4h-pyrimido[1,2-a]pyrimidin-4-one derivatives for use as NLRP3 inflammasome inhibitors for the treatment of neurodegenerative disorder

Abstract

The invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: (I) wherein R1, R2, R3, R4 and ring A (X1, X2, X3, X4, X5 and X6) are as defined in the specification, for treatment of a disease, disorder or condition associated with NLRP3, including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).

Description

HETEROCYCLIC COMPOUND FIELD OF THE INVENTION

[0001] This invention relates to heterocyclic compounds which are inhibitors of theNLRP3 inflammasome, to medicaments which contain them, and to their use to treat diseases, disorders and / or conditions associated with NLRP3, including neurodegenerativediseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease,amyotrophic lateral sclerosis, prion disease and obesity with certain additional risk factors for cardiovascular disease. BACKGROUND OF THE INVENTION

[0002] More than 1% of the world’s population suffers from neurodegenerative diseases,including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and prion disease, all of which lack effective therapies. The incidence of neurodegenerative diseases is expected to double in the coming decades, especially affecting countries with an aging population. See I. Fernández-Cruz and E. Reynaud, “Proteasome Subunits Involved in Neurodegenerative Diseases,” Arch Med Res. 52(1):1-14 (2021).

[0003] One of the pathological hallmarks of neurodegenerative diseases is the aggregationof certain proteins into oligomers or fibrils. These conformational changes result in neurotoxicity, leading to inflammation and neurodegeneration. Although the clinical presentations of these diseases are heterogeneous, they often share common underlying mechanisms and pathophysiologies. See B. N. Dugger and D. W. Dickson, “Pathology of Neurodegenerative Diseases,” Cold Spring Harbor Perspect Biol 9(7): a028035 (2017). Indeed, systemic activation of the innate immune system, which is the first line of host defense against pathogens and tissue injury, and subsequent neuroinflammation play a key role in the onset and the progression of these diseases. See S. Amor, F. Puentes, D. Baker, et al., “Inflammation in neurodegenerative diseases,” Immunology 129(2):154-69 (2010). Neuroinflammation is a physiological response to exogenous and endogenous insults that target the central nervous system (CNS) and represents a protective response in the brain. However, excessive inflammatory responses are detrimental to the CNS. See L. I. Labzin, M. T. Heneka and E. Latz, “Innate Immunity and Neurodegeneration,” Annu Rev Med 69:437- 449 (2018). 160230447.1

[0004] Microglia, which are myeloid cells of the CNS, play a major role during innateimmune responses in the CNS. They express pattern recognition receptors (PRRs) which enable the host to recognize pathogen-associated molecular patterns (PAMPS) and host- or environment-derived danger-associated molecular patterns (DAMPS). See R. M. Ransohoff, M. A. Brown, “Innate immunity in the central nervous system,” J Clin Invest 122(4):1164-71 (2012). PRRs include Toll-like receptors, C-type lectin receptors, RIG-1 like receptors, and nucleotide-binding oligomerization domain-like receptors (NLRs). See P. Broz and V. M. Dixit, “Inflammasomes: mechanism of assembly, regulation and signaling,” Nat Rev Immunol 16(7):407-20 (2016). Engagement of PRRs activates a variety of inflammatory signaling pathways to eliminate infection and repair damaged tissue. The ongoing inflammation found in a variety of neurodegenerative diseases can be maintained by the key innate immune sensor for danger signals, the inflammasomes. There are several different inflammasomes, all defined by the PRRs they contain. Among the PRRs from the NLR family, the NLRs – NLRP1, NLRP3, NLRC4 –and two other PRRs – Pyrin and AIM2 – are known to form inflammasomes. See D. Zheng, T. Liwinski and E. Elinav, “Inflammasome activation and regulation: toward a better understanding of complex mechanisms,” Cell Discov 6:36 (2020).

[0005] The NLRP3 (nucleotide-binding domain (NOD), leucine-rich repeats-containingdomain (LRR), and pyrin domain-containing 3) inflammasome has been the subject of intense interest in the past decade. See N. Kelley, D. Jeltema, Y. Duan, et al., “The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation,” Int J Mol Sci 20(13):3328 (2019). The NLRP3 inflammasome consists of three main components: a pattern recognition receptor (PRR) protein, NLRP3; an apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD), which functions as a central adaptor protein; and an inflammatory caspase, caspase-1. See Kelley et al. (2019). NLRP3 is comprised of three domains: an amino-terminal pyrin domain (PYD); a central NACHT domain, having ATPase activity that is vital for NLRP3 self-association and oligomerization; and a carboxy-terminal LRR domain. See Broz and Dixit (2016).

[0006] The activation of NLRP3 inflammasome involves a two-step process. A first“priming” signal is generated by the detection of PAMPs or DAMPs via TLRs. This priming signal results in NF-κB-dependent transcriptional upregulation of NLRP3 and pro-IL-1, but also controls post-translational modifications of NLRP3. See J. Yang, Z. Liu and T. S. Xiao, “Post-translational regulation of inflammasomes,” Cell Mol Immunol 14(1):65-79 (2017). The initial trigger is followed by a second “activation” signal (β-amyloid, α-synuclein and 260230447.1other proteinaceous insults, ATP, crystals, nucleic acids, toxins) that induces conformational change of the various inflammasome components to subsequently assemble and nucleate the oligomerization of monomeric NLRP3, leading to the formation and activation of the NLRP3 inflammasome. See A. Lu, V. G Magupalli, J. Ruan, et al., “Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes,” Cell 156(6):1193-1206 (2014). This large multimeric protein acts via caspase-1 dependent proteolytic cleavage of several proteins, including pro-interleukin (pro-IL)-18 and pro-IL-1β to their mature inflammatory cytokines, IL-18 and IL-1β. See Kelley et al. (2019). Caspase-1 can also cleave gasdermin D (GSDMD), which facilitates GSDMD’s insertion into cellular membranes to form pores, thus initiating a specific kind of cell death called pyroptosis that releases the soluble intracellular fraction which fuels the inflammatory response. See S. L. Fink and B. T Cookson, “Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages,” Cell Microbiol 8(11):1812-25 (2006).

[0007] Besides this “canonical” NLRP3 inflammasome activation pathway, a“noncanonical” NLRP3 activation pathway has been described in the literature. The noncanonical pathway involves the activation of caspase-4 / 5 (or its mouse ortholog caspase- 11) by cytosolic LPS, the induction of pyroptosis through the cleavage of GSDMD, and the release of high mobility group box 1 protein (HMGB1), resulting in the production of IL-1β. See M. Lamkanfi and V. M. Dixit, “Mechanisms and functions of inflammasomes,” Cell 157(5):1013-22 (2014); F. Shi, Y. Yang, M. Kouadir M, et al., “Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia,” J Neuroimmunol 260(1-2):121-5 (2013). In both pathways, the activation of NLRP3 inflammasome results in the generation of the biologically active form of pro-inflammatory cytokines IL-1β and IL-18 that initiate inflammatory signaling cascades, contributing to neuroinflammation, neuronal injury and cell death. See S. M Allan, P. J. Tyrrell and N. J. Rothwell, “Interleukin-1 and neuronal injury,” Nat Rev Immunol, 5(8):629-40 (2005); A. Alboni, D. Cervia, S. Sugama, et al., “Interleukin 18 in the CNS,” J Neuroinflammation, 7:9 (2010).

[0008] Heterozygous gain of function mutations in the NLRP3 gene have been associatedwith the development of an autoinflammatory condition called cryopyrin-associated periodic syndromes (CAPS). See L. M. Booshehri and H. M. Hoffman, “CAPS and NLRP3,” J Clin Immunol 39(3):277-286 (2019). This is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal and central nervous system inflammation, and is estimated to affect about 1 to 3 individuals per million people 360230447.1worldwide. See L. Cuisset, I. Jeru, B. Dumont, et al., “Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France,” Ann Rheum Dis 70(3):495-9 (2011); Erratum in: Ann Rheum Dis 71(7):1264 (2012). Clinicians classify CAPS disorders based on the severity of symptoms. The most severe form of CAPS is known as neonatal-onset multisystem inflammatory disease (NOMID / CINCA). An intermediate form of CAPS is called Muckle- Wells syndrome (MWS). The familial cold autoinflammatory syndrome (FCAS) is a milder form of CAPS, which is triggered by low temperatures. See Booshehri and Hoffman (2019). Current anti-IL-1 therapies (anakinra, rilonacept, canakinumab) have proven successful in treating CAPS, but clinical experience over the last decade has shown that some CAPS patients are less responsive over time and require higher or more frequent dosing or switching of therapies. See R. Caorsi, L. Lepore, F. Zulian, et al., “The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age,” Arthritis Res Ther 15(1): R33 (2013); S. Urien, C. Bardin, B. Bader- Meunier, et al., “Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes,” BMC Pharmacol Toxicol 14:40 (2013).

[0009] Beyond neurodegenerative diseases, the consequences of NLRP3 inflammasomehyper-activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Obesity, an excessive accumulation of body fat, is recognized as the cause of a plethora of health complications. It is now recognized that obesity is associated with the onset of low-grade metabolic inflammation in both peripheral tissues and the brain in particular the hypothalamus, the brain area responsible for appetite and satiety regulation (Sonnefeld et al., “Is human obesity an inflammatory disease of the hypothalamus?” Eur J Endocrinol.188(3):R37-R45 (2023)).

[0010] The prolonged inflammation that characterizes obesity is induced throughout theproliferating tissue (Hotamisligil and Erbay “Nutrient sensing and inflammation in metabolic diseases” Nat Rev Immunol. (12):923-34 (2008); Odegaard and Chawla “Mechanisms of macrophage activation in obesity-induced insulin resistance” Nat Clin Pract Endocrinol Metab. (11):619-26 (2008)). The accumulation of excessive fat mass, accompanied by the development of adipocytes promotes macrophage infiltration inside tissues (Weisberg et al., “Obesity is associated with macrophage accumulation in adipose tissue” J Clin Invest. 112(12):1796-808 (2003)). The increased inflammation of tissue is cytokine in nature and contributes to the progression of diabetes mellitus (Olefsky and Glass “Macrophages, 460230447.1inflammation, and insulin resistance” Annu Rev Physiol.72:219-46 (2010); Shoelson et al. “Obesity, inflammation, and insulin resistance” Gastroenterology 132(6):2169-80 (2007)). In addition, IL-1β is thought to be connected with the progression of obesity-associated insulin resistance (Jager et al., “Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression” Endocrinology 148(1):241-51 (2007); Netea et al., “Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance” Nat Med.12(6):650-6 (2006); Zorrilla et al., “Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency” Proc Natl Acad Sci U S A. 104(26):11097-102 (2007)). Furthermore, overfeeding leads to stimulation of caspase-1 in adipose tissue in experimental animals (Stienstra et al., “The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity” Cell Metab. 12(6):593-605 (2010)).

[0011] Microglia and astrocytes, which are brain resident glia cells, can predisposeindividuals to excessive weight gain by impairing the hypothalamic energy homeostasis system (Yoo et al., “Tanycyte ablation in the arcuate nucleus and median eminence increases obesity susceptibility by increasing body fat content in male mice” Glia 68(10):1987-2000 (2020); Douglass et al., “Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance” Cell Metab.35(9):1613-1629.e8 (2023); Sonnefeld et al., “Is human obesity an inflammatory disease of the hypothalamus?” Eur J Endocrinol. 188(3):R37-R45 (2023)). It is a predisposition because the gliosis occurs rapidly before the actual weight gain. This inflammation impairs the local signaling of insulin and leptin leading to dysfunction of the regulation of energy balance and thus, weight gain. Although not fully elucidated yet, the mechanism by which this gliosis response occurs involves the passage of dietary saturated fatty acids into the cerebrospinal fluid (Melo et al., “Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α” Cell Rep.30(7):2180-2194.e8 (2020)), thus promoting inflammatory activation of hypothalamic microglia, potentially via Toll-like receptor 4- dependent mechanisms (Milanski et al., “Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity” 29(2):359-70 (2009); Valdearcos et al., “Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function” Cell Rep.9(6):2124-38 (2014); Folick et al., “Metabolic factors in the regulation of hypothalamic innate immune responses in obesity” 54(4):393-402 (2022)). Dysregulated hypothalamic circuits change the interaction between neuronal and non- 560230447.1neuronal cells, contributing to the establishment of inflammatory processes. Interventions that block this gliosis response have demonstrated reductions of the excess weight gain (Valdearcos et al., “Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function” Cell Rep.9(6):2124-38 (2014); Douglass et al., “Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance” Cell Metab.35(9):1613-1629.e8 (2023)). NLRP3 deficiency has been reported to inhibit the progression of obesity-linked insulin resistance (Stienstra et al., “The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity” Cell Metab.12(6):593-605 (2010)).

