94 (dd, J = 10.5, 12.2 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 1.95 - 1.86 (m, 1H), 1.06 - 0.95 (m, 2H), 0.77 - 0.66 (m, 2H). MS(ESI) m / z :C 26 H 27 FN6O2 + Calculated value [M+H] + 474.5, measured value [M+H] + : 475.2 Examples 2-6: ( S )-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-3-(trifluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: 7-Bromo-2-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one PPA (30 mL) was added to a solution of 5-bromo-3-(methylthio)pyrazin-2-amine (2 g, 9.09 mmol) and ethyl 3-oxobutyrate (5.91 g, 45.4 mmol) at 20 °C. The resulting mixture was stirred at 100 °C for 2 h. LCMS showed that the reaction was complete. The reaction was cooled to room temperature. The mixture was added to a solution of NaOH at 0 °C. The pH was adjusted to ~7 using solid NaOH at 0 °C. The reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude compound was purified by rapid silica gel chromatography to give 7-bromo-2-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C9H9BrN3OS + Calculated value [M+H] + 286.0 / 288.0, measured value [M+H] + : 285.7 / 287.7 Step 2: 7-Bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-2-methyl-9-(methylthio)-4 H A suspension of pyrazino[1,2-a]pyrimidin-4-one (350 mg, 1.223 mmol) in THF (8 mL) was supplemented with Pd(PPh3)4 (42.4 mg, 0.037 mmol) and (4-chloro-2-fluorophenyl)boronic acid (320 mg, 1.835 mmol) and CuTC (700 mg, 3.67 mmol). The reaction was heated to 60 °C and stirred for 1 h. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, dissolved in DCM (10 mL), and filtered. The filtrate was washed with saturated NaHCO3 solution until the color changed from dark blue to light yellow. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum to give a crude residue. The residue was purified by rapid silica gel chromatography to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-4- H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 14 H9BrClFN3O + Calculated value [M+H] + 368.0 / 370.0, measured value [M+H] + 367.9 / 369.7 Step 3: 7-Bromo-9-(4-chloro-2-fluorophenyl)-3-iodo-2-methyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-4H A solution of pyrazino[1,2-a]pyrimidin-4-one (300 mg, 0.814 mmol) in AcOH (5 mL) was supplemented with NIS (366 mg, 1.628 mmol), and the resulting mixture was stirred at 80 °C for 1 hour. After completion, the reaction mixture was adjusted to pH ~9 with NaHCO3 aqueous solution (10 mL) and washed with Na2SO3 until the color faded. The mixture was extracted with EtOAc (10 mL × 3). The organic layer was dried with Na2SO4. After filtration and concentration, the residue was suspended in EtOAc (2.0 mL) and the precipitate was collected to give 7-bromo-9-(4-chloro-2-fluorophenyl)-3-iodo-2-methyl-4- H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 14 H8BrClFIN3O + Calculated value [M+H] + 493.9 / 495.8, measured value [M+H] + : 493.7 / 495.7 Step 4: 7-Bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4 H -pyrazino[1,2-a]pyrimidine 4-Pyridoxine To 7-bromo-9-(4-chloro-2-fluorophenyl)-3-iodo-2-methyl-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (130 mg, 0.263 mmol) in DMF (0.5 mL) was supplemented with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (379 mg, 1.972 mmol) and copper(I) iodide (75 mg, 0.394 mmol), and the resulting mixture was stirred at 80 °C for 3 hours. After completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with water (10 mL x 3) and dried over Na2SO4. After filtration and concentration, the crude product was purified by prep-TLC (SiO2, petroleum ether: EtOAc = 5:1, v / v) to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4- H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 15 H8BrClF4N3O + Calculated value [M+H] + 435.9 / 437.9, measured value [M+H] + : 435.7 / 437.7 Step 5: ( S )-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 3-(trifluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Add tripotassium phosphate (88 mg, 0.412 mmol), tripyrazino[1,2-a]pyrimidin-4-one (60 mg, 0.137 mmol), and ( ) to a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (60 mg, 0.137 mmol) in anhydrous dioxane (6 mL) to a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (11.49 mg, 0.014 mmol) and ( ) to a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (60 mg, 0.137 mmol) in anhydrous dioxane (6 mL). S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine (30 mg, 0.179 mmol), and the resulting mixture was stirred at 80 °C for 4 hours under N2. After completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL × 3). The organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by prep-TLC (SiO2, petroleum ether: EtOAc = 1:1, v / v) to obtain the crude product. The crude product was purified by pre-HPLC (water / MeCN, with TFA modifier) ​​to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-3-(trifluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0277] 1 H NMR (400MHz, CDCl3) δ = 8.21 (s, 1H), 7.65 - 7.60 (m, 1H), 7.59 (s,1H), 7.46 (s, 1H), 7.31 (dd, J = 1.8, 8.3 Hz, 1H), 7.26 (d, J =1.9 Hz, 1H), 4.69(dd, J = 2.7, 10.2 Hz, 1H), 4.24 (d, J = 12.6 Hz, 1H), 4.17 (dd, J = 2.4, 11.4 Hz,1H), 3.94 (s, 4H), 3.92 - 3.86 (m, 1H), 3.20 (dt, J = 3.6, 11.4 Hz, 1H), 3.09(dd, J= 10.3, 12.6 Hz, 1H), 2.58 (q, J = 2.7 Hz, 3H). MS (ESI) m / z :C 23 H 20 ClF4N6O2 + Calculated value [M+H] + 523.1 / 525.1, measured value [M+H] + : 523.1 / 525.1 Examples 2-7: ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazole-4- (base)morpholine)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: Ethyl 4-methoxy-2-methyl-3-oxobutyrate At 25 °C, K₂CO₃ (11.22 g, 81 mmol) and MeI (4.29 mL, 68.7 mmol) were added to a stirred mixture of ethyl 4-methoxy-3-oxobutyrate (10 g, 62.4 mmol) in THF (80 mL), and the mixture was stirred at 80 °C for 16 h under a N₂ atmosphere. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (80 mL × 3). The organic layer was washed with brine (100 mL × 3) and dried over Na₂SO₄. After filtration and concentration, the crude product was purified by rapid silica gel chromatography to give ethyl 4-methoxy-2-methyl-3-oxobutyrate. 1 H NMR (400 MHz, CDCl3) δ 4.19 (d, J = 7.2 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.66 (d, J = 7.2 Hz,1H), 3.41 (s, 3H), 1.35 (d, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H) Step 2: 7-Bromo-2-(methoxymethyl)-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one In(OTf)3 (10.21 g, 18.17 mmol) and ethyl 4-methoxy-2-methyl-3-oxobutyrate (6.97 g, 40.0 mmol) were added to a solution of 5-bromo-3-(meththio)pyrazin-2-amine (4 g, 18.17 mmol) in toluene (100 mL), and the resulting mixture was stirred at 125 °C for 12 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by rapid silica gel chromatography. The product was then suspended in petroleum ether: EtOAc = 10:1 (10.0 mL), and the precipitate was collected to give 7-bromo-2-(methoxymethyl)-3-methyl-9-(meththio)-4-methyl-3-methyl-9-(meththio)-3-methyl ... H -Pyrazino[1,2-a]pyrimidin-4-one.

[0278] 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 4.57 (s, 2H), 3.49 (s, 3H), 2.60 (s, 3H), 2.31 (s, 3H). MS(ESI) m / z :C 11 H 12 BrN3O2S + Calculated value [M+H] + 330.1, measured value [M+H] + 329.7 Step 3: 7-Bromo-2-(methoxymethyl)-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one In the glove box, 7-bromo-2-(methoxymethyl)-3-methyl-9-(methylthio)-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (860 mg, 2.60 mmol) in THF (2 mL) was supplemented with copper(I) thiophene-2-carboxylate (745 mg, 3.91 mmol), Pd(Ph3P)4 (90 mg, 0.078 mmol), and (4-chloro-2-fluorophenyl)boronic acid (681 mg, 3.91 mmol). The reaction was heated to 60 °C and stirred for 2 h. After completion, the reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain the residue, which was purified by rapid silica gel chromatography to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-4- H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 16 H 12 BrClFN3O2 + Calculated value [M+H]+: 412.0 / 414.0, Measured value [M+H] + : 411.9 / 413.9 Step 4: ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-7-(2-(1-methyl-1 H -pyr (azol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one In the glove box, 7-bromo-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (30 mg, 0.073 mmol) in dioxane (2 mL) was added with 2-(1-methyl-1 H -pyrazol-4-yl)morpholine (14.59 mg, 0.087 mmol), Cs2CO3 (71.1 mg, 0.218 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (3.73 mg, 7.27 µmol). The resulting mixture was stirred at 60 °C for 3 hours under N2 protection. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to obtain a crude residue. The residue was purified by prep-TLC (petroleum ether:EtOAc = 3:1) to obtain a crude residue, which was further purified by Prep-HPLC (water / MeCN, with TFA modifier) ​​to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H-Pyrazino[1,2-a]pyrimidin-4-one.

[0279] 1 H NMR (400 MHz, CDCl3-d) δ 8.10 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.57(s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 4.71 (d, J = 10.0 Hz, 1H), 4.49 (s, 2H), 4.17 (t, J = 10.0 Hz, 2H), 3.92 (s, 5H), 3.40 (s, 3H), 3.16 (d, J =9.2 Hz, 1H), 3.01-3.07 (m, 1H), 2.35 (s, 3H). MS(ESI) m / z :C 24 H 24 ClFN6O3 + Calculated value [M+H] + 499.2, measured value [M+H] + :499.2.

[0280] Examples 2-8 and 2-9: ( S )-9-(4-chloro-2-fluorophenyl)-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazole-4- (base)morpholine)-4 H -pyrazino[1,2-a]pyrimidin-4-one and ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl) Base-1 H -pyrazol-4-yl)morpholino)-2-(2-methylallyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: 4-Cyclopropyl-3-oxobutyrate Under a nitrogen atmosphere, CDI (19.46 g, 120 mmol) was slowly added to a THF (100 mL) solution of 2-cyclopropylacetic acid (10.01 g, 100 mmol). The mixture was stirred at 25 °C for 1 h. Next, potassium 3-ethoxy-3-oxopropionate (25.5 g, 150 mmol) and magnesium chloride (11.42 g, 120 mmol) were added to the above mixture, and it was stirred at 25 °C for 16 h. After completion, the reaction was quenched with 1.0 N HCl. The mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by rapid silica gel chromatography to give ethyl 4-cyclopropyl-3-oxobutyrate.

[0281] Step 2: Ethyl 4-cyclopropyl-2-methyl-3-oxobutyrate Under a nitrogen atmosphere, MeI (3.44 mL, 55.0 mmol) was added to a solution of ethyl 4-cyclopropyl-3-oxobutyrate (8.51 g, 50 mmol) and K₂CO₃ (10.37 g, 75 mmol) in anhydrous THF (100 mL). The mixture was heated to 75 °C and stirred for 16 h. After completion, the reaction was quenched with water (50 mL), separated, extracted with EtOAc (30 mL x 3), and the organic layers were combined. The organic phases were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid silica gel chromatography to give ethyl 4-cyclopropyl-2-methyl-3-oxobutyrate.

[0282] Step 3: 7-Bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one and 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Toluene (40 mL), 5-bromo-3-(methylthio)pyrazin-2-amine (600 mg, 2.73 mmol), ethyl 4-cyclopropyl-2-methyl-3-oxobutyrate (1507 mg, 8.18 mmol), and In(OTf)3 (1532 mg, 2.73 mmol) were added to a single-necked flask equipped with a Dean-Stark water separator. The mixture was then stirred at 120 °C for 1 h. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography, then further purified by prep. HPLC (water / MeCN, with NH3·H2O modifier) ​​and separated by SFC to give 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one (Rt=3.219 min) and 7-bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one (Rt = 3.959 min). 7-Bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one 1 H NMR (400MHz, CDCl3) δ 8.42(s, 1H), 2.62 (d, J = 6.8 Hz, 2H), 2.49-2.54 (m, 3H), 2.19 (s, 3H), 1.03-1.13(m, 1H), 0.41-0.51 (m, 2H), 0.24 (q, J = 4.8 Hz, 2H). 7-Bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 H-Pyrazino[1,2-a]pyrimidin-4-one 1 H NMR (400MHz, CDCl3) δ 8.42 (s, 1H), 5.45-5.63 (m, 2H), 3.41 (d, J = 4.4 Hz, 2H), 2.51 (s, 3H), 2.18 (s, 3H), 1.62(d, J = 4.8 Hz, 3H).