[0012] Several small molecule inhibitors have recently been reported that block theNLRP3 inflammasome pathways. These include the prototype NLRP3 inhibitor MCC-950. See R. C. Coll, J. R. Hill, C. J. Day, et al., “MCC950 directly targets the NLRP3 ATP- hydrolysis motif for inflammasome inhibition,” Nat Chem Biol 15(6):556-559 (2019); R. C. Coll, A. A. Robertson, J. J. Chae, et al., “A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases,” Nat Med 21(3):248-55 (2015). Other NLRP3 inhibitors include Bay 11-7082, CY-09, oridonin, tranilast, INF-39, glyburide and JC-124. See W. Jiang, M. Li, F. He, et al., “Inhibition of NLRP3 inflammasome attenuates spinal cord injury-induced lung injury in mice,” J Cell Physiol 234(5):6012-6022 (2019). MCC-950 has been used in many studies as a pharmacological tool to demonstrate NLRP3 inflammasome as a viable drug target to development therapeutics for human diseases. See S. E. Corcoran, R. Halai and M. A. Cooper, “Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950,” Pharmacol Rev 73(3):968-1000 (2021).

[0013] Inhibitors of the NLRP3 inflammasome pathways are expected to be useful fortreating neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease,Huntington’s disease, amyotrophic lateral sclerosis and prion disease for treating CAPS associated with heterozygous gain of function mutations in the NLRP3 gene and for treating obesity with certain additional risk factors for cardiovascular disease.

[0014] The following compounds are disclosed in Chem. Commun., 2008, 4962-4964(and its Supplementary Experimental Section) as anti-MRSA dihydrofolate reductase. 660230447.1[ bial activity.and US2020 / 0163973 disclose the followingcompound useful for the treatment of spinal muscular atrophy (SMA) and Huntington’s Disease, and modulating the gen product.

[0017] is disclosed in Tetrahedron Letters 61 (2020) 152269 asone of examples for one-pot green synthesis of 4H-pyrido[1,2-a]pyrimidin-4-one, which is common part for many drugs.the following compounds for treating disease,syndrome, conditions and disorders that are affected by the modulation of NLRP3 and / or the NLRP3 inflammasome. 760230447.1THE INVENTION

[0019] This invention provides heterocyclic compounds, or pharmaceutically acceptablesalts thereof, or solvates thereof, or hydrates thereof. This invention also providesmedicaments that contain pyrimidopyrimidinone derivatives and provides for their use totreat diseases, disorders and / or conditions associated with NLRP3, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and prion disease, and other neurodegenerative disorders.

[0020] One aspect of the invention provides [1] a compound of Formula (I), or apharmaceutically acceptable salt thereof:R1is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8cycloalkyl group, (4) an optionally substituted 4- to 7-membered heterocyclic group, (5) -ORa, or (6) -NRbRc; R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) an optionally substituted C1-6 alkyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an optionally substituted C1-6alkoxy group, (7) -NRbRc, or (8) an optionally substituted 5- or 6- membered aromatic heterocyclic group; R1and R2may bind to form an optionally substituted 5- or 6-membered heterocyclic ring with the adjacent carbon atoms; R3is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8cycloalkyl group, (4) an optionally substituted C1-6alkoxy group, (5) -NRbRc, or (6) an optionally substituted 4- to 7-membered heterocyclic group; R4is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromine atom, or (5) an optionally substituted C1-6 alkyl group; 860230447.1Ring A is a 6-membered ring wherein X1is (i) =C(R5)-, (ii) -C(R5)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X2is (i) =C(R6)-, (ii) -C(R6)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X3is (i) =C(R7)-, (ii) -C(R7)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X4is (i) =C(R8)-, (ii) -C(R8)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X5is (i) =C(R9)-, (ii) -C(R9)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X6is (i) C, or (ii) N; R5is (i) a hydrogen atom, or (ii) a substituent; R6is (i) a hydrogen atom, or (ii) a substituent; R7is (i) a hydrogen atom, or (ii) a substituent; R8is (i) a hydrogen atom, or (ii) a substituent; R9is (i) a hydrogen atom, or (ii) a substituent; proviso that Ring A has at least one substituent on any one of X1, X2, X3, X4, or X5position; and Rais (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group or (iv) an optionally substituted 4- to 7-membered heterocyclic group; Rbis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group, (iv) an optionally substituted C1-6alkoxy group or (v) an optionally substituted 4- to 7-membered heterocyclic group, in each occurrence; and Rcis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group or (iv) an optionally substituted 4- to 7-membered heterocyclic group, in each occurrence.

[0021] [2] A compound of Formula (I’), or a pharmaceutically acceptable salt thereof:an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8cycloalkyl group, (4) an optionally substituted 4- to 7-membered heterocyclic group, (5) -ORa’, or (6) -NRb’Rc’; R2’is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) an optionally substituted C1-6 alkyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an 960230447.1optionally substituted C1-6alkoxy group, (7) -NRb’Rc’, or (8) an optionally substituted 5- or 6- membered aromatic heterocyclic group; R3’is (1) a hydrogen atom, (2) an optionally substituted C1-6alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C1-6 alkoxy group, (5) - NRb’Rc’, or (6) an optionally substituted 4- to 7-membered heterocyclic group; R4’is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromine atom, or (5) an optionally substituted C1-6 alkyl group; Ring A’ is a 6-membered aromatic ring further substituted; and Ra’is (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group or (iv) an optionally substituted 4- to 7- membered heterocyclic group; Rb’is (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group or (iv) an optionally substituted 4- to 7- membered heterocyclic group, in each occurrence; and Rc’is (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group or (iv) an optionally substituted 4- to 7- membered heterocyclic group, in each occurrence, in each occurrence.

[0022] [3] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1], wherein R1is (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom, (ii) a C3-8cycloalkyl group optionally substituted by 1 to 3 hydroxy group, (iii) a C1-6 alkoxy group, (iv) an amino group, (v) a (4- to 7-membered heterocyclic)-amino group optionally substituted by 1 to 3 C1-6alkyl group, (vi) a C1-6 alkyl-carbonyl-amino group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a halogen atom, and(b) a C1-6 alkoxy group,10 60230447.1(vii) a C3-8cycloalkyl-carbonyl-amino group optionally substituted by 1 to 3 halogen atom(s), (viii) a (4- to 7-membered heterocyclic group)-carbonyl-amino group optionally substituted by 1 to 3 halogen atom(s), (ix) a C1-6alkoxy-carbonyl-amino group, (x) a N-C1-6 alkyl- N-C1-6 alkyl-carbonyl-amino group, (xi) a N-C1-6 alkoxy- N-C1-6 alkyl-ureido group, (xii) a hydroxy group, and (xiii) a 4- to 7-membered heterocyclic group, (3) a C3-8cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6alkyl group, (ii) a halogen atom, (iii) a cyano group, (iv) a C1-6 alkoxy group, (v) a hydroxy group, and (vi) a 4- to 7-membered heterocyclyloxy group, (4) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkoxy group, (b) a halogen atom, (c) a C1-6 alkoxy-carbonyl group, and (d) carboxyl group, (ii) a C3-8 cycloalkyl group, (iii) a C1-6alkoxy group, (iv) a halogen atom, (v) a hydroxy group, (vi) a tri-C1-6 alkylsilyloxy group, (vii) a cyano group, (viii) –(CH2)l- (wherein l is an integer of 2 to 4), (ix) –(CH2)mO(CH2)n- (wherein m is an integer of 1 or 2, and n is an integer of 1 or 2), (x) an oxo, 11 60230447.1(xi) a 4- to 7-membered heterocyclyl group, and (xii) –(CH2)pNRd1(CH2)q- (wherein Rd1(a) a hydrogen atom, (b) a C1-6 alkoxy- carbonyl group, or (c) an optionally halogenated 4- to 7-membered heterocyclic group, p is an integer of 1 or 2, and q is an integer of 1 or 2), (5) -ORa1(Ra1is (i) a hydrogen atom,(ii) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected fromthe group consisting of (a) a hydroxy group, (b) a halogen atom, (c) C1-6alkoxy group, and (d) a 4- to 7- membered heterocyclic group optionally substituted by 1 to 34- to 7- membered heterocyclic group, (iii) a 4- to 7- membered heterocyclic group, or(iv) a C3-8 cycloalkyl group optionally substituted by 1 to 3 hydroxy group), or(6) -NRb1Rc1(Rb1is (i) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C3-8cycloalkyl group optionally substituted by 1 to 3 cyano group(s), (b) a halogen atom, (c) a hydroxy group, (d) a C6-10 aryl group optionally substituted by 1 to 3 C1-6 alkoxy(s), and (e) a 4- to 7 membered heterocyclic group optionally substituted by a hydroxy group, (ii) a C3-8cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6alkyl group, (b) a hydroxy group, and (c) a cyano group, (iii) a C1-6alkoxy group or (iv) a 4- to 7-membered heterocylic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of 12 60230447.1(a) a C1-6alkyl group, and (b) a hydroxy group; Rc1is (i) a hydrogen atom, or(ii) a C1-6 alkyl group);R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a C1-6 alkyl group, (4) a C1-6alkoxy group, or (5) a 5- or 6-membered aromatic heterocyclic group; or R1and R2may bind to form 5- or 6-membered heterocyclic ring with the adjacent carbon atoms optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (1) a C1-6alkyl group, (2) a C1-6alkyl-carbonyl group, (3) a C1-6alkoxy- carbonyl group, and (4) a hydroxy group. R3is (1) a hydrogen atom, or (2) a C1-6alkyl group; R4is (1) a hydrogen atom, or (2) a C1-6alkyl group; and Ring A is a benzene ring substituted by 1 to 4 substituent(s) selected from a group consisting of (i) a halogen atom,(ii) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selectedfrom the group consisting of (a) a halogen atom,(b) a hydroxy group, and(c) an optionally halogenated C1-6 alkoxy group,(iii) a C3-6 cycloalkyl group optionally substituted by 1 to 3 substituent(s)selected from the group consisting of (a) a halogen atom,(b) a C1-6 alkyl group, and(c) a cyano group,13 60230447.1(iv) an optionally halogenated C1-6 alkoxy group,(v) a hydroxy group,(vi) a cyano group,(vii) a 4- to 7 membered heterocyclic group, and(viii) a C1-6 alkylsulfonyl group.

[0023] [4] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1], wherein R1is (1) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy group(s) or (2) a C1-6alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is(1) a pyridine ring substituted by 1 to 3 substituent(s) selected from a group consisting of(i) an optionally halogenated C1-6 alkyl group, and(ii) an optionally halogenated C3-6 cycloalkyl group,(2) a pyrimidine ring substituted by 1 to 3 substituent(s) selected from a group consisting of(i) a C1-6 alkyl group, and(ii) a C3-6 cycloalkyl group, or(3) a dihydropyridine ring substituted by 1 to 3 substituent(s) selected from a groupconsisting of (i) a C1-6 alkyl group,(ii) a C3-6 cycloalkyl group, and(iii) an oxo group.

[0024] [5] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1], wherein R1is a C1-6 alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is a benzene ring optionally substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a halogen atom,14 60230447.1(ii) an optionally halogenated C1-6 alkyl group,(iii) an optionally halogenated C3-6 cycloalkyl group, and(iv) a cyano group.

[0025] [6] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1], wherein the compound is selected from: 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2- a]pyrimidin-4-one, 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3- methylbenzonitrile, 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2- a]pyrimidin-4-one, and 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H- pyrimido[1,2-a]pyrimidin-4-one.

[0026] [7] A method of treating a disease, disorder or condition in a subject, whichcomprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1], wherein the disease, disorder or condition is associated with NLRP3.

[0027] [8] A method of treating a disease, disorder or condition in a subject, whichcomprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1], wherein the disease, disorder or condition is associated with a heterozygous gain of function mutation in the NLRP3 gene.

[0028] [9] A method of treating a cryopyrin-associated periodic syndrome (CAPS) in asubject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1].

[0029]

[0010] The method according to the above [9], wherein the cryopyrin-associatedperiodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0030]

[0011] A method of treating a neurodegenerative disease, disorder or condition in asubject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1].

[0031]

[0012] A method of treating Parkinson’s disease, Alzheimer’s disease, Huntington’sdisease, amyotrophic lateral sclerosis or prion disease in a subject, which comprises 15 60230447.1administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1].

[0032]

[0013] A method of treating obesity in a subject, which comprises administering tothe subject an effective amount of a compound or pharmaceutically acceptable salt as defined in the above [1].

[0033]

[0014] A medicament comprising a compound or pharmaceutically acceptable salt asdefined in the above [1].

[0034]

[0015] The medicament according to the above

[0014] , which is an agent for thetreatment of disease, disorder or condition associated with NLRP3.

[0035]

[0016] The medicament according to the above

[0014] , which is an agent for thetreatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

[0036]

[0017] The medicament according to the above

[0014] , which is an agent for thetreatment of a cryopyrin-associated periodic syndrome (CAPS).

[0037]

[0018] The medicament according to the above

[0017] , wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0038]

[0019] The medicament according to the above

[0014] , which is an agent for thetreatment of a neurodegenerative disease.

[0039]

[0020] The medicament according to the above

[0014] , which is an agent for thetreatment of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

[0040]

[0021] The medicament according to the above

[0014] , which is an agent for thetreatment of obesity.

[0041]

[0022] A compound or pharmaceutically acceptable salt as defined in the above [1]for use as a medicament.

[0042]

[0023] A compound or pharmaceutically acceptable salt as defined in the above [1]for use in treating a disease, disorder or condition associated with NLRP3.

[0043]

[0024] A compound or pharmaceutically acceptable salt as defined in the above [1]for use in treating a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

[0044]

[0025] A compound or pharmaceutically acceptable salt as defined in the above [1]for use in treating a cryopyrin-associated periodic syndrome (CAPS). 16 60230447.1

[0045]

[0026] A Compound or pharmaceutically acceptable salt as defined in the above

[0025] wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS)

[0046]

[0027] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1] for use in treating a neurodegenerative disease.

[0047]

[0028] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1] for use in treating Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

[0048]

[0029] A compound or pharmaceutically acceptable salt thereof as defined in theabove [1] for use in treating obesity.

[0049]

[0030] Use of a compound or pharmaceutically acceptable salt as defined the above[1] for the manufacture of a medicament for the treatment of disease, disorder or condition associated with NLRP3.

[0050]

[0031] Use of a compound or pharmaceutically acceptable salt as defined in theabove [1] for the manufacture of a medicament for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

[0051]

[0032] Use of a compound or pharmaceutically acceptable salt as defined in theabove [1] for the manufacture of a medicament for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

[0052]

[0033] The use according to the above

[0032] , wherein the cryopyrin-associatedperiodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0053]

[0034] Use of a compound or pharmaceutically acceptable salt thereof as defined inthe above [1] for the manufacture of a medicament for the treatment of a neurodegenerative disease.

[0054]

[0035] Use of a compound or pharmaceutically acceptable salt thereof as defined inthe above [1] for the manufacture of a medicament for the treatment of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

[0055]

[0036] Use of a compound or pharmaceutically acceptable salt thereof as defined inthe above [1] for the manufacture of a medicament for the treatment of obesity. 17 60230447.1

[0056]

[0037] A combination comprising a compound or pharmaceutically acceptable salt asdefined in the above [1], and at least one additional pharmacologically active agent (hereinafter, it is sometimes also referred as “pharmacologically active compound”).

[0057]

[0038] The combination according to the above

[0037] , wherein the additionalpharmacologically active agent is selected from the group consisting of beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti- inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. DETAILED DESCRIPTION OF THE INVENTION

[0058] Unless otherwise indicated, this disclosure uses definitions provided below.

[0059] “Substituted,” when used in connection with a chemical substituent or moiety (e.g.,a C1-6 alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided valence requirements are met and a chemically stable compound results from the substitution.

[0060] “Optional” or “optionally” refers to the subsequently described event orcircumstances may or may not occur, and the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted heterocyclic group” refers to an unsubstituted heterocyclic group or a substituted heterocyclic group substituted with 1 to 3 substituents. “Optionally substituted hydrocarbon group” refers to an unsubstituted hydrocarbon group or a substituted hydrocarbon group substituted with 1 to 3 substituents.”

[0061] “About” or “approximately,” when used in connection with a measurablenumerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0062] “Alkyl” refers to straight chain and branched saturated hydrocarbon groups,generally having a specified number of carbon atoms (e.g., C1-3 alkyl refers to an alkyl group having 1 to 3 (i.e., 1, 2, or 3) carbon atoms, C1-4alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6 alkyl refers to an alkyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl (isopropyl), n-butyl, s-butyl (sec-butyl), i-butyl (isobutyl), t-butyl (tert-butyl), pent- 1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2- trimethyleth-1-yl, n-hexyl, and the like. 18 60230447.1

[0063] “Alkanediyl” refers to divalent alkyl groups, where alkyl is defined above, andgenerally having a specified number of carbon atoms (e.g., C1-4 alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6alkanediyl refers to an alkanediyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0064] “Alkenyl” refers to straight chain and branched hydrocarbon groups having one ormore carbon-carbon double bonds, and generally having a specified number of carbon atoms (e.g., C2-6 alkenyl refers to an alkenyl group having 2 to 6 (i.e., 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2- propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2- yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0065] “Alkynyl” refers to straight chain or branched hydrocarbon groups having one ormore triple carbon-carbon bonds, and generally having a specified number of carbon atoms (e.g., C2-6alkynyl refers to an alkynyl group having 2 to 6 (i.e., 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1- butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0066] “Alkoxy” refers to straight chain and branched saturated hydrocarbon groupsattached through an oxygen atom, generally having a specified number of carbon atoms (e.g., C1-4alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6 alkoxy refers to an alkoxy group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexoxy, and the like.

[0067] “Alkyl-carbonyl” and “alkylsulfonyl” refer to an alkyl group as defined above,which is attached, respectively, through a carbonyl (C(O)) group or a sulfonyl (SO2) group, and generally having a specified number of carbon atoms (e.g., C1-6 alkyl-carbonyl refers to an alkyl-carbonyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, excluding the carbonyl moiety, C1-6 alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of alkyl-carbonyl groups include 19 60230447.1methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl (propanoyl), n-propylcarbonyl, 2- methylpropanoyl, and the like. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, n-propylsulfonyl, and the like.

[0068] “Alkylamino” including mono- or di-alkylamino group refers to an alkyl group asdefined above, which is attached through at least one amino group, and generally having a specified number of carbon atoms (e.g., C1-6 alkylamino refers to a mono- or di-alkylamino group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and so on). Examples of mono- or di-alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N- methylamino, and the like.

[0069] “Alkyl-carbamoyl” including mono- or di-alkyl-carbamoyl group refers to an alkylgroup as defined above, which is attached through a carbamoyl (CONH2) group, and generally having a specified number of carbon atoms (e.g., C1-6 alkyl-carbamoyl refers to a mono- or di-alkyl-carbamoyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, excluding the carbamoyl moiety, and so on). Examples of mono- or di-alkyl-carbamoyl groups include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl, and the like.

[0070] “Alkyl-carbonylamino” refers to an alkyl-carbonyl as defined above, which isattached through an amino moiety, and generally having a specified number of carbon atoms (e.g., C1-6 alkyl-carbonylamino refers to an alkyl-carbonylamino group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, excluding the carbonyl moiety, and so on). Examples of C1-6alkyl-carbonylamino groups include methylcarbonylamino (acetylamino), ethylcarbonylamino, and the like.

[0071] “Alkoxy-carbonyl” refers to an alkoxy group as defined above, which is attachedthrough a carbonyl (C(O)) group, and generally having a specified number of carbon atoms (e.g., C1-6 alkoxy-carbonyl refers to an alkoxy-carbonyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, excluding the carbonyl moiety, and so on). Examples of C1-6alkoxy- carbonyl groups include methoxycarbonyl, ethoxycarbonyl, and the like.

[0072] “Halo,” “halogen” and “halogeno” may be used interchangeably and refer tofluoro, chloro, bromo, and iodo.

[0073] “Haloalkyl,” “haloalkenyl,” and “haloalkynyl,” refer, respectively, to alkyl,alkenyl, and alkynyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, and alkynyl are defined above, and generally having a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 20 60230447.1chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1- chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0074] “Cycloalkyl” refers to saturated monocyclic and bicyclic hydrocarbon groups,generally having a specified number of carbon atoms that comprise the ring or rings (e.g., C3-8cycloalkyl refers to a cycloalkyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms as ring members). Bicyclic hydrocarbon groups may include isolated rings (two rings sharing no carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms, but not a common bond). The cycloalkyl group may be attached through any ring atom unless such attachment would violate valence requirements, and where indicated, may optionally include one or more non-hydrogen substituents unless such substitution would violate valence requirements.

[0075] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, and the like. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like. Examples of spiro cycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like. Examples of isolated bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0076] “Cycloalkanediyl” refers to divalent cycloalkyl groups, where cycloalkyl is definedabove, and generally having a specified number of carbon atoms (e.g., C3-8cycloalkanediyl refers to a cycloalkanediyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms, and so on). Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2- diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0077] “Cycloalkylidene” refers to divalent monocyclic cycloalkyl groups, wherecycloalkyl is defined above, which are attached through a single carbon atom of the group, 21 60230447.1and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-8cycloalkylidene refers to a cycloalkylidene group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms as ring members). Examples of cycloalkylidene groups include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0078] “Cycloalkenyl” refers to partially unsaturated monocyclic and bicyclichydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings (e.g., C3-8 cycloalkenyl refers to a cycloalkenyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms, and so on). As with cycloalkyl groups, the bicyclic cycloalkenyl groups may include isolated, spiro, fused, or bridged rings. Similarly, the cycloalkenyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of cycloalkenyl groups include the partially unsaturated analogs of the cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0079] “Cycloalkyl-carbonyl” or “cycloalkylsulfonyl” refers to a cycloalkyl group asdefined above, which is attached, respectively, through a carbonyl (C(O)) group or a sulfonyl (SO2) group, and generally having a specified number of carbon atoms (e.g., C3-8 cycloalkyl- carbonyl refers to a cycloalkyl-carbonyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms, excluding the carbonyl moiety, as ring members of cycloalkyl group, C3-8 cycloalkylsulfonyl refers to a cycloalkylsulfonyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8) carbon atoms as ring members of cycloalkyl group, and so on). Examples of cycloalkyl- carbonyl groups include cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl, and the like. Examples of cycloalkylsulfonyl groups include cyclopropylsulfonyl cyclobutylsulfonyl, cyclopentylsulfonyl, and the like.

[0080] “Aryl” refers to fully unsaturated monocyclic aromatic hydrocarbons and topolycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members, and so on). The group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like. 22 60230447.1

[0081] “Acyl group” include a formyl group, a carboxy group, a carbamoyl group, athiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”. Examples of the “acyl group” also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group. Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.

[0082] Preferable examples of the “acyl group” include a formyl group, a carboxy group, aC1-6alkyl-carbonyl group, a C2-6alkenyl-carbonyl group (e.g., crotonoyl), a C3-10cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a C6-14aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C6-14aryl- carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6alkenyl- thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14- membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfino 23 60230447.1group, a C1-6alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C1-6alkylsulfonyl group, a C6-14 arylsulfonyl group, a phosphono group and a mono- or di-C1-6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0083] “Aralkyl” refers to an alkyl group as defined above, wherein one of its hydrogensis substituted by an aryl group as defined above, and generally having a specified number of carbon atoms (e.g., C7-16 aralkyl refers to an aralkyl group having 7 to 16 carbon atoms, and so on). Examples of aralkyl groups include benzyl, phenethyl, naphthylmethyl, phenylpropyl, and the like.

[0084] “Aralkyloxy” refers to a hydroxy group whose hydrogen is substituted by anaralkyl group as defined above, and generally having a specified number of carbon atoms (e.g., C7-16aralkyloxy refers to an aralkyloxy group having 7 to 16 carbon atoms, and so on). Examples of aralkyloxy groups include benzyloxy, phenethyloxy, naphthylmethoxy, phenylpropyloxy, and the like.

[0085] “Aralkyloxy-carbonyl” refers to an aralkyloxy group as defined above, which isattached through a carbonyl (C(O)) group, and generally having a specified number of carbon atoms (e.g., C7-16 aralkyloxy-carbonyl refers to an aralkyloxy-carbonyl group having 7 to 16 carbon atoms, excluding the carbonyl moiety, and so on). Examples of aralkyloxy-carbonyl groups include benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl, phenylpropyloxycarbonyl, and the like.

[0086] “Arylene” refers to divalent aryl groups, where aryl is defined above, and generallyhaving a specified number of carbon atoms that comprise their ring members (e.g., C6-14arylene refers to an arylene group having 6 to 14 carbon atoms as ring members, and so on). Examples of arylene groups include o-phenylene (i.e., benzene-1,2-diyl).