[0283] MS (ESI) m / z :C 13 H 14 BrN3OS + Calculated value [M+2] + 342.1, measured value [M+2] + : 341.8. Prep SFC conditions: Column DAIEL CHIRALPAK IC (250 mm) 30 mm, 10 μm) Conditions: 0.1% NH3·H2O, iPrOH, Start B 30, End B 30, Gradient Time (min) 1, 100% B, Retention Time 1, Flow Rate (mL / min) 80 Step 4: ( S )-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9- (methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (40 mg, 0.118 mmol) in dioxane (2 mL) was added. S )-2-(1-methyl-1 H -pyrazol-4-yl)morpholine (30 mg, 0.179 mmol), Cs₂CO₃ (115 mg, 0.353 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (12.05 mg, 0.024 mmol) were added, and the resulting mixture was stirred at 60 °C for 16 h. After completion, the mixture was treated with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic fractions were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residues were purified by Prep-TLC (SiO₂, EtOAc) to obtain ( S )-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 21 H 26 N6O2S + Calculated value [M+H] + 427.1, measured value [M+H] + 427.1 Step 5: ( S )-9-(4-chloro-2-fluorophenyl)-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyr (azol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Under N2, towards ( S )-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (15 mg, 0.035 mmol) in THF (1 mL) was supplemented with (4-chloro-2-fluorophenyl)boronic acid (6.13 mg, 0.035 mmol), copper(I) thiophene-2-carboxylate (20.12 mg, 0.106 mmol), and Pd(Ph3P)4 (4.06 mg, 3.52 µmol), and the resulting mixture was stirred at 60 °C for 1 h. After completion, the mixture was treated with water (5 mL) and extracted with EtOAc (2 mL x 3). The organic layer was concentrated under vacuum and purified by Prep-HPLC (water / MeCN, using NH3·H2O modifier) ​​to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2-(cyclopropylmethyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. 1 H NMR (400MHz, CDCl3) δ 8.07 (s, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45(s, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 10.0, 2.0 Hz, 1H), 4.71 (dd, J =10.4, 2.8 Hz, 1H), 4.12-4.20 (m, 2H), 3.88-3.96 (m, 4H), 3.07-3.15 (m, 1H), 3.01 (dd, J = 12.4, 10.4 Hz, 1H), 2.61 (d, J= 6.8 Hz, 2H), 2.31 (s, 3H), 1.01-1.10 (m, 1H), 0.43-0.50 (m, 2H), 0.18-0.24 (m, 2H). MS(ESI) m / z :C 26 H 26 ClFN6O2 + Calculated value [M+H] + 509.2 / 511.2, measured value [M+H] + : 509.1 / 511.1 Step 6: (S)-3-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(2-methylallyl)- 9-(methylthio)-4H-pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (40 mg, 0.118 mmol) in dioxane (2 mL) was added. S )-2-(1-methyl-1H-pyrazol-4-yl)morpholine (23.59 mg, 0.141 mmol), Cs2CO3 (115 mg, 0.353 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (12.05 mg, 0.024 mmol) were added, and the resulting mixture was stirred at 60 °C for 16 h. After completion, the mixture was treated with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by Prep-TLC (SiO2, EtOAc) to obtain ( S )-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-2-(2-methylallyl)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 21 H 26 N6O2S + Calculated value [M+H] + 427.1, measured value [M+H] + :427.1.

[0284] Step 7: ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 2-(2-methylallyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Under N2, towards ( S )-3-methyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-2-(2-methylallyl)-9-(methylthio)-4 H 1,2-a]pyrazino[1,2-a]pyrimidin-4-one (15 mg, 0.035 mmol) was added to a solution of (4-chloro-2-fluorophenyl)boronic acid (6.13 mg, 0.035 mmol), copper(I) thiophene-2-carboxylate (20.12 mg, 0.106 mmol), and Pd(Ph3P)4 (4.06 mg, 3.52 µmol) in THF (1 mL), and the resulting mixture was stirred at 60 °C for 1 h. After completion, the mixture was treated with water (5 mL) and extracted with EtOAc (2 mL x 3). The organic layer was concentrated under vacuum and purified by Prep-HPLC (water / MeCN, with NH3·H2O modifier) ​​to obtain ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-2-(2-methylallyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. 1 HNMR (400MHz, CDCl3) δ 8.07 (s, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 7.24 (d, J = 10.0 Hz, 1H), 5.47-5.61 (m, 2H), 4.67-4.75 (m, 1H), 4.12-4.18 (m, 2H), 3.89-3.95 (m, 5H), 3.41 (d, J = 4.8 Hz, 2H),3.07-3.15 (m, 1H), 2.97-3.05 (m, 1H), 2.29 (s, 3H), 1.67 (d, J = 4.8 Hz, 3H). MS(ESI) m / z :C 26 H 26 ClFN6O2 + Calculated value [M+H] + 509.2 / 511.2, measured value [M+H] + : 509.1 / 511.1 Example 2-10: 9-(4-chloro-2-fluorophenyl)-7-(4-(2,2-difluoroacetyl)piperazin-1-yl)-2,3-dimethyl-4 H -Pyrazine [1,2-a]pyrimidin-4-one Step 1: 4-(2,3-Dimethyl-9-(methylthio)-4-oxo-4 H -pyrazino[1,2-a]pyrimidin-7-yl)piperazine- Synthesis of tert-butyl 1-carboxylic acid At room temperature, in a glove box, the compound 7-bromo-2,3-dimethyl-9-(methylthio)-4 H 4,2-a]pyrazino[1,2-a]pyrimidin-4-one (4.5 g, 14.99 mmol) was added to a stirred solution of 1,4-dioxane (15 mL) containing piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 14.99 mmol), cesium carbonate (14.65 g, 45.0 mmol), and chloro(2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.164 g, 1.499 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled at room temperature, quenched with water (250 mL), and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude substance was purified by silica gel chromatography to obtain compound 4-(2,3-dimethyl-9-(methylthio)-4-oxo-4- H -Pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylic acid tert-butyl ester. MS (ESI) m / z :C 19 H 28 N5O3S + Calculated value [M+H] + 406.18, measured value 406.28 Step 2: Compound 4-(9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-4 H -pyrazino[1,2-a]pyrimidine Synthesis of tert-butyl pyridinium-7-yl)piperazine-1-carboxylate At room temperature, in a glove box, 4-(2,3-dimethyl-9-(methylthio)-4-oxo-4 H4-(9-(4-chloro-2-fluorophenyl)piperazine-1-carboxylic acid ester) (4.5 g, 11.10 mmol) was added to a stirred solution of 1,4-dioxane (15 mL) with stirring. (4-chloro-2-fluorophenyl)boronic acid (2.90 g, 16.65 mmol), copper(I) thiophene-2-carboxylate (3.17 g, 16.65 mmol), and tetrakis(triphenylphosphine)palladium(O) (4.5 g, 3.89 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (40 mL) and water (25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography. The purified fractions were combined and concentrated under reduced pressure to give compound 4-(9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-4- H -Pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS (ESI) C 24 H 28 ClFN5O3 + Calculated value [M+H] + : 488.18, measured value 488.32 Step 3: Compound 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(piperazin-1-yl)-4 H -pyrazin[1,2- Synthesis of pyrimidine-4-one hydrochloride At 0 °C, the compound 4-(9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-4 H A stirred solution of 2.0 g (4.10 mmol) of pyrazino[1,2-a]pyrimidin-7-yl)piperazine-1-carboxylic acid tert-butyl ester (1,2-a]pyrimidin-7-yl)piperazine-1-carboxylic acid was mixed with 4 M 1,4-dioxane hydrochloride (0.486 mL, 4.10 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was ground with diethyl ether (500 mL) and concentrated under reduced pressure to give compound 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(piperazin-1-yl)-4- H -Pyrazino[1,2-a]pyrimidine-4-one hydrochloride.

[0285] LCMS (ESI) C 19 H 20 ClFN5O + Calculated value [M+H] + : 388.13, measured value 388.11. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.25 (br s, 2H), 8.08 (s, 1H), 7.72 (t, J = 7.60 Hz, 1H), 7.63 (dd, J = 2.00, 9.60 Hz, 1H), 7.48 (dd, J = 2.00, 8.20 Hz, 1H), 3.69 (t, J =5.20 Hz, 4H), 3.25 (s, 4H), 2.34 (s, 3H), 2.18 (s, 3H).

[0286] Step 4: Compound 9-(4-chloro-2-fluorophenyl)-7-(4-(2,2-difluoroacetyl)piperazin-1-yl)-2,3-di Methyl-4 H Synthesis of pyrazino[1,2-a]pyrimidin-4-one At room temperature, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(piperazin-1-yl)-4 H A stirred solution of pyrazino[1,2-a]pyrimidin-4-one hydrochloride (15 mg, 35.35 µmol, 1.0 eq) in DMF (1500 µl) was supplemented with DIPEA (18 µl, 106.05 µmol, 3.0 eq), HATU (20.16 mg, 53.02 µmol, 1.5 eq), and 2,2-difluoroacetic acid (3.39 mg, 35.35 µmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by Prep HPLC. The fractions were collected and lyophilized to give 9-(4-chloro-2-fluorophenyl)-7-(4-(2,2-difluoroacetyl)piperazin-1-yl)-2,3-dimethyl-4- H -Pyrazino[1,2-a]pyrimidin-4-one.

[0287] LCMS (ESI) C 21 H 20 ClF3N5O2 + Calculated value [M+H] + : 466.12, measured value 466.19. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.01 (s, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.62 (dd, J =2.00, 10.0 Hz, 1H), 7.47 (dd,J = 2.00, 8.4 Hz, 1H), 6.8 (t, J = 52.8 Hz, 1H), 3.70 (br s, 4H), 3.51 (br s, 4H), 2.32 (s, 3H), 2.17 (s, 3H).

[0288] The examples shown in Table 2-1 below were prepared using suitable initial raw materials according to a procedure similar to that outlined in Examples 2-1 to 2-10 above.

[0289] Table 2-1: Examples 2-11 to 2-78 Example 2-79: ( S )-5-(4-chloro-2-fluorophenyl)-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-1,3-dihydro-10 H - Furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one Step 1: 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-2,5-dihydrofuran-3-carboxylic acid ethyl ester A mixture of 5-bromo-3-(methylthio)pyrazin-2-amine (2.0 g, 9.09 mmol) and ethyl 4-oxotetrahydrofuran-3-carboxylate (4.31 g, 27.3 mmol) in AcOH (30 mL) was stirred at 120 °C for 3 h. The mixture was filtered and the solid was concentrated under reduced pressure to give crude ethyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-2,5-dihydrofuran-3-carboxylate, which required no further purification. MS (ESI) m / z :C 12 H 15 Calculated value of BrN3O3S [M+H] + 360.1 / 362.1, measured value [M+H]+ 360.2 / 362.2.

[0290] Step 2: 7-Bromo-5-(methylthio)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one The mixture of ethyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-2,5-dihydrofuran-3-carboxylic acid (900 mg, 2.498 mmol) in diphenyl ether (1 mL) was stirred at 280 °C for 20 min using a sand bath. Afterward, the mixture was filtered and the solids were concentrated under reduced pressure to give crude 7-bromo-5-(methylthio)-1,3-dihydro-10 H - Furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, no further purification required. MS (ESI) m / z :C 10 Calculated value of H9BrN3O2S [M+H] + 314.0 / 316.0.0, measured value [M+H] + 314.1 / 316.1.