[0087] “Heterocycle”, “heterocyclic” and “heterocyclyl” may be used interchangeably andrefer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6heterocyclyl refers to a heterocyclyl group having 2 to 6 (i.e., 2, 3, 4, 5 or 6) carbon atoms and, e.g., 1 to 4 (i.e., 1, 2, 3 or 4) heteroatoms, as ring members, while 5- or 6- membered heterocyclic group refers to a heterocyclyl group having 5 or 6 atoms as ring members in total of carbon atoms and heteroatoms). As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group may be 24 60230447.1attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2- dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0088] “Heterocycle-diyl” refers to heterocyclyl groups which are attached through tworing atoms of the group, where heterocyclyl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 (i.e., 2, 3, 4, 5 or 6) carbon atoms and, e.g., 1 to 4 (i.e., 1, 2, 3 or 4) heteroatoms, as ring members). Examples of heterocycle-diyl groups include the multivalent analogs of the heterocycle groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5- ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1- piperazinyl-6-ylidene, and the like.

[0089] “Heteroaromatic”, “aromatic heterocyclyl / heterocyclic” and “heteroaryl” may beused interchangeably and refer to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C1-9 heteroaryl refers to a heteroaryl group having 1 to 9 (i.e., 1, 2, 3, 4, 5, 6, 7, 8 or 9) carbon atoms and, e.g., 1 to 4 (i.e., 1, 2, 3 or 4) heteroatoms, as ring members) and may include any bicyclic group in which any of the above-listed monocyclic heterocycles are fused to a benzene ring. The heteroaryl group may be attached through any ring atom (or ring atoms for fused rings), and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, 25 60230447.1thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5- diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1- thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0090] Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl,isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2- c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5- c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4- c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2- c]pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6- naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6- naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4- b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5- d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazinyl.

[0091] “Heteroarylene” refers to heteroaryl groups which are attached through two ringatoms of the group, where heteroaryl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C3-5heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and, e.g., 1 to 4 (i.e., 1, 2, 3 or 4) heteroatoms, as ring members). Examples of heteroarylene groups include the multivalent analogs of the heteroaryl groups described above, such as pyridine-2,3-diyl, pyridine-3,4- diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0092] “Non-aromatic heterocyclic / heterocyclyl” (including “3- to 8-membered non-aromatic heterocyclic group)” refers to heterocyclic group other than heteroaryl groups as mentioned above. Preferable examples of the “non-aromatic heterocyclic group” include 3- to 26 60230447.18-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and

[0093] 9- to 14-membered fused polycyclic (preferably bi or tricyclic) non-aromaticheterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3- b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-^-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[0094] In the present specification, examples of the “nitrogen-containing heterocyclicgroup” include a “heterocyclic group” containing at least one nitrogen atom as a ring- constituting atom.

[0095] In the present specification, examples of the “optionally substituted heterocyclicgroup” include a heterocyclic group optionally having substituent(s) selected from the substituent group A as described later.

[0096] “Oxo” refers to a double bonded oxygen (=O).

[0097] Examples of the “substituent” (including “hetero-containing substituents”) includea halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.

[0098] Examples of the “hydrocarbon group” (including “hydrocarbon group” of“optionally substituted hydrocarbon group”) include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6alkynyl group, a C3-10cycloalkyl group, a C3-10cycloalkenyl group, a C6-14aryl group and a C7-16 aralkyl group. 27 60230447.1

[0099] “Hetero-containing substituents” refers to substituents containing at least oneheteroatom. Examples of the “hetero-containing substituents” include a halogen atom, a cyano group, a nitro group, a heterocyclyl group, a heteroaryl group, an alkyl group substituted by hetero-containing substituents (such as halo-alkyl, amino-alkyl, cyano-alkyl, alkoxy-alkyl, and the like), a cycloalkyl substituted by hetero-containing substituents (such as halo-cycloalkyl, cyano-cycloalkyl, hydroxy-cycloalkyl, and the like), an optionally substituted alkoxy group, and the like.

[0100] Examples of the “optionally substituted hydrocarbon group” include a hydrocarbongroup optionally having substituent(s) selected from the following substituent group A.

[0101] [substituent group A](1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6alkoxy group, (7) a C6-14 aryloxy group (e.g., phenoxy, naphthoxy), (8) a C7-16aralkyloxy group (e.g., benzyloxy), (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), (11) a C1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12) a C6-14aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) a C1-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a mono- or di-C1-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C6-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C1-6alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), 28 60230447.1(19) a C6-14arylsulfonyloxy group optionally substituted by a C1-6alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C1-6 alkyl-carbonyl group, (26) a C6-14 aryl-carbonyl group, (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29) a C1-6alkoxy-carbonyl group, (30) a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2- naphthyloxycarbonyl), (31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or di-C1-6alkyl-carbamoyl group, (35) a C6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C1-6 alkylsulfonyl group, (39) a C6-14arylsulfonyl group, (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated C1-6 alkylsulfinyl group, (42) a C6-14arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, 29 60230447.1(45) a mono- or di-C1-6alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino), (46) a mono- or di-C6-14 arylamino group (e.g., phenylamino), (47) a 5- to 14-membered heterocyclylamino group (e.g., pyridylamino) optionally substituted by 1 to 3 C1-6 alkyl group(s), (48) a C7-16 aralkylamino group (e.g., benzylamino), (49) a formylamino group, (50) a C1-6 alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom (e.g., fluorine atom) and (ii) a C1-6 alkoxy group (e.g., methoxy), (51) an optionally halogenated C3-10cycloalkyl-carbonyl-amino group (e.g., cyclopropylcarbonylamino), (52) an optionally halogenated (4- to 7-membered heterocyclic group)-carbonyl-amino group (e.g., tetrahydropyranylcarbonylamino, pyridylcarbonylamino), (53) a (C1-6alkyl)(C1-6alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (54) a C6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (55) a C1-6alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (56) a C7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (57) a C1-6alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (58) a C6-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (59) a N-C1-6 alkoxy- N-C1-6 alkyl-ureido group (e.g., N-methoxy-N-methyl-ureido), (60) a C1-6alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom, (ii) a hydroxy group, (iii) a C3-8 cycoalkyl group, (iv) a C6-10 aryl group optionally substituted by 1 to 3 C1-6alkoxy group(s), (v) an optionally halogenated C1-6 alkoxy group, (vi) a 4- to 7 membered heterocyclic group, (vii) a C1-6 alkoxy-carbonyl group, and (viii) carboxyl group, (61) a C2-6 alkenyl group, (62) a C2-6 alkynyl group, (63) an optionally halogenated C3-10cycloalkyl group, (64) a C3-10 cycloalkenyl group, (65) a C6-14aryl group, 30 60230447.1(66) a group represented by the formula: -(CH2)a-O-(CH2)b-, wherein each of a and b is the integer of 0 to 3 and the sum of a and b is 2 to 4, (67) a group represented by the formula: -(CH2)c-, wherein c is the integer of 2 to 4, (68) a group represented by the formula: -(CH2)dNRx(CH2)e- (wherein Rx(i) a hydrogen atom, (ii) a C1-6alkoxy-carbonyl (e.g., tert-butoxycarbonyl) or (iii) an optionally halogenated 4- to 7-membered heterocyclic group, p is an integer of 1 or 2, and q is an integer of 1 or 2) and (69) a tri C1-6 alkylsilyloxy group.

[0102] The number of the above-mentioned substituents in the “optionally substitutedhydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0103] “Leaving group” refers to any group that leaves a molecule during a fragmentationprocess, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH2- and OH- can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO2, and metals.

[0104] “Opposite enantiomer” refers to a molecule that is a non-superimposable mirrorimage of a reference molecule, which may be obtained by inverting all the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0105] “Stereoisomer” and “stereoisomers” of a compound with given stereochemicalconfiguration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (Z / E) of the compound. For example, if a compound has S,R,Z 31 60230447.1stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration. If the stereochemical configuration of a compound is not specified, then “stereoisomer” refers to any one of the possible stereochemical configurations of the compound.

[0106] “Substantially pure stereoisomer” and variants thereof refer to a sample containinga compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.

[0107] “Pure stereoisomer” and variants thereof refer to a sample containing a compoundhaving a specific stereochemical configuration and which comprises at least about 99.5% of the sample.

[0108] “Subject” refers to a mammal, including a human.

[0109] “Pharmaceutically acceptable” substances refer to those substances which aresuitable for administration to subjects.

[0110] “Treating” refers to reversing, alleviating, inhibiting the progress of, or preventinga disease, disorder or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disease, disorder or condition.

[0111] “Treatment” refers to the act of “treating,” as defined immediately above.

[0112] “Drug,” “drug substance,” “active pharmaceutical ingredient,” and the like, refer toa compound (e.g., compounds of Formula (I), including subgeneric compounds and compounds specifically named in the specification, or pharmaceutically acceptable salts thereof, or solvates thereof, or hydrates thereof) that may be used for treating a subject in need of treatment.

[0113] “Effective amount” of a drug, “therapeutically effective amount” of a drug, and thelike, refer to the quantity of the drug that may be used for treating a subject and may depend on the weight and age of the subject and the route of administration, among other things.

[0114] “Excipient” refers to any diluent or vehicle for a drug.

[0115] “Medicament” refers to the combination of one or more drug substances and one ormore excipients. Sometimes such combination is also described as “formulation” or “pharmaceutical composition”.

[0116] “Drug product,” “pharmaceutical dosage form,” “dosage form,” “final dosageform” and the like, refer to a pharmaceutical composition or a medicament suitable for treating a subject in need of treatment and generally may be in the form of tablets, capsules, 32 60230447.1sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.

[0117] “Disease, disorder or condition associated with NLRP3” and similar phrases relateto a disease, disorder or condition in a subject for which inhibition of the NLRP3 inflammasome pathway may provide a therapeutic or prophylactic benefit.

[0118] The following abbreviations may be used in the specification: Ac (acetyl); Ac2O(acetic anhydride); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); AmPhos (bis(di-tert- butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)); API (active pharmaceutical ingredient); aq (aqueous); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); Bn (benzyl); Boc (tert-butoxycarbonyl); BrettPhos (2-(dicyclohexylphosphino)3,6-dimethoxy- 2’,4’,6’-triisopropyl-1,1’-biphenyl); BrettPhos-Pd-G3 ([(2-di-cyclohexylphosphino-3,6- dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’- biphenyl)]palladium(II)methanesulfonate); Cbz (carbobenzyloxy); Troc (2,2,2- trichloroethoxycarbonyl); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec- 7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethane); DCM (dichloromethane); DEA (diethylamine); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine, Hünig’s Base); DMA (N,N-dimethylacetamide); DMAP (4- dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMP (Dess-Martin periodinane); DMSO (dimethylsulfoxide); dppf (1,1′- bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC50 (effective concentration at half maximal response); EDA (ethoxylated dodecyl alcohol, Brj®35); EDC (N-(3- dimethylaminopropyl)-N′-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); ELS (evaporative light scattering); eq (equivalents); Et (ethyl); Et3N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); HATU (2-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V)); HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); HOAc (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC50(concentration at 50% inhibition); IPA (isopropanol); IPAc (isopropyl acetate); IPE (isopropyl ether); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperoxybenzoic acid); Me (methyl); MeOH (methanol); MTBE (methyl tert-butyl ether); mp (melting point); NaOt-Bu (sodium tertiary butoxide); NMM (N-methylmorpholine); NMP 1-methylpyrrolidin-2-one); OTf (triflate); PE (petroleum ether); Ph (phenyl); pEC50(-log10(EC50), where EC50is given in molar (M) units); pIC50 (-log10(IC50), where IC50 is given in molar (M) units); PMB (p- methoxylbenzyl); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE 33 60230447.1(polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (bromotripyrrolidinophosphonium hexafluorophosphate); PCy3(tricyclohexylphosphine); RT (room temperature, approximately 20 °C to 25 °C); SFC (supercritical fluid chromatography); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); Tris buffer (2- amino-2-hydroxymethyl-propane-1,3-diol buffer); XPhos (2-dicyclohexylphosphino-2’,4’,6’- triisopropylbiphenyl); XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl- 1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II)); and XPhos-Pd-G4 methanesulfonato(2-dicyclohexylphosphino-2’,4’,6’-tri-i-propyl-1,1’-biphenyl)(2’- methylamino-1,1’-biphenyl-2-yl)palladium(II).