[0291] Step 3: ( S )-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H - Furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one In 100 o At C, 7-bromo-5-(methylthio)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one (100 mg, 0.318 mmol), ( S A mixture of 2-(1-methyl-1H-pyrazol-4-yl)morpholine (160 mg, 0.955 mmol), rac-BINAP Pd G4 (32.0 mg, 0.032 mmol), and Cs2CO3 (311 mg, 0.955 mmol) in 1,4-dioxane (2 mL) was stirred for 1 h. The mixture was filtered and the filtrate was purified by Prep-HPLC (water (0.1% TFA)-MeCN) to obtain ( S )-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z :C 18 H 21 Calculated value of N6O3S [M+H] + 401.0, measured value [M+H] + 401.1.

[0292] Step 4: ( S )-5-(4-chloro-2-fluorophenyl)-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-1,3-di Hydrogen-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one In the glove box, to ( S )-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H A solution of 1,4-d-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one (60 mg, 0.150 mmol) in THF (1 mL) was supplemented with copper(I) thiophene-2-carboxylate (86 mg, 0.45 mmol), Pd(Ph3P)4 (17.3 mg, 0.015 mmol), and (4-chloro-2-fluorophenyl)boronic acid (31.3 mg, 0.180 mmol). The reaction was heated to 60 °C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (2 mL) and extracted with EtOAc (2 mL x 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by Prep-HPLC (water (0.1% TFA)-MeCN) to give ( S )-5-(4-chloro-2-fluorophenyl)-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z :C 23 H 21 Calculated value of ClFN6O3 [M+H] + 483.2 / 485.2, measured value [M+H] + 483.1 / 485.1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.23 ​​(s,1 H), 7.56 - 7.62 (m, 2 H), 7.47 (s, 1 H), 7.29 - 7.33 (m, 1 H), 7.23 - 7.26(m, 1 H), 5.25 (t, J = 2.32 Hz, 2 H), 5.02 (t, J = 2.38 Hz, 2 H), 4.71 (dd, J=10.13, 2.74 Hz, 1 H), 4.14 - 4.24 (m, 2 H), 3.98 (br s, 1 H), 3.94 (s, 3 H), 3.88 - 3.93 (m, 1 H), 3.13 - 3.23 (m, 1 H), 3.07 (dd, J = 12.40, 10.37 Hz, 1H).

[0293] Example 2-80: ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-2-(tri-) Fluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: 7-Bromo-2-hydroxy-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one 5-Bromo-3-(methylthio)pyrazin-2-amine (2.0 g, 9.09 mmol), diethyl 2-methylmalonate (4.75 g, 27.3 mmol), and polyphosphoric acid (20 mL) were charged into a 50 mL round-bottom flask. The mixture was then slowly stirred at 100 °C for 16 h. The mixture was added to cold water (100 mL), stirred, and filtered. The solid was then purified by rapid silica gel chromatography to give 7-bromo-2-hydroxy-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z Calculated value of C9H9BrN3O2S [M+H] + 302.0 / 304.0, measured value [M+H] + 301.9 / 303.9.

[0294] Step 2: 7-Bromo-2-(methoxymethoxy)-3-methyl-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-2-hydroxy-3-methyl-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (1.5 g, 4.96 mmol) in THF (30 mL) was mixed with K₂CO₃ (2.06 g, 14.9 mmol) and bromomethyl methyl ether (1.24 g, 9.93 mmol), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was filtered and washed with EtOAc (100 mL). The organic layer was concentrated under reduced pressure to give a crude product. The solid was ground with MeOH (10 mL) and filtered. The filter cake was washed with petroleum ether (5 mL) to give 7-bromo-2-(methoxymethoxy)-3-methyl-9-(methylthio)-4- H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 11H 13 Calculated value of BrN3O3S [M+H] + 346.0 / 348.0, measured value [M+H] + 345.9 / 347.9. 1 HNMR (400 MHz, CD3OD) δ 8.51-8.58 (m, 1H), 5.71 (d, J = 9.6 Hz, 2H), 3.57 (s, 3H), 2.61 (s, 3H), 2.15 (s, 3H).

[0295] Step 3: ( S )-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-2-(methoxymethoxy)-3-methyl-9-(methylthio)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (600 mg, 1.73 mmol) in dioxane (15 mL) was added. S )-2-(1-methyl-1H-pyrazol-4-yl)morpholine (579 mg, 3.46 mmol), Cs2CO3 (1693 mg, 5.2 mmol), rac-BINAP Pd G4 (174 mg, 0.174 mmol), and the resulting mixture was stirred at 80 °C for 16 h under N2. The mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The solids were ground with MeOH (10 mL) and filtered to give ( S )-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 19 H 25 Calculated value of N6O4S [M+H] + 433.1, measured value [M+H] + 433.1.

[0296] Step 4: ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H - Pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Towards( S )-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-9-(methylthio)-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (450 mg, 1.04 mmol) in THF (15 mL) was supplemented with (4-chloro-2-fluorophenyl)boronic acid (363 mg, 2.08 mmol), copper(I) thiophene-2-carboxylate (595 mg, 3.12 mmol), and Pd(PPh3)4 (60.1 mg, 0.052 mmol), and the resulting mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude solid. The solid was ground with MeOH (5 mL) and filtered to give ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 24 H 25 Calculated value of ClFN6O4 [M+H] + 515.2 / 517.2, measured value [M+H] + 515.1 / 517.1. 1 H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.61-7.67 (m, 2H), 7.49 (s, 1H), 7.28-7.31 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 5.43 (s, 2H), 4.69-4.75(m, 1H), 4.14-4.20 (m, 2H), 3.99 (s, 3H), 3.88-3.94 (m, 2H), 3.46 (s, 3H),3.10-3.18 (m, 1H), 3.03 (dd, J = 12.4, 10.4 Hz, 1H), 2.22 (s, 3H).

[0297] Step 5: ( S )-9-(4-chloro-2-fluorophenyl)-2-hydroxy-3-methyl-7-(2-(1-methyl-1 H -pyrazole-4-yl) Morpholin-4 H -Pyrazino[1,2-a]pyrimidin-4-one At 0℃, towards ( S )-9-(4-chloro-2-fluorophenyl)-2-(methoxymethoxy)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (350 mg, 0.680 mmol) in CH2Cl2 (7 mL) was slowly supplemented with TFA (5.0 mL, 64.9 mmol), and the resulting mixture was stirred at 0 °C for 2 h. The mixture was concentrated, and the resulting residue was ground with MeOH (5 mL) and filtered. The filter cake was washed with petroleum ether (5 mL) to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2-hydroxy-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 22 H 21 Calculated value of ClFN6O3 [M+H] + 471.1 / 473.1, measured value [M+H] + 471.1 / 473.1.

[0298] Step 6: ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 4-Oxo-4 H -Pyrazino[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate At 0℃, towards ( S )-9-(4-chloro-2-fluorophenyl)-2-hydroxy-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (300 mg, 0.637 mmol) in DCM (20 mL) was supplemented with 2,6-dimethylpyridine (273 mg, 2.55 mmol) and Tf₂O (0.323 mL, 1.91 mmol), and the resulting mixture was stirred at 0 °C for 3 h. The mixture was quenched with water (20 mL) and extracted with DCM (10 mL x 2). The combined organic fractions were concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography to obtain ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4-oxo-4 H -Pyrazino[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate. MS (ESI) m / z :C 23 H 20 Calculated value of ClF4N6O5S [M+H] + 603.1 / 605.1, measured value [M+H] + 603.1 / 605.1.

[0299] Step 7: ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 2-(trimethyltinyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Towards( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4-oxo-4 H A solution of pyrazino[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate (150 mg, 0.249 mmol) in dioxane (8 mL) was supplemented with hexamethyldistin (245 mg, 0.746 mmol), lithium chloride (105 mg, 2.48 mmol), and tetra(triphenylphosphine)palladium(0) (28.7 mg, 0.025 mmol). The test tube was purged with N2, and the mixture was stirred at 80 °C for 3 h. The reaction solution was filtered and concentrated under vacuum to obtain crude ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H (-pyrazol-4-yl)morpholino)-2-(trimethylstannyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, which was used directly in the next step without further purification. MS (ESI) m / z :C 25 H 29 Calculated value of ClFN6O2Sn [M+H] + 617.1 / 619.1, measured value [M+H] + 617.0 / 619.0.

[0300] Step 8: ( S )-9-(4-chloro-2-fluorophenyl)-2-iodo-3-methyl-7-(2-(1-methyl-1 H (-pyrazole-4-yl) (P-4) H -Pyrazino[1,2-a]pyrimidin-4-one Towards( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-2-(trimethyltinyl)-4 H A mixture of pyrazino[1,2-a]pyrimidin-4-one (150 mg, 0.243 mmol) in DCM (10 mL) was added with I2 (185 mg, 0.729 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The mixture was treated with KF aqueous solution (2 mL), NaS2O3 aqueous solution (1 mL), and water (5 mL) and extracted with DCM (15 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The solids were ground with MeCN (3 mL) and filtered to obtain ( S )-9-(4-chloro-2-fluorophenyl)-2-iodo-3-methyl-7-(2-(1-methyl-1H -pyrazol-4-yl)morpholino)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 22 H 20 Calculated value of ClFIN6O2 [M+H] + 581.0 / 583.0, measured value [M+H] + 580.9 / 582.9.

[0301] Step 9: ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)- 2-(trifluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Towards( S )-9-(4-chloro-2-fluorophenyl)-2-iodo-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (30 mg, 0.052 mmol) in DMSO (2 mL) was supplemented with 1,10-phenanthroline (4.65 mg, 0.026 mmol), potassium fluoride (9.00 mg, 0.155 mmol), trimethyl borate (16.1 mg, 0.155 mmol), copper(I) iodide (4.92 mg, 0.026 mmol), and (trifluoromethyl)trimethylsilane (44.1 mg, 0.310 mmol), and the resulting mixture was stirred at 60 °C for 3 h under N2. The mixture was treated with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep. HPLC (water (0.01% TFA)-MeCN) to obtain ( S )-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(1-methyl-1 H -pyrazol-4-yl)morpholino)-2-(trifluoromethyl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 23 H 20 Calculated value of ClF4N6O2 [M+H] + 523.1 / 525.1, measured value [M+H] + 523.1 / 525.1. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.66-7.72 (m, 1H), 7.64 (s, 1H),7.49 (s, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 4.71 (dd, J = 10.0, 2.4 Hz, 1H), 4.25 (d, J = 12.4 Hz, 1H), 4.14-4.20 (m, 1H), 3.95-4.01(m, 4H), 3.88-3.94 (m, 1H), 3.16-3.24 (m, 1H), 3.09 (dd, J = 12.4, 10.4 Hz, 1H), 2.44 (d, J = 1.6 Hz, 3H).

[0302] Examples 2-81 and 2-82: ( S or R )-7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-di Hydrogen-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one and ( R or S )-7-(2,2-difluoro-6-(2-methylpyridine) (Pyridine-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidine- 10-keto Step 1: 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H - Furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one To 7-bromo-5-(methylthio)-1,3-dihydro-10 H A solution of 100 mg, 0.318 mmol, of furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one in dioxane (3 mL) was added to 2,2-difluoro-6-(2-methylpyridin-4-yl)morpholine (82 mg, 0.382 mmol), Cs₂CO₃ (311 mg, 0.955 mmol), and rac-BINAP Pd G₄ (32.0 mg, 0.032 mmol), and the resulting mixture was stirred at 100 °C for 16 h under N₂. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by pre-HPLC (water (0.1% TFA)-MeCN) to give 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z :C 20 H 20 Calculated value of F2N5O3S [M+H] + 448.0, measured value [M+H] + 448.0.

[0303] Step 2: 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-di Hydrogen-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one In the glove box, 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(methylthio)-1,3-dihydro-10 H 1,4-d]pyrazino[1,2-a]pyrimidin-10-one (55 mg, 0.123 mmol) was added to a solution of 1,4-furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one (2 mL) in THF, along with copper(I) thiophene-2-carboxylate (70.3 mg, 0.369 mmol), Pd(PPh3)4 (14.2 mg, 0.012 mmol), and (2,4-difluorophenyl)boronic acid (29.1 mg, 0.184 mmol). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN) to give 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z :C 25 H 20 Calculated value of F4N5O3 [M+H] + 514.0, measured value [M+H] + 514.0.

[0304] Step 3: ( S or R )-7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)- 1,3-Dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one and ( R or S )-7-(2,2-difluoro-6-(2-methyl) (pyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a] Chiral SFCs of Pyrimidine-10-one Through chiral-SFC [Column DAICL CHIRALPAK AD (250mm)] 30mm, 10μm); Conditions: CO2-EtOH (0.1% NH3H2O)] Resolution 7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one (40 mg, 0.078 mmol) to give 2-81 (SFC peak 1): ( S or R )-7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, and 2-82 (SFC peak 2): ( R or S )-7-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-5-(2,4-difluorophenyl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one.

[0305] Ex 2-81 (SFC Peak 1): MS (ESI) m / z :C 25 H 20 Calculated value of F4N5O3 [M+H] + 514.0, measured value [M+H] + 514.1. 1 H NMR (400 MHz, CDCl3-) d ) δ ppm 8.58 (d, J = 5.13 Hz, 1 H), 8.29 (s, 1 H), 7.64 - 7.71 (m, 1 H), 7.27 (s, 1 H), 7.20 (d, J = 5.01 Hz, 1 H), 7.07 (td, J =8.23, 2.15 Hz, 1 H), 6.95 - 7.02 (m, 1 H), 5.32 (dd, J = 10.97, 2.74 Hz, 1 H),5.26 (t, J = 2.32 Hz, 2 H), 5.03 (t, J = 2.26 Hz, 2 H), 4.60 (dd, J= 12.93, 3.28Hz, 1 H), 4.38 (br d, J =13.11 Hz, 1 H), 3.37 - 3.51 (m, 1 H), 3.10 (dd, J =12.82, 11.38 Hz, 1 H), 2.63 (s, 3 H).

[0306] Ex 2-82 (SFC Peak 2): MS (ESI) m / z :C 25 H 20 Calculated value of F4N5O3 [M+H] + 514.0, measured value [M+H] + 514.1. 1 H NMR (400 MHz, CDCl3-) d ) δ ppm 8.58 (d, J = 5.13 Hz, 1 H), 8.30 (s, 1 H), 7.67 (td, J = 8.26, 6.38 Hz, 1 H), 7.27 (s, 1 H), 7.20 (d, J = 5.01 Hz, 1 H),7.04 - 7.11 (m, 1 H), 6.99 (ddd, J = 9.98, 8.85, 2.38 Hz, 1 H), 5.32 (dd, J =11.09, 2.74 Hz, 1 H), 5.26 (t, J = 2.44 Hz, 2 H), 5.03 (t, J = 2.44 Hz, 2 H), 4.60 (dd, J = 13.05, 3.16 Hz, 1 H), 4.37 (br d, J = 13.23 Hz, 1 H), 3.37 - 3.51(m, 1 H), 3.10 (dd, J = 12.8, 11.2 Hz, 1 H), 2.63 (s, 3 H).

[0307] Examples 2-83, 2-84, 2-85, 2-86: 9-(2,4-Difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3- Tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl- 7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 H -pyrazino[1,2-a] Pyrimidin-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3- Tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4-difluorophenyl)-2,3-dimethyl- 7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a] Pyrimidin-4-one Step 1: 2,3-Dimethyl-9-(methylthio)-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2- H -pyran-4-yl)- 4 H -Pyrazino[1,2-a]pyrimidin-4-one In a glove box, a mixture of NiCl2·DME (102 mg, 0.466 mmol) and benzalkonium hydrochloride (73.0 mg, 0.466 mmol) in DMA (15 mL) was stirred. 7-Bromo-2,3-dimethyl-9-(methylthio)-4- H -Pyrazino[1,2-a]pyrimidin-4-one (700 mg, 2.33 mmol), 4-iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2 H -Pyran (987 mg, 3.50 mmol), TBAI (861 mg, 2.33 mmol), and zinc powder (610 mg, 9.33 mmol). The reaction mixture was stirred at 40 °C for 1 h. The reaction was concentrated and the residue was dissolved in water (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (water (0.1% TFA)-MeCN) to give 2,3-dimethyl-9-(methylthio)-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 19 H 26 Calculated value of N3O3S [M+H] + 376.1, measured value [M+H] + 376.2.

[0308] Step 2: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2- H -Pyran-4- (Base)-4 H -Pyrazino[1,2-a]pyrimidin-4-one In the glove box, 2,3-dimethyl-9-(methylthio)-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (90 mg, 0.240 mmol) in THF (5 mL) was supplemented with copper(I) thiophene-2-carboxylate (68.6 mg, 0.360 mmol), Pd(PPh3)4 (8.31 mg, 7.19 µmol), and (2,4-difluorophenyl)boronic acid (76 mg, 0.479 mmol). The reaction was heated to 60 °C and stirred for 2 h. The mixture was quenched with an aqueous solution of NH3H2O ​​(5 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC with water (0.1% TFA)-MeCN to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 24 H 26 Calculated value of F2N3O3 [M+H] + 442.2, measured value [M+H] + 442.1.

[0309] Step 3: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2- H -Pyran-4- (Base)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Resolution of 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(tetrahydrofuran-3-yl)tetrahydro-2-yl) by chiral-SFC (column DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm)). H -pyran-4-yl)-4 H -pyrazino[1,2-a]pyrimidin-4-one (73 mg, 0.165 mmol) to give 2-83 SFC peak 1: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one, 2-84 SFC peak 2: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one, 2-85 SFC peak 3: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one, and 2-86 SFC peak 4: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-Tetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0310] Ex 2-83, SFC peak 1: MS (ESI) m / z :C 24 H 26 Calculated value of F2N3O3 [M+H] + 442.2, measured value [M+H] + 442.1. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.57 (dt, J = 6.6,8.2 Hz, 1H),7.08 - 6.79 (m, 2H), 4.12 (dd, J = 3.4,11.5 Hz, 1H), 3.84 - 3.74 (m, 2H), 3.69(q, J = 7.6 Hz, 1H), 3.59 - 3.44 (m, 2H), 3.28 (dd, J= 8.0,9.6 Hz, 1H), 3.06 -2.92 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.06 - 1.95 (m, 1H), 1.94 - 1.76(m, 4H), 1.54 (q, J = 12.2 Hz, 2H).

[0311] Ex 2-84, SFC peak 2: MS (ESI) m / z :C 24 H 26 Calculated value of F2N3O3 [M+H] + 442.2, measured value [M+H] + 442.1. 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.70 - 7.43 (m, 1H), 7.03 - 6.79 (m, 2H), 4.08 (dd, J = 4.0,11.3 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.74 - 3.61 (m,2H), 3.52 (dt, J = 2.0,11.8 Hz, 1H), 3.25 (br t, J = 9.5 Hz, 1H), 2.99 (tt, J =3.5,11.9 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.05 (br d, J = 12.6 Hz, 1H), 1.95 - 1.77 (m, 3H), 1.62 - 1.41 (m, 3H).

[0312] Ex 2-85, SFC peak 3: MS (ESI) m / z :C 24 H 26 Calculated value of F2N3O3 [M+H] + 442.2, measured value [M+H] + 442.1. 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.71 - 7.42 (m, 1H), 7.06 - 6.76 (m, 2H), 4.08 (dd, J= 3.2,11.6 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.72 - 3.61 (m,2H), 3.52 (dt, J = 2.3,11.8 Hz, 1H), 3.29 - 3.20 (m, 1H), 2.98 (tt, J = 3.6,12.0Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.09 - 2.00 (m, 1H), 1.97 - 1.87 (m,2H), 1.86 - 1.75 (m, 1H), 1.65 - 1.44 (m, 3H).

[0313] Ex 2-86, SFC peak 4: MS (ESI) m / z :C 24 H 26 Calculated value of F2N3O3 [M+H] + 442.2, measured value [M+H] + 442.1. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.57 (dt, J = 6.6,8.2 Hz, 1H),7.03 - 6.76 (m, 2H), 4.12 (dd, J = 3.4,11.5 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.69(q, J = 7.6 Hz, 1H), 3.58 - 3.45 (m, 2H), 3.28 (dd, J = 8.0,9.5 Hz, 1H), 3.04 -2.93 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.04 - 1.95 (m, 1H), 1.94 - 1.86(m, 3H), 1.86 - 1.77 (m, 2H), 1.60 - 1.48 (m, 1H).

[0314] Examples 2-87, 2-88, 2-89, 2-90: 5-(2,4-Difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl) Tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 5-(2,4- (difluorophenyl)-7-((2) S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -Pyran-4- 1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 5-(2,4-difluorophenyl)-7- ((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-1,3-dihydro- 10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one and 5-(2,4-difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4- d]pyrazino[1,2-a]pyrimidin-10-one Step 1: 5-(2,4-difluorophenyl)-7-(2-(2-methylpyridin-4-yl)tetrahydro-2- H -pyran-4-yl)-1,3- Dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one In the presence of 7-(2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-5-(methylthio)-1,3-dihydro-10 H THF (439 μL) was added to a 20 mL red-capped vial containing 18.0 mg (43.9 μmol) of furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 2,4-difluorophenylboronic acid (8.66 mg, 54.8 μmol), tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (8.03 mg, 8.77 μmol), copper(I) thiophene-2-carboxylate (20.9 mg, 110 μmol), and tris(furan-2-yl)phosphine (2.04 mg, 8.77 μmol). The mixture was purged with N2 and heated on a hot plate at 70 °C for 10 min. The mixture was cooled to room temperature and DCM was added to the reaction mixture. The resulting mixture was filtered through a diatomaceous earth plug filter. The organic phase was separated and concentrated by adding saturated aqueous NaHCO3 solution to the DCM layer. The residue was diluted with DMSO and purified by reversed-phase Prep-HPLC to give 5-(2,4-difluorophenyl)-7-(2-(2-methylpyridin-4-yl)tetrahydro-2- H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one. MS (ESI) m / z :C 26 H 23 Calculated value of F2N4O3 [M+H] + 477.2, measured value [M+H] + 477.2.

[0315] The isomers were separated by chiral SFC using a Chiral IB-N column (21 x 250 mm, 5 μm) with 30% MeOH w / 0.1% NH4OH as a modifier to obtain peak 1 of SFC 2-87: 5-(2,4-difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 2-88 SFC peak 2: 5-(2,4-difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 2-89 SFC peak 3: 5-(2,4-difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one, 2-90 SFC peak 4: 5-(2,4-difluorophenyl)-7-((2 S 4 S or 2 R 4 R or 2 S 4 R or 2 R 4 S )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-1,3-dihydro-10 H -furano[3,4-d]pyrazino[1,2-a]pyrimidin-10-one.

[0316] Ex 2-87, SFC peak 1: MS (ESI) m / z :C 26 H 23 Calculated value of F2N4O3 [M+H] + 477.2, measured value [M+H] + 477.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (d, J= 4.9 Hz, 1H), 7.79(q, J = 7.5 Hz, 1H), 7.46 (t, J = 9.7 Hz, 1H), 7.30 (t, J = 8.3 Hz, 1H), 7.22 (s,1H), 7.14 (d, J = 4.9 Hz, 1H), 5.14 (s, 2H), 4.98 (s, 2H), 4.82 (d, J = 6.5 Hz,1H), 3.93 – 3.88 (m, 1H), 3.85 – 3.82 (m, 1H), 3.46-3.45 (m, 1H), 2.47 (s,3H), 2.41 (d, J = 14.3 Hz, 1H), 2.19-2.07 (m, 3H).

[0317] Ex 2-88, SFC peak 2: MS (ESI) m / z :C 26 H 23 Calculated value of F2N4O3 [M+H] + 477.2, measured value [M+H] + 477.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.79(q, J = 8.2 Hz, 1H), 7.48 – 7.43 (m, 1H), 7.30 (td, J = 8.5, 2.3 Hz, 1H), 7.22(s, 1H), 7.14 (d, J = 4.9 Hz, 1H), 5.14 (s, 2H), 4.98 (s, 2H), 4.82 (dd, J = 8.3,2.9 Hz, 1H), 3.93 – 3.88 (m, 1H), 3.85-3.83 (m, 1H), 3.48 – 3.44 (m, 1H), 2.47 (s, 3H), 2.41 (dd, J = 10.0, 4.6 Hz, 1H), 2.19-2.08 (m, 3H).