[0119] As described below, this disclosure concerns compounds of Formula (I), orpharmaceutically acceptable salts thereof, or solvates thereof, or hydrates thereof (collectively, sometimes to be referred to as compound (I) in the present specification). This disclosure also concerns materials and methods for preparing compounds of Formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, or hydrates thereof, medicaments which contain them, and the use of compounds of Formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, or hydrates thereof, (optionally in combination with other pharmacologically active agent(s)) for treating neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, prion disease and other diseases, disorders and / or conditions associated with NLRP3.

[0120] The definition of each variable in Formula (I) is explained in detail in thefollowing.

[0121] R1 is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) anoptionally substituted C3-8 cycloalkyl group, (4) an optionally substituted 4- to 7-membered heterocyclic group, (5) -ORa(wherein Rais (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group or (iv) an optionally substituted 4- to 7-membered heterocyclic group), or (6) -NRbRc(wherein Rbis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7-membered heterocyclic group; and Rcis (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7- membered heterocyclic group). 34 60230447.1

[0122] As one embodiment, R1 is preferably(1) a hydrogen atom, (2) a C1-6alkyl group (e.g., methyl, ethyl, iso-propyl, iso-butyl, sec-butyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom (e.g, a fluorine atom) (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 hydroxy group, (iii) a C1-6 alkoxy group (e.g., methoxy), (iv) an amino group, (v) a (4- to 7-membered heterocyclic)-amino group (e.g., pyrazolylamino) optionally substituted by 1 to 3 C1-6 alkyl group (e.g., methyl), (vi) a C1-6alkyl-carbonyl-amino group (e.g., acetylamino, ethylcarbonylamino) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a halogen atom (e.g., fluorine atom), and(b) a C1-6 alkoxy group (e.g., methoxy),(vii) a C3-8cycloalkyl-carbonyl-amino group (e.g., cyclopropylcarbonylamino) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine atom), (viii) a (4- to 7-membered heterocyclic group)-carbonyl-amino group (e.g, tetrahydropyranylcarbonylamino, pyridylcarbonylamino) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine atom), (ix) a C1-6alkoxy-carbonyl-amino group (e.g., methoxycarbonylamino, tert- butoxycarbonylamino), (x) a N-C1-6alkyl- N-C1-6alkyl-carbonyl-amino group (e.g., N-acetyl-N- methylamino), (xi) a N-C1-6alkoxy- N-C1-6alkyl-ureido group (e.g., N-methoxy-N-methyl- ureido), (xii) a hydroxy group, and (xiiii) a 4- to 7-membered heterocyclic group (e.g., pyrazolyl), (3) a C3-8cycloalkyl group (e.g., cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group (e.g., methyl) (ii) a halogen atom (e.g., a fluorine atom), (iii) a cyano group, (iv) a C1-6alkoxy group (e.g., methoxy), 35 60230447.1(v) a hydroxy group, and (vi) a 4- to 7-membered heterocyclyloxy group (e.g, tetrahydropyranyloxy), (4) a 4- to 7-membered heterocyclic group (e.g., azetidinyl, oxetany, pyrazolyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazepanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkoxy group (e.g., methoxy), (b) a halogen atom (e.g., fluorine atom), (c) a C1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), and (d) carboxyl group, (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl), (iii) a C1-6alkoxy group (e.g., methoxy), (iv) a halogen atom (e.g., fluorine atom), (v) a hydroxy group, (vi) a tri-C1-6 alkylsilyloxy group (e.g., tert-butyl-dimethylsilyloxy), (vii) a cyano group, (viii) -(CH2)l- (wherein l is an integer of 2 to 4) (e.g., -(CH2)2-), (ix) -(CH2)mO(CH2)n- (wherein m is an integer of 1 or 2, and n is an integer of 1 or 2) (e.g., -CH2OCH2-, -(CH2)2OCH2-), (x) an oxo, (xi) a 4- to 7-membered heterocyclyl group (e.g, oxetanyl, tetrahydropyranyl, 1,1- dioxothiopyranyl), and (xii) -(CH2)pNRd1(CH2)q- (wherein Rd1(a) a hydrogen atom, (b) a C1-6alkoxy- carbonyl (e.g., tert-butoxycarbonyl), or (c) an optionally halogenated 4- to 7- membered heterocyclic group (e.g, oxetanyl, pyridazinyl, chloropyridazinyl), p is an integer of 1 or 2, and q is an integer of 1 or 2) (e.g., -CH2NHCH2-, - CH2N(C(O)OC(CH3)3)CH2-, -CH2N(3-oxetanyl)CH2-, -CH2N(4-pyperazinyl)CH2-), (5) -ORa1(Ra1is (i) a hydrogen atom,(ii) a C1-6 alkyl group (e.g., methyl, ethyl, propyl) optionally substituted by 1 to 3substituent(s) selected from the group consisting of 36 60230447.1(a) a hydroxy group, (b) a halogen atom (e.g., a fluorine atom), (c) C1-6alkoxy group (e.g., methoxy), and (d) a 4- to 7- membered heterocyclic group (e.g., pyrazolyl) optionally substituted by 1 to 34- to 7- membered heterocyclic group (e.g., tetrahydropyranyl), (iii) a 4- to 7- membered heterocyclic group (e.g., tetrahydrofuryl), or(iv) a C3-8 cycloalkyl group (e.g., cyclobutyl) optionally substituted by 1 to 3hydroxy group), or (6) -NRb1Rc1(Rb1is (i) a C1-6alkyl group (e.g., methyl, ethyl, propyl, iso-propyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C3-8 cycloalkyl group (e.g., cyclopropyl optionally substituted by 1 to 3cyano group(s), (b) a halogen atom (e.g., fluorine atom),(c) a hydroxy group,(d) a C6-10 aryl group (e.g. phenyl) optionally substituted by 1 to 3 C1-6alkoxy(s) (e.g., methoxy), and (e) a 4- to 7 membered heterocyclic group (e.g., oxetanyl) optionallysubstituted by a hydroxy group, (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiroheptanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6alkyl group (e.g., methyl), (b) a hydroxy group, and (c) a cyano group, (iii) a C1-6 alkoxy group (e.g., methoxy) or (iv) a 4- to 7-membered heterocylic group (e.g., oxetanyl, pyrazolyl, tetrahydrofuryl, tetrahydropyranyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6alkyl (e.g., methyl), and (b) a hydroxy group; Rc1is 37 60230447.1(i) a hydrogen atom, or (ii) a C1-6 alkyl (e.g., methyl)).

[0123] R1 is more preferably(1) a C1-6 alkyl group (e.g., iso-propyl) optionally substituted by 1 to 3 hydroxy group(s),(2) a C3-8 cycloalkyl group (e.g., cyclopropyl), or(3) a C1-6 alkoxy group (e.g., methoxy).

[0124] R1 is furthermore preferably a C1-6 alkoxy group (e.g., methoxy).

[0125] R2 is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) anoptionally substituted C1-6 alkyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an optionally substituted C1-6alkoxy group, (7) -NRbRc(wherein Rband Rcare as defined above), or (8) an optionally substituted 5- or 6-membered aromatic heterocyclic group.

[0126] As one embodiment, R2 is preferably(1) a hydrogen atom, (2) a fluorine atom, (3) a C1-6 alkyl group (e.g., methyl), (4) a C1-6alkoxy group (e.g., methoxy), or (5) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl).

[0127] R2 is more preferably, a hydrogen atom.

[0128] R1 and R2 may bind to form an optionally substituted 5- or 6-memberedheterocyclic ring with the adjacent carbon atoms.

[0129] As one embodiment, R1 and R2 may bind to form 5- or 6-membered heterocyclicring (e.g., tetrahydrofuran, tetrahydropyran, morpholine) with the adjacent carbon atoms optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (1) a C1-6alkyl group (e.g., methyl), (2) a C1-6 alkyl-carbonyl group (e.g., acetyl), (3) a C1-6 alkoxy- carbonyl group (e.g., tert-butoxycarbonyl), and (4) a hydroxy group.

[0130] R3 is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) anoptionally substituted C3-8cycloalkyl group, (4) an optionally substituted C1-6alkoxy group, (5) -NRbRc(wherein Rband Rcare as defined above), or (6) an optionally substituted 4- to 7- membered heterocyclic group.

[0131] As one embodiment, R3 is preferably (1) a hydrogen atom, or (2) a C1-6 alkyl group(e.g., methyl).

[0132] R3 is more preferably, a hydrogen atom.

[0133] R4 is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromineatom, or (5) an optionally substituted C1-6alkyl group. 38 60230447.1

[0134] As one embodiment, R4 is preferably (1) a hydrogen atom, or (2) a C1-6 alkyl group(e.g., methyl).

[0135] R4 is more preferably, a hydrogen atom.Ring A is a 6-membered ring whereinX1is (i) =C(R5)-, (ii) -C(R5)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X2is (i) =C(R6)-, (ii) -C(R6)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X3is (i) =C(R7)-, (ii) -C(R7)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X4is (i) =C(R8)-, (ii) -C(R8)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X5is (i) =C(R9)-, (ii) -C(R9)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X6is (i) C, or (ii) N; R5is (i) a hydrogen atom, or (ii) a substituent; R6is (i) a hydrogen atom, or (ii) a substituent; R7is (i) a hydrogen atom, or (ii) a substituent; R8is (i) a hydrogen atom, or (ii) a substituent; R9is (i) a hydrogen atom, or (ii) a substituent; proviso that Ring A has at least one substituent on any one of X1, X2, X3, X4, or X5position;

[0136] As one embodiment, Ring A is preferably a benzene ring further substituted.

[0137] Ring A is more preferably a benzene ring substituted by 1 to 4 substituent(s)selected from a group consisting of (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom),(ii) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1to 3 substituent(s) selected from the group consisting of (a) a halogen atom (e.g, fluorine atom), (b) a hydroxy group, and (c) an optionally halogenated C1-6 alkoxy group (e.g., methoxy, difluoromethoxy), (iii) a C3-6 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3substituent(s) selected from the group consisting of (a) a halogen atom (e.g., fluorine atom), (b) a C1-6alkyl group (e.g., methyl) and (c) a cyano group, (iv) an optionally halogenated C1-6 alkoxy group (e.g., methoxy,difluoromethoxy) (v) a hydroxy group,(vi) a cyano group,39 60230447.1(vii) a 4- to 7 membered heterocyclic group (e.g., azetidinyl, oxetanyl,pyrazoly), and (viii) a C1-6 alkylsulfonyl group (e.g., methylsulfonyl).

[0138] Ring A is furthermore preferably a benzene ring substituted by 1 to 3 substituent(s)selected from a group consisting of (i) a halogen atom (e.g., fluorine atom, chlorine atom),(ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl),(iii) an optionally halogenated C3-6 cycloalkyl (e.g., cyclopropyl,fluorocyclopropyl), and (iv) a cyano group.

[0139] As one embodiment, Ring A is preferably a pyridine ring further substituted.

[0140] Ring A is more preferably a pyridine ring substituted by 1 to 3 substituent(s)selected from a group consisting of (i) an optionally halogenated C1-6 alkyl group (e.g., methyl, trifluoromethyl),and (ii) an optionally halogenated C3-6 cycloalkyl group (e.g., cyclopropyl).

[0141] As one embodiment, Ring A is preferably a pyrimidine ring further substituted.

[0142] Ring A is more preferably a pyrimidine ring substituted by 1 to 3 substituent(s)selected from a group consisting of (i) a C1-6 alkyl group (e.g., methyl), and(ii) a C3-6 cycloalkyl group (e.g., cyclopropyl).

[0143] As one embodiment, Ring A is preferably a dihydropyridine ring furthersubstituted.

[0144] Ring A is more preferably a dihydropyridine ring substituted by 1 to 3substituent(s) selected from a group consisting of (i) a C1-6 alkyl group (e.g., methyl),(ii) a C3-6 cycloalkyl group (e.g., cyclopropyl), and(iii) an oxo group.

[0145] Preferable embodiment of a compound of Formula (I) includes the followingcompounds.