[0318] Ex 2-89, SFC peak 3: MS (ESI) m / z :C 26 H 23 Calculated value of F2N4O3 [M+H] + 477.2, measured value [M+H] + 477.1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.83 (s, 1 H), 8.49 (d, J = 5.1 Hz, 1 H),7.72 - 7.64 (m, 1 H), 7.22 (s, 1 H), 7.14 - 7.11 (m, 1 H), 7.10 - 7.04 (m, 1H), 7.04 - 6.97 (m, 1 H), 5.28 (t, J = 2.7 Hz, 2 H), 5.07 (t, J = 2.7 Hz, 2 H),4.93 - 4.89 (m, 1 H), 3.99 - 3.94 (m, 2 H), 3.45 - 3.36 (m, 1 H), 2.58 (s, 3H), 2.55 - 2.47 (m, 1H), 2.37 - 2.29 (m, 1 H), 2.23 - 2.17 (m, 2 H).

[0319] Ex 2-90, SFC peak 4: MS (ESI) m / z :C 26 H 23 Calculated value of F2N4O3 [M+H] + 477.2, measured value [M+H] + 477.1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.83 (s, 1 H), 8.49 (d, J = 5.2 Hz, 1 H),7.71 - 7.64 (m, 1 H), 7.22 (s, 1 H), 7.14 - 7.11 (m, 1 H), 7.10 - 7.04 (m, 1H), 7.03 - 6.97 (m, 1 H), 5.28 (t, J = 2.7 Hz, 2 H), 5.07 (t, J= 2.7 Hz, 2 H),4.94 - 4.88 (m, 1 H), 3.99 - 3.93 (m, 2 H), 3.44 - 3.37 (m, 1 H), 2.58 (s, 3H), 2.54 - 2.47 (m, 1 H), 2.37 - 2.29 (m, 1 H), 2.23 - 2.17 (m, 2 H).

[0320] The examples shown in Table 2-2 below were prepared using appropriate initial raw materials, following a procedure similar to that outlined in Examples 2-1 to 2-10 and 2-79 to 2-90 above.

[0321] Table 2-2: Examples 2-91 to 2-133 Example 2-134 9-(2,4-Difluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-(trifluoromethyl)pyridin-4-yl)tetrahydro- 2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: 7-((2) R 4 S )-2-(2-bromopyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorobenzene) 2,3-dimethyl-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one At 0 °C, TMS-Br (0.301 mL, 2.31 mmol) was added to a solution of 7-((CIS)-2-(2-chloropyridin-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (160 mg, 0.331 mmol) in MeCN (4 mL) and stirred for 20 min. The resulting mixture was then stirred at 110 °C for 16 h under N2. The solvent was removed under reduced pressure, and the residue was dissolved in water (10 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with a gradient of [0-30]% ethyl acetate / petroleum ether) to obtain 7-((2 R 4S )-2-(2-bromopyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z: C 25 H 22 Calculated value of BrF₂N₄O₂ [M+H] + : 527.1 / 529.1, measured value 527.1 / 529.1.

[0322] Step 2: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-(trifluoromethyl)pyridine-4- Tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one Add 7-((2-) to the dried 8 mL vial containing 0.4 mL of DMF. R 4 S )-2-(2-bromopyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4 H -pyrazino[1,2-a]pyrimidin-4-one (20 mg, 0.038 mmol) and (1,10-o-phenanthroline)(trifluoromethyl)copper(I) (60 mg, 0.192 mmol). The vials were sealed with PTFE-lined caps and heated at 80 °C for 8 h. The solutions were cooled to room temperature, and the reaction mixture was diluted with 10 mL of EtOAc. The reaction mixture was washed with H2O (3 x 10 mL) and brine (1 x 10 mL), the organic layer was dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography. The residue was purified by Prep-HPLC (column daicel chiralpak AD (250 mm x 30 mm, 10 μm) under CO2-ETOH (0.1% NH3H2O) conditions to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 R 4 S )-2-(2-(trifluoromethyl)pyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 26 H 22 Calculated value of F5N4O2 [M+H] + : 517.1, measured value 517.1. 1 H NMR (400MHz, CDCl3) δ 8.62 (d, J= 5.0 Hz, 1H), 8.50 (s, 1H), 7.67 (s, 1H), 7.55 (dt, J =6.5, 8.2 Hz, 1H), 7.43 (d, J = 4.8 Hz, 1H), 6.96 (dt, J = 2.3, 8.2 Hz, 1H), 6.92- 6.83 (m, 1H), 4.55 (dd, J = 1.6, 11.3 Hz, 1H), 4.46 - 4.24 (m, 1H), 3.94 -3.59 (m, 1H), 3.37 - 3.07 (m, 1H), 2.37 (s, 3H), 2.27 (br d, J = 13.0 Hz, 1H),2.21 (s, 3H), 2.04 - 1.93 (m, 2H), 1.72 (q, J = 12.0 Hz, 1H).

[0323] Example 2-135 9-(2,4-Difluorophenyl)-7-((2 R 4 S )-2-(2-isopropylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)- 2,3-Dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one At 0 ℃, towards 7-((2 R 4 S )-2-(2-chloropyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4 H -pyrazino[1,2-a]pyrimidin-4-one (50 mg, 0.104 mmol), Fe(acac)3 (3.66 mg, 10.3 µmol) was added to a mixture of THF (1 mL) and NMP (0.1 mL), and isopropyl magnesium chloride (0.259 mL, 0.518 mmol) was added. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with ammonium chloride aqueous solution (3 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by prep-HPLC (MeCN / water (0.1% TFA)) to give 9-(2,4-difluorophenyl)-7-((2 R 4 S )-2-(2-isopropylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 28 H 29 Calculated value of F2N4O2 [M+H] + : 491.2, measured value 491.2. 1 H NMR (CDCl3, 400 MHz) δ 8.86 (d, J =5.50 Hz, 1 H), 8.59 (s, 1 H), 7.72 (s, 1 H), 7.59 - 7.67 (m, 2 H), 6.93 - 7.07 (m, 2 H), 4.70 - 4.77 (m, 1 H), 4.40 - 4.48(m, 1 H), 3.80 - 3.89 (m, 1 H), 3.48 - 3.59 (m, 1 H), 3.26 - 3.36 (m, 1 H), 2.45 (s, 3 H), 2.34 - 2.42 (m, 1 H), 2.29 (s, 3 H), 2.06 - 2.16 (m, 2 H),1.72 - 1.84 (m, 1 H), 1.41 - 1.48 (m, 6 H).

[0324] Example 2-136 7-((2 R 4 S )-2-(2-(bicyclo[1.1.1]pentan-1-yl)pyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9- (2,4-Difluorophenyl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one Under N2, 7-((2) R 4 S )-2-(2-bromopyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4 H A mixture of pyrazino[1,2-a]pyrimidin-4-one (50 mg, 0.095 mmol), bicyclo[1.1.1]pentane-1-yltrifluoro-l4-borane potassium salt (49.5 mg, 0.284 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (10.6 mg, 9.48 µmol), Ni(dtbbpy)Br2 (6.9 mg, 0.014 mmol), and Na2CO3 (40.2 mg, 0.379 mmol) in DMA (1 mL) was stirred at 25 °C for 4 h in a 450 nm photoreactor. The mixture was filtered and the filtrate was purified by prep-HPLC (MeCN / water (0.1% TFA)) to give 7-((2R 4 S )-2-(2-(bicyclo[1.1.1]pentan-1-yl)pyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-9-(2,4-difluorophenyl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 30 H 29 Calculated value of F2N4O2 [M+H] + : 515.2, measured value 515.2. 1 H NMR (CDCl3,400 MHz) δ 8.79 - 8.86 (m, 1H), 8.59 (s, 1H), 7.55 - 7.69 (m, 3H), 6.94 -7.07 (m, 2H), 4.68 - 4.75 (m, 1H), 4.40 - 4.46 (m, 1H), 3.80 - 3.87 (m, 1H), 3.27 - 3.36 (m, 1H), 2.69 (s, 1H), 2.45 (s, 3H), 2.40 (s, 6H), 2.32 - 2.38(m, 1H), 2.29 (s, 3H), 2.04 - 2.12 (m, 2H), 1.74 - 1.82 (m, 1H).

[0325] Examples 2-137 and 138 1-(2,4-Difluorophenyl)-7,8-dimethyl-3-((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidin-4-yl)tetra Hydrogen-2 H -pyran-4-yl)-6 H -Pyrido[1,2-a]pyrazin-6-one and 1-(2,4-difluorophenyl)-7,8-dimethyl-3- ((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidin-4-yl)tetrahydro-2 H -pyran-4-yl)-6 H -pyrido[1,2-a]pyrazin-6-one Step 1: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-(6-methylpyrimidin-4-yl)-3,6-dihydro-2 H - pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one To 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (400 mg, 1.09 mmol) in dioxane (10 mL) was supplemented with t-BuOLi (192 mg, 2.403 mmol), XPhos Pd G2 (17.1 mg, 0.022 mmol), and 4-methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-yl)benzenesulfonylhydrazine (394 mg, 1.09 mmol), and the resulting mixture was stirred at 110 °C for 1 h. Water (20 mL) was added to the mixture and it was extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, ethyl acetate / petroleum ether = 1 / 1, v / v) to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-(6-methylpyrimidin-4-yl)-3,6-dihydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 25 H 22 Calculated value of F2N5O2 [M+H] + 462.2, measured value 462.1.

[0326] Step 2: 1-(2,4-Difluorophenyl)-7,8-dimethyl-3-((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidine-4- Tetrahydro-2- H -pyran-4-yl)-6 H -Pyrido[1,2-a]pyrazin-6-one and 1-(2,4-difluorophenyl)-7,8-dimethyl- 3-((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidin-4-yl)tetrahydro-2 H -pyran-4-yl)-6 H -pyrido[1,2-a]pyrazine- 6-keto Under N2, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-(6-methylpyrimidin-4-yl)-3,6-dihydro-2 H -pyran-4-yl)-4 HA solution of pyrazino[1,2-a]pyrimidin-4-one (50.0 mg, 0.108 mmol) in THF (1 mL) was supplemented with TEA (0.076 mL, 0.542 mmol) and palladium(II) chloride (1.921 mg, 10.83 µmol). Then, Et3SiH (63.0 mg, 0.542 mmol) was added via syringe at 0 °C, and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum. DCM (0.5 mL) and MnO2 (47.1 mg, 0.542 mmol) were added to the residue. The mixture was stirred at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (MeCN / water (0.05% NH3OH)) to give 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(6-methylpyrimidin-4-yl)tetrahydro-2- H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 25 H 24 Calculated value of F2N5O2 [M+H] + : 464.2, measured value 464.1. SFC separation: through chiral SFC [(DAICELCHIRALPAK AD (250mm) 30mm, 10μm) Conditions: CO2-EtOH (0.1% NH3H2O) Start B 45% End B 45%, Gradient time (min) 80; 100% B hold, Flow rate (mL / min): 4] Resolution 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(6-methylpyrimidin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -pyrazino[1,2-a]pyrimidin-4-one (21 mg, 0.045 mmol) to give Ex 2-137, SFC peak 1: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H-pyrazino[1,2-a]pyrimidin-4-one, and Ex 2-138, SFC peak 2: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-((2 S 4 R or 2 R 4 S )-2-(6-methylpyrimidin-4-yl)tetrahydro-2 H -pyran-4-yl)-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0327] Ex 2-137, SFC peak 1: MS (ESI) m / z :C 25 H 24 Calculated value of F2N5O2 [M+H] + : 464.2, measured value 464.2. 1 H NMR (400MHz, CDCl3) δ ppm 9.01 (s, 1 H), 8.56 (s, 1 H), 7.59 - 7.67 (m, 1H), 7.43 (s, 1 H), 6.99 - 7.06 (m, 1 H), 6.92 - 6.98 (m, 1 H), 4.58 (br d, J =10.61 Hz, 1 H), 4.33 - 4.42 (m, 1 H), 3.78 - 3.88 (m, 1 H), 3.20 - 3.34 (m, 1H), 2.57 - 2.60 (m, 1 H), 2.56 (s, 3 H), 2.44 (s, 3 H), 2.28 (s, 3 H), 2.02 -2.10 (m, 2 H), 1.72 - 1.82 (m, 1 H).

[0328] Ex 2-138, SFC peak 2: MS (ESI) m / z :C 25 H 24 Calculated value of F2N5O2 [M+H] + : 464.2, measured value 464.2. 1 H NMR (400MHz, CDCl3) δ ppm 9.01 (s, 1 H), 8.56 (s, 1 H), 7.59 - 7.67 (m, 1H), 7.43 (s, 1 H), 6.99 - 7.06 (m, 1 H), 6.91 - 6.99 (m, 1 H), 4.58 (br d, J=10.49 Hz, 1 H), 4.33 - 4.41 (m, 1 H), 3.79 - 3.88 (m, 1 H), 3.23 - 3.34 (m, 1H), 2.57 - 2.61 (m, 1 H), 2.56 (s, 3 H), 2.44 (s, 3 H), 2.28 (s, 3 H), 2.00 -2.07 (m, 2 H), 1.72 - 1.83 (m, 1 H).

[0329] Examples 2-139, 140, 141 and 142 9-(2,4-Difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl) Tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -pyrazino[1,2-a]pyrimidin-4-one, 9-(2,4-difluorophenyl)-7- ((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl Base-4 H -pyrazino[1,2-a]pyrimidin-4-one, 9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5, 5-Dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-Dimethyltetrahydrofuran-3-yl)tetrahydro- 2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one Step 1: 9-(2,4-difluorophenyl)-7-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2 H -pyr (4-yl)-2,3-dimethyl- ... H -Pyrazino[1,2-a]pyrimidin-4-one To a solution of 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (100 mg, 0.273 mmol) in dioxane (2 mL) and water (400 µL), 2-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetraethyl-1,3,2-dioxane (99 mg, 0.273 mmol), Na₂CO₃ (87 mg, 0.819 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.9 mg, 0.027 mmol) were added. The resulting mixture was stirred for 3 h at 80 °C under N₂ protection. Add water (10 mL) to the mixture and extract with EtOAc (5 mL x 3). Wash the combined organic fractions with brine (10 mL), dry with Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by prep. TLC (petroleum ether: EtOAc = 1:1) to give 9-(2,4-difluorophenyl)-7-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 26 H 27 Calculated value of F2N3O3 [M+H] + : 468.2, measured value 468.1.

[0330] Step 2: 9-(2,4-difluorophenyl)-7-(2-(5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -Pyran-4- 2,3-dimethyl-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one Under N2, 9-(2,4-difluorophenyl)-7-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H A solution of pyrazino[1,2-a]pyrimidin-4-one (100 mg, 0.214 mmol) in THF (3 mL) was supplemented with TEA (0.149 mL, 1.069 mmol) and palladium(II) chloride (3.79 mg, 0.021 mmol). Triethylsilane (124 mg, 1.07 mmol) was then added via syringe at 0 °C, and the resulting mixture was stirred at 25 °C for 12 h. The solution was then filtered and concentrated under reduced pressure. Manganese(IV) oxide (18.6 mg, 0.214 mmol) was added to the solution in DCM (3.00 mL), and the resulting mixture was stirred at 25 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by prep. TLC (EtOAc = 100%) to give 9-(2,4-difluorophenyl)-7-(2-(5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2-yl) H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one. MS (ESI) m / z :C 26 H 29 Calculated value of F2N3O3 [M+H] + : 470.2, measured value 470.3.

[0331] Chiral SFC separation: via SFC #1 (column DAICLICHI ALCEL OD (250 mm) (30mm, 10μm) Conditions: CO2-MeOH (0.1% NH3H2O), Start B 30%, End B 30%, Gradient time (min) 10; 100% B Hold time 10, Flow rate (mL / min) 80, Injection time 35) Separation product: 9-(2,4-difluorophenyl)-7-(2-(5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H-pyrazino[1,2-a]pyrimidin-4-one (50 mg, 0.106 mmol) to obtain peaks 1 and 2. Passed through SFC #2 (column DAICEL CHIRALPAK AD (250 mm)) to obtain peaks 1 and 2. 30mm, 10μm) Conditions CO2-MeOH (0.1%NH3H2O) Start B 30% End B 30%, Gradient time (min) 60 100% B Hold time 1, Flow rate (mL / min) 80, Injection 60) Separation peak 1 to obtain SFC peak 1, 9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one and SFC peak 2,9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one. Via SFC #3 (column DAICELCHIRALPAK AD (250 mm) 30mm, 10μm) Conditions CO2-MeOH (0.1% NH3H2O) Start B 35% End B 35%, Gradient time (min) 60 100% B Hold time 1, Flow rate (mL / min) 80, Injection 60) Separation peak 2 to obtain SFC peak 3, 9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one and SFC peak 4,9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one.

[0332] Ex 2-139, SFC peak 1, 9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one: MS (ESI) m / z :C 26 H 29 F2N3O3 + Calculated value [M+H] + 470.2, measured value [M+H] + :470.2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1 H), 7.60 - 7.69 (m, 1 H), 6.94 - 7.07 (m, 2 H), 4.15- 4.24 (m, 1 H), 3.93 (t, J =8.29 Hz, 1 H), 3.58 - 3.65 (m, 2 H), 3.31 - 3.40(m, 1 H), 2.97 - 3.11 (m, 1 H), 2.47 - 2.54 (m, 1 H), 2.45 (s, 3 H), 2.29 (s, 3 H), 1.91 - 2.04 (m, 5H), 1.69 - 1.74 (m, 1H), 1.32 (s, 3H), 1.22 (s, 3H).

[0333] Ex 2-140, SFC peak 2,9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R)-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one: MS (ESI) m / z :C 26 H 29 Calculated value of F2N3O3 [M+H] + : 470.2, measured value 470.2. 1 H NMR (400 MHz, CDCl3) δppm 8.54 (s, 1 H), 7.60 - 7.68 (m, 1 H), 7.01 - 7.07 (m, 1 H), 6.93 - 7.00(m, 1 H), 4.12 - 4.18 (m, 1 H), 4.04 - 4.10 (m, 1 H), 3.77 - 3.83 (m, 1 H), 3.55 - 3.63 (m, 1 H), 3.00 - 3.12 (m, 1 H), 2.47 - 2.53 (m, 1 H), 2.45 (s, 3H), 2.29 (s, 3 H), 1.94 - 2.09 (m, 3 H), 1.82 - 1.91 (m, 2 H), 1.42 - 1.47 (m, 1 H), 1.31 (s, 3 H), 1.21 (s, 3 H).

[0334] Ex 2-141, SFC peak 3,9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one: MS (ESI) m / z :C 26 H 29 Calculated value of F2N3O3 [M+H] + : 470.2, measured value 470.2. 1H NMR (400 MHz, CDCl3) δppm 8.54 (s, 1 H), 7.61 - 7.68 (m, 1 H), 7.01 - 7.08 (m, 1 H), 6.94 - 7.00 (m, 1 H), 4.12 - 4.18 (m, 1 H), 4.04 - 4.10 (m, 1 H), 3.78 - 3.83 (m, 1 H), 3.56 - 3.63 (m, 1 H), 3.30 - 3.36 (m, 1 H), 3.01 - 3.10 (m, 1 H), 2.47 - 2.53(m, 1 H), 2.45 (s, 3 H), 2.29 (s, 3 H), 1.94 - 2.11 (m, 3 H), 1.81 - 1.91 (m, 2 H), 1.41 - 1.47 (m, 1 H), 1.31 (s, 3 H), 1.21 (s, 3 H).

[0335] Ex 2-142, SFC peak 4,9-(2,4-difluorophenyl)-7-((2 S 4 R or 2 R 4 S )-2-(( S or R )-5,5-dimethyltetrahydrofuran-3-yl)tetrahydro-2 H -pyran-4-yl)-2,3-dimethyl-4 H -Pyrazino[1,2-a]pyrimidin-4-one: MS (ESI) m / z :C 26 H 29 Calculated value of F2N3O3 [M+H] + : 470.2, measured value 470.2. 1 H NMR (400 MHz, CDCl3) δppm 8.54 (s, 1 H), 7.64 (td, J =8.23, 6.56 Hz, 1 H), 7.04 (td, J =7.87, 2.38 Hz,1 H), 6.93 - 7.00 (m, 1 H), 4.18 (dd, J =11.32, 4.05 Hz, 1 H), 3.93 (t, J=8.23Hz, 1 H), 3.57 - 3.65 (m, 2 H), 3.32 - 3.38 (m, 1 H), 3.01 - 3.10 (m, 1 H), 2.47 - 2.54 (m, 1 H), 2.45 (s, 3 H), 2.29 (s, 3 H), 1.94 - 2.00 (m, 3 H), 1.84 - 1.92 (m, 1 H), 1.63 - 1.73 (m, 2 H), 1.32 (s, 3 H), 1.22 (s, 3 H).

[0336] The examples shown in Tables 2-3 below were prepared using suitable initial raw materials according to procedures similar to those outlined in Examples 2-1 to 2-10, 2-79 to 2-90, and 2-134 to 2-142 above.

[0337] Table 2-3: Examples 2-143 to 2-335 Other exemplary compounds Other exemplary compounds 3-1 to 3-98 are listed in Table 3 below.

[0338] Table 3 The synthesis of the isomers of Example 3-10 is described in Examples 2-130 to 2-133.

[0339] The synthesis of the isomers of Example 3-19 is described in Examples 2-2 to 2-4.

[0340] The synthesis of the isomers of Examples 3-82 is described in Examples 2-79.

[0341] The synthesis of the isomers of Examples 3-92 is described in Examples 2-80.

[0342] The synthesis of the isomers of Example 3-31 is described in Examples 2-162 to 2-164.

[0343] The synthesis of the isomers of Examples 3-55 is described in Examples 2-287.

[0344] Examples 4-1 and 4-2: 4-(2,4-difluorophenyl)-2-((2 R 6 S or 2 S 6 R )-2-methyl-6-(2-methylpyridin-4-yl)morpholino)- 7,8-Dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6) H )-ketones and 4-(2,4-difluorophenyl)-2-((2 R 6 S or 2 S 6 R )-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a] Pyrimidine-10(6) H )-ketone Step 1: 5-Amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid A solution of 5-amino-2,6-dichloropyrimidine-4-carboxylic acid (4.5 g, 21.63 mmol) in 1,4-dioxane (100 mL) was supplemented with (4-chloro-2-fluorophenyl)boronic acid (3.40 g, 19.5 mmol), K₂CO₃ (8.97 g, 64.9 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1.58 g, 2.16 mmol), and water (11 mL), and the resulting mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (20 mL x 2). The pH of the aqueous phase was adjusted to approximately 4 by stepwise addition of HCl (1 M) and extracted with EtOAc (50 mL x 3). The combined organic fractions were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (10% MeOH / ethyl acetate gradient) to give 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid. MS (ESI) m / z :C 11 Calculated value of H6Cl2FN3O2 [M+H] + 286.0 / 288.0, measured value [M+H] + 286.0 / 288.0.

[0345] Step 2: 2-Chloro-4-(2,4-difluorophenyl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10 (6 H )-ketone POCl3 (0.783 mL, 8.40 mmol) was added to a solution of 5-amino-2-chloro-6-(2,4-difluorophenyl)pyrimidine-4-carboxylic acid (800 mg, 2.80 mmol) in toluene (50 mL) at 20 °C, and the mixture was stirred for 20 min. Then, pyrrolidine-2-one (358 mg, 4.20 mmol) was added, and the resulting mixture was stirred at 110 °C under N2 for 16 h. The reaction solution was concentrated under vacuum. The mixture was added in portions to water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were concentrated under reduced pressure. The residues were purified by rapid silica gel chromatography (0–80% ethyl acetate / petroleum ether gradient) to give 2-chloro-4-(2,4-difluorophenyl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidine-10(6 H )-Ketone. MS (ESI) m / z :C 15 H 10 Calculated value of ClF2N4O [M+H] + 335.0 / 337.0, measured value [M+H] + 335.0 / 337.0.