[0146] [Compound A]R1is (1) a hydrogen atom, (2) an optionally substituted C1-6alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted 4- to 7-membered heterocyclic group, (5) -ORa, or (6) -NRbRc; 40 60230447.1R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) an optionally substituted C1-6 alkyl group, (5) an optionally substituted C3-8 cycloalkyl group, (6) an optionally substituted C1-6alkoxy group, (7) -NRbRc, or (8) an optionally substituted 5- or 6- membered aromatic heterocyclic group; R1and R2may bind to form an optionally substituted 5- or 6-membered heterocyclic ring with the adjacent carbon atoms; R3is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C1-6 alkoxy group, (5) -NRbRc, or (6) an optionally substituted 4- to 7-membered heterocyclic group; R4is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromine atom, or (5) an optionally substituted C1-6 alkyl group; Ring A is a 6-membered ring wherein X1is (i) =C(R5)-, (ii) -C(R5)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X2is (i) =C(R6)-, (ii) -C(R6)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X3is (i) =C(R7)-, (ii) -C(R7)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X4is (i) =C(R8)-, (ii) -C(R8)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X5is (i) =C(R9)-, (ii) -C(R9)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X6is (i) C, or (ii) N; R5is (i) a hydrogen atom, or (ii) a substituent; R6is (i) a hydrogen atom, or (ii) a substituent; R7is (i) a hydrogen atom, or (ii) a substituent; R8is (i) a hydrogen atom, or (ii) a substituent; R9is (i) a hydrogen atom, or (ii) a substituent; proviso that Ring A has at least one substituent on any one of X1, X2, X3, X4, or X5position; and Rais (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7- membered heterocyclic group; Rbis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group, (iv) an optionally substituted C1-6alkoxy group, or (v) an optionally substituted 4- to 7-membered heterocyclic group, in each occurrence; and Rcis (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7- membered heterocyclic group, in each occurrence. 41 60230447.1

[0147] [Compound B]R1is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8cycloalkyl group, (4) an optionally substituted 4- to 6-membered heterocyclic group, (5) -ORa(wherein Rais (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8cycloalkyl group, or (iv) an optionally 4- to 7- membered heterocyclic group), or (6) -NRbRc(wherein Rbis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7-membered heterocyclic group; and Rcis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, or (iv) an optionally substituted 4- to 7-membered heterocyclic group); R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) an optionally substituted C1-6alkyl group, (5) an optionally substituted C3-8cycloalkyl group, (6) an optionally substituted C1-6 alkoxy group, (7) -NRbRc(wherein Rband Rcare as defined above), or (8) an optionally substituted 5- or 6-membered aromatic heterocyclic group; R3is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8cycloalkyl group, (4) an optionally substituted C1-6alkoxy group, (5) -NRbRc(wherein Rband Rcare as defined above), or (6) an optionally substituted 4- to 7-membered heterocyclic group; and R4is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromine atom, or (5) an optionally substituted C1-6 alkyl group; and Ring A is a 6-membered ring further substituted.

[0148] [Compound C]R1is (1) a hydrogen atom, (2) a C1-6 alkyl group (e.g., methyl, ethyl, iso-propyl, iso-butyl, sec-butyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom (e.g., a fluorine atom), (ii) a C3-8cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 hydroxy group, (iii) a C1-6alkoxy group (e.g., methoxy), (iv) an amino group, (v) a (4- to 7-membered heterocyclic)-amino group (e.g., pyrazolylamino) optionally substituted by 1 to 3 C1-6alkyl group (e.g., methyl), (vi) a C1-6 alkyl-carbonyl-amino group (e.g., acetylamino, ethylcarbonylamino) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of 42 60230447.1(a) a halogen atom (e.g., fluorine atom), and (b) a C1-6 alkoxy group (e.g., methoxy), (vii) a C3-8cycloalkyl-carbonyl-amino group (e.g., cyclopropylcarbonylamino) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine atom), (viii) a (4- to 7-membered heterocyclic group)-carbonyl-amino group (e.g, tetrahydropyranylcarbonylamino, pyridylcarbonylamino) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine atom), (ix) a C1-6 alkoxy-carbonyl-amino group (e.g., methoxycarbonylamino, tert- butoxycarbonylamino), (x) a N-C1-6alkyl- N-C1-6alkyl-carbonyl-amino group (e.g., N-acetyl-N- methylamino), (xi) a N-C1-6alkoxy- N-C1-6alkyl-ureido group (e.g., N-methoxy-N-methyl- ureido), (xii) a hydroxy group, and (xiii) a 4- to 7-membered heterocyclic group (e.g., pyrazolyl) (3) a C3-8cycloalkyl group (e.g., cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6alkyl group (e.g., methyl) (ii) a halogen atom (e.g., a fluorine atom), (iii) a cyano group, (iv) a C1-6alkoxy group (e.g., methoxy), (v) a hydroxy group, and (vi) a 4- to 7-membered heterocyclyloxy group (e.g, tetrahydropyranyloxy), (4) a 4- to 7-membered heterocyclic group (e.g., azetidinyl, oxetany, pyrazolyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazepanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkoxy group (e.g., methoxy), (b) a halogen atom (e.g., fluorine atom), (c) a C1-6alkoxy-carbonyl group (e.g., ethoxycarbonyl), and (d) carboxyl group, (ii) a C3-8cycloalkyl group (e.g., cyclopropyl), 43 60230447.1(iii) a C1-6alkoxy group (e.g., methoxy), (iv) a halogen atom (e.g., fluorine atom), (v) a hydroxy group, (vi) a tri-C1-6 alkylsilyloxy group (e.g., tert-butyl-dimethylsilyloxy), (vii) a cyano group, (viii) –(CH2)l- (wherein l is an integer of 2 to 4) (e.g., -(CH2)2-), (ix) –(CH2)mO(CH2)n- (wherein m is an integer of 1 or 2, and n is an integer of 1 or 2) (e.g., -CH2OCH2-, -(CH2)2OCH2-), (x) an oxo, (xi) a 4- to 7-membered heterocyclyl group (e.g, oxetanyl, tetrahydropyranyl, 1,1- dioxothiopyranyl), and (xii) –(CH2)pNRd1(CH2)q- (wherein Rd1(a) a hydrogen atom, (b) a C1-6alkoxy- carbonyl group (e.g., tert-butoxycarbonyl), or (c) an optionally halogenated 4- to 7- membered heterocyclic group (e.g, oxetanyl, pyridazinyl, chloropyridazinyl), p is an integer of 1 or 2, and q is an integer of 1 or 2) (e.g., -CH2NHCH2-, - CH2N(C(O)OC(CH3)3)CH2- , -CH2N(3-oxetanyl)CH2-, -CH2N(4-pyperazinyl)CH2-), (5) -ORa1(Ra1is (i) a hydrogen atom, (ii) a C1-6 alkyl group (e.g., methyl, ethyl, propyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a hydroxy group, (b) a halogen atom (e.g., a fluorine atom), (c) C1-6 alkoxy group (e.g., methoxy), and (d) a 4- to 7- membered heterocyclic group (e.g., pyrazolyl) optionally substituted by 1 to 34- to 7- membered heterocyclic group (e.g., tetrahydropyranyl), (iii) a 4- to 7- membered heterocyclic group (e.g., tetrahydrofuryl), or (iv) a C3-8cycloalkyl group (e.g., cyclobutyl) optionally substituted by 1 to 3 hydroxy group, or (6) -NRb1Rc1(Rb1is (i) a C1-6 alkyl group (e.g., methyl, ethyl, propyl, iso-propyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of 44 60230447.1(a) a C3-8 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3cyano group(s), (b) a halogen atom (e.g., fluorine atom),(c) a hydroxy group,(d) a C6-10 aryl group (e.g. phenyl) optionally substituted by 1 to 3 C1-6alkoxy(s) (e.g., methoxy), and (e) a 4- to 7 membered heterocyclic group (e.g., oxetanyl) optionallysubstituted by a hydroxy group, (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiroheptanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6alkyl group (e.g., methyl), (b) a hydroxy group, and (c) a cyano group, (iii) a C1-6 alkoxy group (e.g., methoxy), or (iv) a 4- to 7-membered heterocylic group (e.g., oxetanyl, pyrazolyl, tetrahydrofuryl, tetrahydropyranyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkyl group (e.g., methyl), and (b) a hydroxy group; Rc1is (i) a hydrogen atom, or (ii) a C1-6alkyl group (e.g., methyl)); R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a C1-6alkyl group (e.g., methyl), (4) a C1-6 alkoxy group (e.g., methoxy), or (5) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl); or R1and R2may bind to form 5- or 6-membered heterocyclic ring (e.g., tetrahydrofuran, tetrahydropyran, morpholine) with the adjacent carbon atoms optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (1) a C1-6 alkyl group (e.g., methyl), (2) a C1-6 alkyl-carbonyl group (e.g., acetyl), (3) a C1-6alkoxy-carbonyl group (e.g., tert-butoxycarbonyl), and (4) a hydroxy group. 45 60230447.1R3is (1) a hydrogen atom, or (2) a C1-6alkyl group (e.g., methyl); R4is (1) a hydrogen atom, or (2) a C1-6 alkyl group (e.g., methyl); and Ring A is a benzene ring substituted by 1 to 4 substituent(s) selected from a group consisting of (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), (ii) a C1-6alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a halogen atom (e.g, fluorine atom), (b) a hydroxy group, and (c) an optionally halogenated C1-6alkoxy group (e.g., methoxy, difluoromethoxy), (iii) a C3-6cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a halogen atom (e.g., fluorine atom), (b) a C1-6 alkyl group (e.g., methyl), and (c) a cyano group, (iv) an optionally halogenated C1-6alkoxy group (e.g., methoxy, difluoromethoxy), (v) a hydroxy group, (vi) a cyano group, (vii) a 4- to 7 membered heterocyclic group (e.g., azetidinyl, oxetanyl, pyrazoly), and (viii) a C1-6 alkylsulfonyl group (e.g., methylsulfonyl).

[0149] [Compound D]R1is (1) a C1-6 alkyl group (e.g., iso-propyl) optionally substituted by 1 to 3 hydroxy group(s) or (2) a C1-6alkoxy group (e.g.,methoxy); R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is (1) a pyridine ring substituted by 1 to 3 substituent(s) selected from a group consisting of 46 60230447.1(i) an optionally halogenated C1-6alkyl group (e.g., methyl, trifluoromethyl), and (ii) an optionally halogenated C3-6 cycloalkyl group (e.g., cyclopropyl), (2) a pyrimidine ring substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a C1-6 alkyl group (e.g., methyl), and (ii) a C3-6cycloalkyl group (e.g., cyclopropyl), or (3) a dihydropyridine ring substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a C1-6 alkyl group (e.g., methyl), (ii) a C3-6 cycloalkyl group (e.g., cyclopropyl), and (iii) an oxo group.

[0150] [Compound E]R1is (1) a hydrogen atom, (2) a C1-6alkyl group (e.g., methyl, ethyl, iso-propyl, sec-butyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom (e.g, a fluorine atom) (ii) a C1-6 alkyl-carbonyl-amino group (e.g., acetylamino), and (iii) a hydroxy group, (3) a C3-8 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, (iii) a C1-6alkoxy group (e.g., methoxy), and (iv) a 4- to 7-membered heterocyclyloxy group (e.g, tetrahydropyranyloxy), (4) a 4- to 7-membered heterocyclic group (e.g., azetidinyl, oxetany, pyrazolyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazepanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6alkyl group (e.g., methyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkoxy group (e.g., methoxy), and (b) a halogen atom (e.g., fluorine atom) (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl), (iii) a C1-6alkoxy group (e.g., methoxy), 47 60230447.1(iv) a halogen atom (e.g., fluorine atom), (v) a hydroxy group, (vi) a tri-C1-6alkylsilyloxy group (e.g., tert-butyl-dimethylsilyloxy), (vii) a cyano group, (viii) –(CH2)l- (wherein l is an integer of 2 to 4) (e.g., -(CH2)2-), (ix) –(CH2)mO(CH2)n- (wherein m is an integer of 1 or 2, and n is an integer of 1 or 2) (e.g., -CH2OCH2-, -(CH2)2OCH2-, and (x) an oxo group, (5) -ORa1(Ra1is (i) a hydrogen atom,(ii) a C1-6 alkyl group (e.g., methyl, ethyl, propyl) optionally substituted by 1 to 3substituent(s) selected from the group consisting of (a) a hydroxy group, (b) a halogen atom (e.g., a fluorine atom), and (c) C1-6alkoxy group (e.g., methoxy), or (iii) a 4- to 7- membered heterocyclic group (e.g., tetrahydrofuryl)), or(6) -NRb1Rc1(Rb1is (i) a C1-6 alkyl group (e.g., methyl, ethyl, propyl, iso-propyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C3-8 cycloalkyl group (e.g., cyclopropyl optionally substituted by 1 to 3 cyano group(s), (b) a halogen atom (e.g., fluorine atom), (c) a hydroxy group, (d) a C6-10 aryl group (e.g. phenyl) optionally substituted by 1 to 3 C1-6 alkoxy(s) (e.g., methoxy), and (e) 4- to 7 membered heterocyclic group (e.g., oxetanyl) optionally substituted by a hydroxy group, (ii) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiroheptanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkyl group (e.g., methyl), (b) a hydroxy group, and 60230447.1(c) a cyano group, or (iii) a 4- to 7-membered heterocylic group (e.g., oxetanyl, pyrazolyl, tetrahydrofuryl, tetrahydropyranyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6alkyl group (e.g., methyl), and (b) a hydroxy group; Rc1is (i) a hydrogen atom, or (ii) a C1-6 alkyl group (e.g., methyl)); R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a C1-6alkyl group (e.g., methyl), or (4) a C1-6 alkoxy group (e.g., methoxy); R3is (1) a hydrogen atom, or (2) a C1-6alkyl group (e.g., methyl); R4is (1) a hydrogen atom, or (2) a C1-6 alkyl group (e.g., methyl); and Ring A is more preferably a benzene ring optionally substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),(ii) a C1-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3substituent(s) selected from the group consisting of (a) a halogen atom (e.g, fluorine atom),(b) a hydroxy group, and(c) an optionally halogenated C1-6 alkoxy group (e.g., methoxy,difluoromethoxy), (iii) an optionally halogenated C3-6 cycloalkyl group (e.g., cyclopropyl,fluorocyclopropyl), (iv) an optionally halogenated C1-6 alkoxy group (e.g., methoxy,difluoromethoxy), and (v) a cyano group.

[0151] [Compound F]R1is(1) a C1-6 alkyl group (e.g., iso-propyl) optionally substituted by 1 to 3 hydroxy group(s),(2) a C3-8 cycloalkyl group (e.g., cyclopropyl), or(3) a C1-6 alkoxy group (e.g., methoxy);R2is a hydrogen atom; R3is a hydrogen atom; 49 60230447.1R4is a hydrogen atom; and Ring A is a benzene ring optionally substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a halogen atom (e.g., fluorine atom, chlorine atom),(ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl),(iii) an optionally halogenated C3-6 cycloalkyl group (e.g., cyclopropyl,fluorocyclopropyl), and (iv) a cyano group.

[0152] [Compound G]R1is a C1-6alkoxy group (e.g., methoxy); R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is a benzene ring optionally substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a halogen atom (e.g., fluorine atom, chlorine atom), (ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl), (iii) an optionally halogenated C3-6cycloalkyl group (e.g., fluorocyclopropyl), and (iv) a cyano group.

[0153] Specific examples of a compound of Formula (I) include the compounds ofExamples 1 to 317.

[0154] More preferably, following compounds are preferable.(1) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 38) or a salt thereof;(2) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 54) or a salt thereof;(3) 5-cyclopropyl-2-(8-cyclopropyl-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3-methylbenzonitrile (Example 62) or a salt thereof;(4) 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3-methylbenzonitrile (Example 230) or a salt thereof;(5) 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 302) or a salt thereof; and(6) 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 305) or a salt thereof. 50 60230447.1

[0155] Furthermore preferably, following compounds are preferable.(1) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 38) or a salt thereof;(2) 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3-methylbenzonitrile (Example 230) or a salt thereof;(3) 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 302) or a salt thereof; and(4) 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 305) or a salt thereof.

[0156] Compounds of Formula (I) include embodiments described in the precedingparagraphs and compounds specifically named in the examples, may exist as salts, complexes, solvates, hydrates, and liquid crystals. Likewise, compounds of Formula (I) that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0157] Compounds of Formula (I) may form pharmaceutically acceptable complexes,salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0158] Pharmaceutically acceptable base salts include salts derived from bases, includingmetal cations, such as an alkali or alkaline earth metal cation, as well as amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, 51 60230447.1and procaine. For a discussion of useful acid addition and base salts, see S. M. Berge et al., J. Pharm. Sci. (1977) 66:1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0159] Pharmaceutically acceptable salts may be prepared using various methods. Forexample, a compound of Formula (I) may be reacted with an appropriate acid or base to give the desired salt. Alternatively, a precursor of the compound of Formula (I) may be reacted with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, a salt of the compound of Formula (I) may be converted to another salt (or free form) through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, the salt may be isolated by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0160] Compounds of Formula (I) may exist in a continuum of solid states ranging fromfully amorphous to fully crystalline. The term “amorphous” refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”). The term “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).

[0161] Compounds of Formula (I) may also exist in unsolvated and solvated forms. Theterm “solvate” describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol) which is other than water. The term “hydrate” means a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0162] A currently accepted classification system for solvates and hydrates of organiccompounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are ones in which the 52 60230447.1solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules lie in lattice channels where they are next to other solvent molecules. In metal-ion coordinated solvates, the solvent molecules are bonded to the metal ion.

[0163] When the solvent or water is tightly bound, the complex will have a well-definedstoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will typically be observed.

[0164] Compounds of Formula (I) may also exist as multi-component complexes (otherthan salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions but could also be a complex of a neutral molecule with a salt. Co- crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and M. J. Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0165] When subjected to suitable conditions, compounds of Formula (I) may exist in amesomorphic state (mesophase or liquid crystal). The mesomorphic state lies between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as “thermotropic” and mesomorphism resulting from the addition of a second component, such as water or another solvent, is described as “lyotropic.” Compounds that have the potential to form lyotropic mesophases are described as “amphiphilic” and include molecules which possess a polar ionic moiety (e.g., -COOˉNa+, -COOˉK+, -SO3ˉNa+) or polar non-ionic moiety (such as -NˉN+(CH3)3). See, e.g., N. H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0166] Each compound of Formula (I) may exist as polymorphs, stereoisomers, tautomers,or some combination thereof, may be isotopically-labeled, may result from the administration of a prodrug, or form a metabolite following administration.

[0167] “Prodrugs” refer to compounds having little or no pharmacological activity thatcan, when metabolized in vivo, undergo conversion to compounds having desired pharmacological activity. Prodrugs may be prepared by replacing appropriate functionalities 53 60230447.1present in pharmacologically active compounds with “pro-moieties” as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of Formula (I) having carboxylic acid, hydroxy, or amino functional groups, respectively. For further discussions of prodrugs, see e.g., T. Higuchi and V. Stella “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).

[0168] “Metabolites” refer to compounds formed in vivo upon administration ofpharmacologically active compounds. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula (I) having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0169] Compounds of Formula (I) may exist as stereoisomers that result from the presenceof one or more stereogenic centers, one or more double bonds, or both. The stereoisomers may be pure, substantially pure, or mixtures. Such stereoisomers may also result from acid addition or base salts in which the counter-ion is optically active, for example, when the counter-ion is D-lactate or L-lysine.

[0170] Compounds of Formula (I) may exist as tautomers, which are isomers resultingfrom tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto- enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0171] Compounds of Formula (I) may exhibit more than one type of isomerism.

[0172] Geometrical (cis / trans) isomers may be separated by conventional techniques suchas chromatography and fractional crystallization.

[0173] Conventional techniques for preparing or isolating a compound having a specificstereochemical configuration include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, etc., and the appropriate diastereoisomer converted to the compound having the requisite stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds (1994). 54 60230447.1

[0174] Compounds of Formula (I) may possess isotopic variations, in which at least oneatom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Isotopes suitable for inclusion in compounds of Formula (I) include, for example, isotopes of hydrogen, such as2H and3H; isotopes of carbon, such as11C,13C and14C; isotopes of nitrogen, such as13N and15N; isotopes of oxygen, such as15O,17O and18O; isotopes of sulfur, such as35S; isotopes of fluorine, such as18F; isotopes of chlorine, such as36Cl, and isotopes of iodine, such as123I and125I. Use of isotopic variations (e.g., deuterium,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium,3H, or14C), which may be useful in drug and / or substrate tissue distribution studies. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.

[0175] Compound (I) may be prepared using the techniques described below. Some of themethods and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in several treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2from the decarboxylation of a di-acid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0176] In the methods and examples below, certain compounds may be prepared usingprotecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of 55 60230447.1useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0177] Generally, the chemical transformations described throughout the specificationmay be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78 °C to 0 °C). Any reference in the disclosure and claims to a stoichiometric range, a temperature range, a pH range, etc., whether expressly using the word “range,” also includes the indicated endpoints.

[0178] Many of the chemical transformations may also employ one or more compatiblesolvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl- propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2- ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy- ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1,-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

[0179] In the schemes, below, substituent identifiers (e.g., X, L, R1, R2, R3, R4, R5, R6, R7,and R8) are as defined above for Formula (I). As mentioned earlier, some of the starting materials and intermediates may include protecting groups, which are removed prior to the final product. In such cases, the substituent identifier refers to moieties defined in Formula (I) 56 60230447.1and to those moieties with appropriate protecting groups. For example, a starting material or intermediate in the synthetic methods may include a potentially reactive (secondary) amine. In such cases, the amine would include the moiety with or without, say, a Boc or Cbz group attached to the amine.

[0180] The production method of the compound of the present invention is explainedbelow.

[0181] The raw material compound and reagent used and the compound obtained in eachstep in the following production method may be each in a form of a salt, and examples of such salt include those similar to the salts of the compound of the present invention and the like.

[0182] When the compound obtained in each step is a free form, it can be converted to theobjective salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or the other salt according to a method known per se.

[0183] The compound obtained in each step can be used directly as the reaction mixture oras a crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.

[0184] When the raw material compound and reagent used in each step are commerciallyavailable, the commercially available product can also be used directly.

[0185] In the reaction in each step, while the reaction time varies depending on the kind ofthe reagent and solvent to be used, it is generally 1 minute to 48 hours, preferably 10 minutes to 8 hours, unless otherwise specified.

[0186] In the reaction in each step, while the reaction temperature varies depending on thekind of the reagent and solvent to be used, it is generally -78 ^C to 300 ^C, preferably -78 ^C to 150 ^C, unless otherwise specified.

[0187] In the reaction in each step, while the pressure varies depending on the kind of thereagent and solvent to be used, it is generally 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.

[0188] Microwave synthesizer such as Initiator manufactured by Biotage and the like maybe used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally room temperature to 300 ^C, 57 60230447.1preferably 50 ^C to 250 ^C, unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0189] In the reaction in each step, the reagent is used in an amount of 0.5 equivalents to20 equivalents, preferably 0.8 equivalents to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in a solvent amount.

[0190] Unless otherwise specified, the reaction in each step is carried out without solvent,or by dissolving or suspending the raw material compound in a suitable solvent. Examples of the solvent include those described in Examples and the following solvents. alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the like; amides: N,N-dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; nitriles: acetonitrile and the like; sulfoxides: dimethyl sulfoxide and the like; aromatic organic bases: pyridine and the like; anhydrides: acetic anhydride and the like; organic acids: formic acid, acetic acid, trifluoroacetic acid and the like; inorganic acids: hydrochloric acid, sulfuric acid and the like; esters: ethyl acetate and the like; ketones: acetone, methyl ethyl ketone and the like; water.

[0191] The above-mentioned solvent can be used in a mixture of two or more kindsthereof in an appropriate ratio.

[0192] When a base is used for the reaction in each step, examples thereof include thosedescribed in Examples and the following bases. inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like; 58 60230447.1organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N- dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like; metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides: sodium hydride and the like; metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; organic lithiums: n-butyllithium and the like.

[0193] When an acid or an acid catalyst is used for the reaction in each step, examplesthereof include those described in Examples and the following acids and acid catalysts. inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like; organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10- camphorsulfonic acid and the like; Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

[0194] Unless otherwise specified, the reaction in each step is carried out according to amethod known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.14- 15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.1 -Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in Examples.

[0195] In each step, the protection or deprotection reaction of a functional group is carriedout according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P.J. Kocienski), or the like, or the method described in Examples. 59 60230447.1

[0196] Examples of the protecting group for a hydroxy group of an alcohol and the likeand a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, methyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester-type protecting groups such as acetate ester and the like; sulfonate ester-type protecting groups such as methanesulfonate ester and the like; carbonate ester-type protecting groups such as tert-butylcarbonate and the like, and the like.

[0197] Examples of the protecting group for a carbonyl group of an aldehyde includeacetal-type protecting groups such as dimethylacetal and the like; cyclic acetal-type protecting groups such as 1,3-dioxane and the like, and the like.

[0198] Examples of the protecting group for a carbonyl group of a ketone include ketal-type protecting groups such as dimethylketal and the like; cyclic ketal-type protecting groups such as 1,3-dioxolane, 1,3-dioxane and the like; oxime-type protecting groups such as O- methyloxime and the like; hydrazone-type protecting groups such as N,N-dimethylhydrazone and the like, and the like.

[0199] Examples of the protecting group for a carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-type protecting groups such as N,N-dimethylamide and the like, and the like.