[0346] Step 3: 4-(2,4-difluorophenyl)-2-((2 R 6 S or 2 S 6 R Is it )-2-methyl-6-(2-methylpyridin-4-yl)? lino)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketones and 4-(2,4-difluorophenyl)-2- ((2 R 6 S or 2 S 6 R )-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-7,8-dihydropyrimidino[5,4-d]pyrrolo [1,2-a]pyrimidine-10(6 H )-ketone To 2-chloro-4-(2,4-difluorophenyl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H A solution of 4-(2,4-difluorophenyl)-2-((cis-2-methyl-6-(2-methylpyridin-4-yl)morpholine (20.68 mg, 0.108 mmol) and DIPEA (0.047 mL, 0.269 mmol) in dioxane (2 mL) was added, and the resulting mixture was stirred at 80 °C for 3 h. The reaction solution was filtered, concentrated under vacuum, and purified by prep. HPLC (water (0.1% TFA)-MeCN) to give solid 4-(2,4-difluorophenyl)-2-((cis-2-methyl-6-(2-methylpyridin-4-yl)morpholine). generation )-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketone. Enantiomers were separated by chiral SFC: [column DAICELCHIRALPAK AD (250 mm x 30 mm, 10 μm); conditions: CO2-EtOH (0.1% NH3H2O)] to give 4-1 (SFC peak 1): 4-(2,4-difluorophenyl)-2-((2-)-ketone. R 6 S or 2 S 6 R )-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketone, and 4-2 (SFC peak 2): 4-(2,4-difluorophenyl)-2-((2 R 6 S or 2 S 6 R )-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one.

[0347] Ex 4-1 (SFC Peak 1): MS (ESI) m / z :C 26 H 25 Calculated value of F2N6O2 [M+H] + 491.1, measured value [M+H] + :491.2.1 1H NMR (400 MHz, CDCl3) δ ppm 8.44 - 8.52 (m, 1 H), 7.59 - 7.69 (m, 1H), 7.27 - 7.28 (m, 1 H), 7.19 (br d, J J = 4.89 Hz, 1 H), 6.99 - 7.06 (m, 1 H), 6.91 - 6.98 (m, 1 H), 4.81 - 5.05 (m, 2 H), 4.58 (dd, J J = 10.67, 2.44 Hz, 1 H), 4.17 - 4.26 (m, 2 H), 3.79 - 3.92 (m, 1 H), 3.08 (t, J J = 7.93 Hz, 2 H), 2.79 - 2.93 (m, 2 H), 2.58 (s, 3 H), 2.28 (quin, J J = 7.54 Hz, 2 H), 1.38 (d, J J = 6.20 Hz, 3 H).

[0348] Ex 4-2 (SFC peak 2): MS (ESI) m / z : C 26 21 25 H24F2N6O2 + Calculated [M+H] + : 491.1, found [M+H] + : 491.2. 1 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (d, J J = 5.25 Hz, 1 H), 7.59 - 7.68 (m, 1 H), 7.27 - 7.30 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.00 - 7.05 (m, 1 H), 6.95 (td, J J = 9.54, 2.38 Hz, 1 H), 4.84 - 5.05 (m, 2 H), 4.54 - 4.64 (m, 1 H), 4.17 - 4.26 (m, 2 H), 3.81 - 3.92 (m, 1 H), 3.08 (t, J= 8.11 Hz, 2 H), 2.79 - 2.92(m, 2 H), 2.59 (s, 3 H), 2.23 - 2.32 (m, 2 H), 1.38 (d, J = 6.20 Hz, 3 H).

[0349] Examples 4-3 and 4-4: 4-(4-chloro-2-fluorophenyl)-2-((2 R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -Pyran- 4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6) H )-ketones and 4-(4-chloro-2-fluorophenyl)-2- ((2 R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyran Pyrimidine-10(6)-[1,2-a]pyrimidine-10(6) H )-ketone Step 1: 4-(4-chloro-2-fluorophenyl)-2-(2-(2-methylpyridin-4-yl)tetrahydro-2- H -pyran-4-yl)-7,8- Dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6) H )-ketone Under N2, 2-chloro-4-(4-chloro-2-fluorophenyl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6) H A solution of 4-(4-bromotetrahydro-2-oxo)one (40 mg, 0.114 mmol) in DMA (5 mL) was added. H 2-pyran-2-yl)-2-methylpyridine (43.8 mg, 0.171 mmol), pyridine-2-formamidine hydrochloride (8.9 mg, 0.057 mmol), TBAI (42.1 mg, 0.114 mmol), zinc (22.3 mg, 0.342 mmol), and nickel(II) chloride DME complex (7.51 mg, 0.034 mmol) were added, and the resulting mixture was stirred at 50 °C for 16 h under N2. The mixture was treated with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (5.0 mL), and manganese(IV) oxide (99 mg, 1.139 mmol) was added. The resulting mixture was stirred at 50 °C for 1 h. The reaction solution was filtered, concentrated, and purified by HPLC (water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-MeCN) to obtain crude 4-(4-chloro-2-fluorophenyl)-2-(2-(2-methylpyridin-4-yl)tetrahydro-2- H -pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-Ketone. MS (ESI) m / z :C 25 H 24 Calculated value of ClFN6O2 [M+H] +492.1 / 494.1, measured value [M+H] + :492.0 / 494.0.

[0350] Step 2: 4-(4-chloro-2-fluorophenyl)-2-((2 R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H - pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6) H )-ketones and 4-(4-chloro-2-fluorobenzene (base)-2-((2) R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-7,8-dihydropyrimidin[5, 4-d]pyrrolo[1,2-a]pyrimidine-10(6 H Chiral SFCs of )-ketones Through chiral-SFC [pillar DAICEL CHIRALPAK AD (250 mm)] 30 mm, 10 μm) conditions: CO2-MeOH (0.1% NH3H2O)] resolution 4-(4-chloro-2-fluorophenyl)-2-(2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketone (12 mg, 0.024 mmol) to give 4-3 (SFC peak 1): 4-(4-chloro-2-fluorophenyl)-2-((2 R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketone, and 4-4 (SFC peak 2): 4-(4-chloro-2-fluorophenyl)-2-((2 R 4 S or 2 S 4 R )-2-(2-methylpyridin-4-yl)tetrahydro-2 H -pyran-4-yl)-7,8-dihydropyrimidino[5,4-d]pyrrolo[1,2-a]pyrimidin-10(6 H )-ketone.

[0351] Ex 4-3, SFC peak 1: MS (ESI) m / z :C 25 H 24 Calculated value of ClFN6O2 [M+H] + 492.1 / 494.1, measured value [M+H] + :492.0 / 494.0. 1 H NMR (400 MHz, CDCl3) δ 8.51 (br d, J = 4.9 Hz, 1H), 7.60(t, J= 7.9 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.24 (br d, J = 1.9 Hz, 1H), 7.23 -7.20 (m, 1H), 4.55 (br d, J = 11.3 Hz, 1H), 4.39 - 4.33 (m, 1H), 4.32 - 4.27(m, 2H), 3.81 (br d, J = 2.4 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.17 (t, J = 7.9 Hz,2H), 2.61 (s, 3H), 2.37 - 2.30 (m, 3H), 2.21 (br dd, J = 4.1, 12.6 Hz, 1H),2.13 (br d, J = 1.4 Hz, 1H), 1.96 (br d, J = ...

Claims

1. A compound of formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 is C or N; X 2 is C or N, provided that X 1 and X 2 are not simultaneously N; X 3 is C or N; X 4 is C or N; X 5 It is C or N; X 6 Selected from -CH2-, -N(CH3)- and -O-, and y is 0 or 1; R 1 It is -C 1-10 Alkyl group, -(CH2) z -OH or -(CH2)-N(CH3); R 2 It is -C 1-10 Alkyl or -OC 1-6 alkyl; Where R 1 and R 2 C 1-10 Alkyl and R 2 -OC 1-6 Alkyl groups are unsubstituted or independently converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; Alternatively, R 1 and R 2 Connected together to form C 3-7 Cycloalkyl or three- to seven-membered heterocyclic groups Wherein C 3-7 The cycloalkyl or three- to seven-membered heterocyclic group is unsubstituted or converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 They must be connected together to form C 3-7 Cycloalkyl or three- to seven-membered heterocyclic groups; A is selected from (i)C 3-7 cycloalkyl groups and (ii) heterocyclic groups consisting of the following: (1) Seven carbon atoms and one nitrogen atom, (2) Six carbon atoms and (i) one O atom, (ii) one N atom or (iii) one O and one N atom, or (3) Four carbon atoms and one nitrogen atom, or (4) ,in: Y 1 It is CH, CF, O, or N; Y 2 It is CH or N; Y 3 It is CH or N; R 5 Selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluorine and =O; Where R 5 -C(=O)-C 3-8 The cycloalkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine atoms each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, and -SCH3; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 16a and R 16b It can be hydrogen, fluorine, or methyl independently; R 6 Selected from hydrogen, C 3-7 Cycloalkyl, heterocyclic and heteroaryl groups, Where R 6 C 3-7 The cycloalkyl moiety is either unsubstituted or substituted with a heteroaryl group or one or two fluorine atoms. Where R 6 The heterocyclic or heteroaryl group is unsubstituted or substituted by one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 3 Selected from the following: (a) 、(b) 、(c) 、(d) 、(e) 、 (f) (g) (h) (i) and (j) , R 7 and R 9 Independently selected from hydrogen, methyl, and halogen; R 8 R 10 and R 11 Independently selected from hydrogen, halogen, -C 1-4 Alkyl groups, -CF3, and -SCH3; X 7 It is C or N; R 12 and R 12’ Each is independently selected from hydrogen, -CF3, -OCF3, -(CH3)2, and fluorine; R 13 and R 13’ Each is independently selected from hydrogen and fluorine; R 4 R 14 and R 17 Each is independently selected from hydrogen and fluorine; Where X 4 When it is C, R 17 It is fluorine; and When X 5 When it is N, R 4 It is hydrogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the following: , , , , , , , , , , and .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): (II) Or its pharmaceutically acceptable salt, wherein: X 1 It is C or N; X 2 It is C or N, where X 1 When it is N, X 2 It is C, and the condition is X. 1 and X 2 They are not both N; Y 1 It is O or N; Y 2 It is CH or N; R 1 It is -C 1-4 alkyl; Where R 1 C 1-4 The alkyl moiety is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; R 2 It is -C 1-4 Alkyl or -OC 1-4 alkyl; Where R 2 C 1-4 The alkyl moiety is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; or R 1 and R 2 They are linked together to form three- to seven-membered cycloalkyl or heterocyclic groups; The three- to seven-membered cycloalkyl or heterocyclic group is optionally oxidized by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution; And the condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 They must be linked together to form three- to seven-membered cycloalkyl or heterocyclic groups; R 10 Selected from hydrogen, halogens, -C 1-3 Alkyl groups, -CF3, and -SCH3; R 7 R 8 R 9 R 10 and R 11 Independently selected from hydrogen, methyl, and halogen; R 5 Selected from hydrogen, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -C(=O)-heteroaryl and -C(=O)-C(CH3)2-heteroaryl; Where Y 1 When it is O, R 5 It does not exist; Where R 5 -C(=O)-C 3-8 The cycloalkyl group is unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine groups each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, -SCH3, and one or two fluorine molecules. Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -C(=O)-heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one or two substituents, which are independently selected from -C each time they appear. 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl groups, -CF3 groups, and fluorine; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; R 6 Selected from hydrogen and heteroaryl groups; Where R 6 The heteroaryl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from -C. 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl groups, -CF3 groups, and fluorine; and y is 0 or 1.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof. Where X 1 It is C, X 2 It is N, and R 1 and R 2 Linked together to form a three- to seven-membered cycloalkyl or heterocyclic group, wherein the three- to seven-membered cycloalkyl or heterocyclic group is unsubstituted or converted by one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl substitution.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein X 1 It is N.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 and 5, wherein R 1 and R 2 Each is a methyl group.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 1 and R 2 Together they form C 5-8 Cycloalkyl or heterocyclic groups containing one O atom.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 5 Selected from -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl and -C(=O)-C(CH3)2-heteroaryl; Where R 5 The -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are composed of the following: (1) Four carbon atoms and one O atom, (2) Three carbon atoms and (i) N and O, (ii) N and S, or (iii) N and NH; (3) Two carbon atoms and three nitrogen atoms; (4) Seven carbon atoms and N and O; and Where R 5 The -C(=O)- heterocyclic group is composed of the following: (1) Three, four, five, six or seven carbon atoms and one O atom, (2) Four carbon atoms and (i) two O atoms or (ii) N atoms and O atoms, or (3) Six carbon atoms, two O atoms, and one N atom.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 6 It is in position 1 by -C 1-10 Alkyl-substituted pyrazoles.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 6 It was -C 1-10 Alkyl-substituted pyridine.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3, wherein R 10 It is either fluorine or chlorine, R 9 It is fluorine and R 7 It is hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3, wherein R 10 It is chlorine, R 9 It is fluorine and R 7 It is hydrogen.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III): (III) Where X 1 X 2 R 1 R 2 and R 10 It is as defined in claim 1.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IV). (IV) in: X 1 It is C or N; X 2 It is C or N, and the condition is X. 1 and X 2 They are not both N; R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring C Z yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated, and contains a heteroatom selected from N, O, and S; or (iii) A 9- or 10-membered bicyclic heterocyclic alkyl group, wherein the 9- or 10-membered bicyclic heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two factors. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; The condition is when X 1 It is C and X 2 When it is N, then R 1 and R 2 With X 1 and X 2 Together they must form a ring C Z ; Y 2 It is C(H) or N; Y 4 It is CH2 or O; R 6 yes: (a) Ring C 6 Among them, ring C 6 yes: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) A 4- to 6-membered saturated monocyclic heterocyclic alkyl group containing a heteroatom selected from N, O and S; (iii) A 6- to 10-membered fused or bridged heterobicyclic system containing one or two heteroatoms independently selected from N, O, and S; wherein the 6- to 10-membered heterobicyclic system is: (a) Fully saturated, or (b) Contains one aromatic ring and one partially unsaturated ring; (iv) C 3-7 Saturated cycloalkyl groups; or (v) Phenyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or R 6ac R 6a Substituent substitution; Where R 6ac It is -(CH2) v -C ac ; C ac yes (I)C 3-6 Monocyclic cycloalkyl; (II)C 7-12 Bicyclic cycloalkyl; (III) 3 to 6-membered monocyclic heterocyclic alkyl groups, wherein the 3 to 6-membered monocyclic heterocyclic alkyl groups are saturated and contain 1 to 2 heteroatoms independently selected from N, O and S; (IV) A 6- to 10-membered bicyclic heterocyclic alkyl group, wherein the 6- to 10-membered bicyclic heterocyclic alkyl group is saturated or partially saturated and contains 1 to 2 heteroatoms independently selected from N, O and S; (V) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O and S; (VI) A 6- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, and S; or (VII) Phenyl or naphthyl; Where C ac It is unsubstituted or composed of one or two independent molecules selected from halogen, amino, oxo, C 1-12 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkylamino, C 1-3 Dialkylamino, C 1-3 Alkoxy and C 1-3 Alkoxy (C 1-3 Alkyl substituents; (b) C 1-6 alkyl; (c)C 1-6 fluoroalkyl; (d)C 1-6 Alkoxy; (e)C 1-3 Alkoxy (C 1-3 )alkyl; (f)C 1-3 Hydroxyalkyl; Each R A Independently, it is fluorine C 1-3 Alkyl or C 1-3 Alkoxy; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen, methyl, or trifluoromethyl; q is 1 or 2; r is 0, 1, or 2; s is 0 or 1; and v is 0, 1, or 2.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V). (V)， in: R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring C Z yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; or (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two factors. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; Y 2 It is C(H) or N; R 6 yes (a) Ring C 6 , that is: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) 4 to 6-membered saturated heterocyclic alkyl groups containing a heteroatom selected from N, O and S; (iii) A 6- to 10-membered fused or bridged heterobicyclic system containing one or two heteroatoms independently selected from N, O, and S; wherein the 6- to 10-membered heterobicyclic system is: (a) Fully saturated, or (b) Contains one aromatic ring and one partially unsaturated ring; or (iv) C 3-6 cycloalkyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkoxy or R 6ac R 6a Substituent substitution; Where R 6ac It is -(CH2) v -C ac ; C ac yes (I)C 3-6 Monocyclic cycloalkyl; (II) A 3- to 6-membered monocyclic heterocyclic alkyl group, wherein the 3- to 6-membered monocyclic heterocyclic alkyl group is saturated and contains 1 to 2 heteroatoms independently selected from N, O and S; or (III) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O and S; Where C ac It is unsubstituted or has one or two groups selected from halogen, amino, cyano, oxo, C 1-12 Alkyl, C 1-3 fluoroalkyl, C 1-3 Alkylamino, C 1-3 Dialkylamino, C 1-3 Alkoxy, C 1-3 Alkoxy (C 1-3 Alkyl substituents, (b) C 1-6 alkyl; (c)C 1-3 Hydroxyalkyl; (d)C 1-3 Halogenated alkyl; or (e) Cyano group; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen; and R 16a and R 16b Independently, it consists of H, fluorine, and C. 1-3 Alkyl or C 1-3 fluoroalkyl; Alternatively, R 16a and R 16b Together with the carbon atom to which it is attached, they form C 3-6 cycloalkyl; and y is 0 or 1.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z .

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , , or ;and Where p is 0, 1 or 2.

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein Y 2 It is N.

19. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein Y 2 It is C(H).

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes or .

21. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 6 It is an unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuranyl group.

22. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , or ; where t is 0, 1 or 2.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VII). (VII), in: Ring C z It is a cyclopentenyl, cyclohexenyl, dihydrofuran, or dihydropyran ring; Each R Z Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; Ring C 6 yes (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) Five- to six-membered saturated monocyclic or bicyclic heterocyclic alkyl groups containing one O heteroatom; or (iii) C 3-7 cycloalkyl; Each R 6a Independently selected from halogens, C 1-3 Alkyl, cyano, C 1-3 Alkoxy and C 3-6 cycloalkyl; or Each R A It is independently fluorine or C1-C3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is a halogen; methyl or trifluoromethyl; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , , and .

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , , , , , , or .

26. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , or .

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VIII). (VIII), in: Ring C z It is a cyclopentene, cyclohexene, dihydrofuran, or dihydropyran ring; Each R Z Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; Y 4 It is CH2 or O; Ring C 6 yes (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) 5- to 6-membered saturated heterocyclic alkyl groups containing one O heteroatom; or (iii) C 3-7 cycloalkyl; Each R 6a Independently selected from halogens, C 1-3 Alkyl, cyano, C 1-3 Alkoxy and C 3-6 cycloalkyl; or Each R A It is independently fluorine or C1-C3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is a halogen; methyl or trifluoromethyl; p is 0, 1, or 2; q is 1 or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , , , , , , or .

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VI). (WE) in: Y 2 It is C(H) or N; Y 4 It is C(H) or O; Each R Z Selected independently from C 1-3 Alkyl, C 1-3 Fluoroalkyl groups and halogens; R 6 yes: (a) Ring C 6 Among them, ring C 6 yes: (i) 5 to 6-membered monocyclic heteroaryl groups containing 1 to 2 heteroatoms independently selected from N, O and S; (ii) A 5- to 6-membered saturated heterocyclic alkyl group containing a heteroatom selected from N, O, and S; or (iii) C 3-7 cycloalkyl; Among them, ring C 6 It is unsubstituted or composed of one or two independent elements selected from halogens, C 1-3 Alkyl, cyano, C 1-3 Alkoxy or C 3-6 cycloalkyl R 6a Substituent substitution; or (b) C 1-6 alkyl; R A Is it fluorine or C? 1-3 alkyl; R 7 R 8 and R 11 It is either H or halogen; R 10 It is halogen; and p is 0, 1, or 2; q is 1 or 2; r is 0, 1, or 2; as well as s is 0 or 1.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , or .

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 6 It is an unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuranyl group.

32. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , , , , , , , , , , or .

33. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the fraction is... yes , .

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IX). (IX), in: R 1 and R 2 C is independent 1-3 Alkyl, or alternatively, R 1 and R 2 Together with the attached carbon atom, it forms a ring C Z ; Among them, ring C Z yes: (i) Non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl groups; or (ii) a 5- or 6-membered heterocyclic alkyl group, wherein the 5- or 6-membered heterocyclic alkyl group is non-aromatic and partially unsaturated and contains a heteroatom selected from N, O and S; Among them, ring C Z It is either unsubstituted or selected independently from C by one or two other factors. 1-3 Alkyl, C 1-3 R of fluoroalkyl and halogen Z Substituent substitution; R 5 Selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C 1-10 Alkyl, -C(=O)-C 1-10 Alkyl, -C(=O)-C 3-8 Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluorine and =O; Where R 5 -C(=O)-C 3-8 The cycloalkyl group is unsubstituted or substituted with one or two substituents, each substituent being independently selected from unsubstituted or -C groups substituted with one or two fluorine atoms each time it appears. 1-2 Alkyl, heteroaryl, -NH-C(=O)-OC 1-10 Alkyl groups, -OCH3, -CH2CH2OCH3, and -SCH3; Where R 5 -SO2C 1-10 Alkyl or -C(=O)-C 1-10 The alkyl group is unsubstituted or -OC 1-3 Alkyl, cyclopentyl, isopropenyl, or one, two, or three fluorine-substituted compounds; Where R 5 The -C(=O)-aryl, -C(=O)-heterocyclic, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl groups are unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from -C. 1-10 Alkyl, -OC 1-10 Alkyl, -C(=O)-OC 1-10 Alkyl, -C 3-5 Cycloalkyl, methylbenzyl, -CF3, fluorine, and =O; R 16a and R 16b Independently, it consists of H, fluorine, and C. 1-3 Alkyl or C 1-3 fluoroalkyl; Alternatively, R 16a and R 16b Together with the carbon atom to which it is attached, they form C 3-6 cycloalkyl; R 7 R 8 and R 11 It is independently H or halogen; and R 10 It is a halogen; methyl or trifluoromethyl.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example numbers 1-1 to 1-259, 2-1 to 2-235, 4-1 to 4-30, 5-1 to 5-2, 6-1 to 6-9 and 7-1 to 7-5.

36. A pharmaceutical composition comprising an effective amount of any one of claims 1-35, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is suitable for oral, injectable, intramuscular, subcutaneous, intravenous or intraperitoneal administration.

38. The pharmaceutical composition according to claim 36 or claim 37, wherein the pharmaceutical composition is adapted for oral administration.

39. A method for activating the TREM2 receptor in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-35, or the pharmaceutical composition of any one of claims 36-38.

40. A method for treating or preventing conditions associated with loss of TREM2 function in a subject, comprising administering to the subject an effective amount of any one of claims 1-35, a pharmaceutically acceptable salt, or any one of claims 36-38, a pharmaceutical composition.

41. A method for treating or preventing neurodegenerative diseases in a subject, comprising administering to the subject an effective amount of any one of claims 1-35, or a pharmaceutically acceptable salt, or any one of claims 36-38, a pharmaceutical composition.

42. The method of claim 41, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, demyelinating diseases, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), tau disease, Nasu-Hakola disease, or adult-onset axonoglobulinosis and glial leukoencephalopathy (ALSP).

43. The method of claim 41 or claim 42, wherein the neurodegenerative condition is Alzheimer's disease.

44. The method according to any one of claims 39-43, wherein the subject is a human being.

45. The method according to any one of claims 39-43, further comprising the step of administering tau-targeted therapy or β-amyloid-targeted therapy.

46. ​​The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-35, used to prepare a medicament for treating or preventing neurodegenerative diseases in a subject.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-35, for use in treatment.

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