[0200] Examples of the protecting group for a thiol include ether-type protecting groupssuch as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.

[0201] Examples of the protecting group for an amino group and an aromatic heterocyclesuch as imidazole, pyrrole, indole and the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenylmethylamine and the like; sulfonamide-type protecting groups such as methanesulfonamide and the like, and the like.

[0202] The protecting groups can be removed according to a method known per se, forexample, by employing a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method, and the like.

[0203] When reduction reaction is carried out in each step, examples of the reducing agentto be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such 60 60230447.1as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; iron; zinc and the like. When carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar’s catalyst and the like may be employed.

[0204] When oxidation reaction is carried out in each step, examples of the oxidizingagent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N- bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

[0205] When radical reaction is carried out in each step, examples of the radical initiatorto be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water- soluble radical initiators such as 4,4’-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2- tetraphenyldisilane, diphenylsilane, samarium iodide and the like.

[0206] When Wittig reaction is carried out in each step, examples of the Wittig reagent tobe used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0207] When Horner-Emmons reaction is carried out in each step, examples of the reagentto be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithiums and the like.

[0208] When Friedel-Crafts reaction is carried out in each step, a combination of a Lewisacid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin etc.) is used as a reagent. Alternatively, an organic acid or 61 60230447.1an inorganic acid can also be used instead of a Lewis acid, and an anhydride such as acetic anhydride and the like can also be used instead of an acid chloride.

[0209] When aromatic nucleophilic substitution reaction is carried out in each step, anucleophile (e.g., an amine, imidazole, alcohol etc.) and a base (e.g., an inorganic base, an organic base etc.) are used as a reagent.

[0210] When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-additionreaction (Michael addition reaction) by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, and examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

[0211] When Grignard reaction is carried out in each step, examples of the Grignardreagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent.

[0212] When Knoevenagel condensation reaction is carried out in each step, a compoundhaving an activated methylene group with two electron withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as a reagent.

[0213] When Vilsmeier-Haack reaction is carried out in each step, phosphoryl chlorideand an amide derivative (e.g., N,N-dimethylformamide etc.) are used as a reagent.

[0214] When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried outin each step, examples of the azidating agent to be used include diphenylphosphorylazide (DPPA), trimethylsilylazide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and the like are employed.

[0215] When reductive amination reaction or reductive alkylation reaction is carried out ineach step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include 62 60230447.1ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like.

[0216] When Mitsunobu reaction is carried out in each step, a cyanomethylenetrialkylphosphorane (e.g., cyanomethylenetrimethylphosphorane, cyanomethylenetributylphosphorane), or a combination of an azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and a phosphine (e.g., triphenylphosphine, tri-n-butylphosphine) is used as a reagent.

[0217] When esterification reaction, amidation reaction or urea formation reaction iscarried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as anhydrides, activated esters, sulfates and the like; esters, especially, for amidation reaction. Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1- carbonyldiimidazole (CDI) and the like; diphenylphosphorylazide (DPPA); benzotriazol-1- yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; combinations thereof and the like. When carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system. When the esters are converted to the corresponding carboxamides, examples of the reagent include ammonia and the like.

[0218] When coupling reaction is carried out in each step, examples of the metal catalystto be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1’- bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases, metal alkoxides and the like. 63 60230447.1

[0219] When deoxyamination reaction is carried out in each step, examples of the reagentto be used include phosphonium salt such as PyBOP, PyBroP and the like.

[0220] When thiocarbonylation reaction is carried out in each step, phosphoruspentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4- dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent) etc.) can also be used instead of phosphorus pentasulfide.

[0221] When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N- chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like to the reaction system.

[0222] When halogenation reaction of a hydroxy group is carried out in each step,examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed. Alternatively, a method of producing an alkyl halide via two steps comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed.

[0223] When Arbuzov reaction is carried out in each step, examples of the reagent to beused include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0224] When sulfonate esterification reaction is carried out in each step, examples of thesulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

[0225] When hydrolysis reaction is carried out in each step, an acid or a base is used as areagent. For acid hydrolysis reaction of the tert-butyl ester, formic acid, triethylsilane and the like may be added to reductively-trap tert-butyl cation which is by-produced. For hydrolysis reaction of the cyano group, examples of the base include potassium carbonate, sodium hydroxide and the like. In addition, an oxidant may be added to the reaction system, and examples thereof include hydrogen peroxide and the like. 64 60230447.1

[0226] When dehydration reaction is carried out in each step, examples of the dehydratingagent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N,N’-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0227] When Chan-Lam reaction is carried out in each step, examples of the metalcatalyst to be used include copper compounds such as copper(I) bromide, copper(I) iodide, copper(II) acetate and the like. In addition, a base may be added to the reaction system, and examples thereof include organic bases and the like.

[0228] When Ullmann reaction is carried out in each step, examples of the metal catalystto be used include copper compounds such as copper(I) bromide, copper(I) iodide, copper(II) acetate and the like, and examples of the ligand include N,N,N’,N’-tetramethylethylene diamine and the like. In addition, a base may be added to the reaction system, and examples thereof include organic bases, inorganic bases and the like.

[0229] When alkylation reaction is carried out in each step, examples of the base to beused include potassium carbonate, tripotassium phosphate, triethylamine, N,N- diisopropylethylamine, pyridine, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, n-butyllithium and the like. In addition, an inorganic salt may be added to the reaction system, and examples thereof include lithium bromide and the like.

[0230] When deoxofluorination reaction is carried out in each step, examples of thefluorinating agent to be used include bis(2-methoxyethyl)aminosulfur trifluoride, diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, N,N-diethyl- S,S-difluorosulfiliminium tetrafluoroborate, difluoro-4-morpholinylsulfonium tetrafluoroborate and the like.

[0231] When Hofmann rearrangement reaction is carried out in each step, examples of thereagent to be used include lead tetraacetate, iodobenzene diacetate and the like.

[0232] When thiourea formation reaction or thiocarbamation reaction is carried out ineach step, examples of the reagent to be used include thiophosgene and the like, and examples of the base include organic bases, sodium hydride and the like.

[0233] When cyclopropanation reaction is carried out in each step, examples of thereagent to be used include diiodomethane, dibromomethane, dibromodifluoromethane, dibromofluoromethane, (trifluoromethyl)trimethylsilane, (bromodifluoromethyl)trimethylsilane, (dibromofluoromethyl)trimethylsilane, carbon tetrafluoride, sodium trifluoroacetate and the like. 65 60230447.1

[0234] When compound (I) and intermediate for the production of compound (I) have aconvertible functional group (e.g., a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a mercapto group, a C1-6alkoxy-carbonyl group, a C6-14aryloxy-carbonyl group, a C7-16 aralkyloxy-carbonyl group, a sulfo group, a sulfide group, a halogen atom, an optionally halogenated C1-6alkylsulfonyloxy group, a cyano group, an aminocarbonyl group, a boryl group etc.), various compounds can be produced by converting such functional group according to a method known per se or a method analogous thereto.

[0235] Carboxyl group can be converted, for example, by reactions such as esterification,reduction, amidation, conversion reaction to optionally protected amino group and the like.

[0236] Amino group can be converted, for example, by reactions such as amidation,sulfonylation, nitrosation, alkylation, arylation, imidation and the like.

[0237] Hydroxy group can be converted, for example, by reactions such as esterification,carbamoylation, sulfonylation, alkylation, fluorination, arylation, oxidation, halogenation and the like.

[0238] Carbonyl group can be converted, for example, by reactions such as reduction,oxidation, fluorination, imination (including oximation, hydrazonation), (thio)ketalization, alkylidenation, thiocarbonylation and the like.

[0239] Mercapto group can be converted, for example, by reactions such as alkylation,oxidation and the like.

[0240] C1-6 alkoxy-carbonyl group, C6-14 aryloxy-carbonyl group and C7-16 aralkyloxy-carbonyl group can be converted, for example, by reactions such as reduction, hydrolysis and the like.

[0241] Sulfo group can be converted, for example, by reactions such as sulfonamidation,reduction and the like.

[0242] Sulfide group can be converted, for example, by reactions such as oxidation andthe like.

[0243] Halogen atom can be converted, for example, by various nucleophilic substitutionreactions, various coupling reactions and the like.

[0244] Optionally halogenated C1-6 alkylsulfonyloxy group can be converted, for example,by various nucleophilic substitution reactions, various coupling reactions and the like.

[0245] Cyano group can be converted, for example, by reactions such as reduction,hydrolysis and the like.

[0246] Aminocarbonyl group can be converted, for example, by reactions such asdehydration, reduction and the like. 66 60230447.1

[0247] Boryl group can be converted, for example, by oxidation, various couplingreactions and the like.

[0248] In each of the above-mentioned reactions, when the compound is obtained in a freeform, it may be converted to a salt according to a conventional method. When it is obtained as a salt, it may be converted to a free form or other salt according to a conventional method.

[0249] The conversion of these functional group can be carried out according to a methodknown per se, for example, the method described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock, or the like.

[0250] Compound (I) obtained in each reaction scheme can be isolated and purified byknown separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, each material compound used in each reaction scheme can be isolated and purified by those similar to the above-mentioned known separation and purification means. The material compound may be used directly in the next step as the reaction mixture without isolation.

[0251] When compound (I) has isomers such as an optical isomer, a stereoisomer, aregioisomer and a rotamer and the like, such isomers and a mixture thereof are also encompassed in compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from racemate is also encompassed in compound (I). These isomers can be obtained as single products according to synthetic methods known per se, separation methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), optical resolutions (e.g., fractional recrystallization method, chiral column method, diastereomer method and the like).

[0252] Compound (I) may be a crystal, and the crystal form may be single or a mixture ofcrystal forms, both of which are encompassed in compound (I). The crystal can be produced according to a crystallization method known per se.

[0253] The compound (I) may be a solvate (e.g., hydrate) or a non-solvate (e.g., non-hydrate etc.) and both are encompassed in compound (I).

[0254] The compounds labeled with isotopes (e.g., 3H, 14C, 35S, 125I etc.) and the like arealso encompassed in compound (I).

[0255] A deuterium conversion form wherein 1H is converted to 2H(D) is alsoencompassed in compound (I). 67 60230447.1

[0256] Compound (I) labeled or substituted with an isotope can be used as, for example, atracer (PET tracer) used for Positron Emission Tomography (PET), and therefore, it is useful in the fields of medical diagnosis and the like.

[0257] Compound (I) of the present invention can be synthesized according to theproduction method described below.

[0258] Each variable in the formulas of the reaction schemes is as defined above, unlessotherwise specified.

[0259] Compound (I) can be produced from compound (1) or (7) according to scheme 1below. In the scheme, Z represents a dihydroxyboryl group or a pinacolboryl group (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl). In the scheme, LG1and LG2represent leaving groups. Examples of leaving groups include halogen atoms, optionally halogenated C1-6 alkylsulfonyl groups (e.g., methanesulfonyl, ethanesulfonyl), optionally halogenated C1-6alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C6-14 arylsulfonyloxy groups optionally substituted by a C1-6alkyl group (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like.

[0260] or can beproduced according to a method known per se.

[0262] Compound (2) may be commercially available or can be produced by subjectingcompound (1) to an amination reaction with an ammonia solution or subjecting compound (7) to a base-mediated cyclization reaction with guanidine. Examples of bases to be used include sodium ethoxide. 68 60230447.1

[0263] Compound (4) can be produced by subjecting compound (2) to a cyclizationreaction with compound (3).

[0264] Compound (5) can be produced by subjecting compound (4) to a sulfonylationreaction with sulfonylation reagents or a halogenation reaction with phosphoryl halides. Examples of sulfonylation reagents to be used include trifluoromethanesulfonic anhydride and p-toluenesulfonyl chloride. Examples of phosphoryl halides to be used include phosphoryl chloride and phosphoryl bromide.

[0265] Compound (I) can be produced by subjecting compound (5) to a coupling reactionwith compound (6a) or to an aromatic nucleophilic substitution reaction with (6b).

[0266] Compound (I-a), (I-b), and (I-c), where R1 is -ORa, an optionally substitutedheterocyclic group or -NRbRc, can be produced from compound (8) according to the following scheme 2. In the scheme, LG represents a leaving group. Examples of leaving groups include halogen atoms and the like. In the scheme, the formula:substituted heterocycle.

[0267] according to a method known per se.

[0269] Compound (8) can be produced according to the scheme 1.

[0270] Compound (9) can be produced by subjecting compound (8) to an acid-basedhydrolysis reaction. Examples of acids to be used include pyridinium chloride. 69 60230447.1

[0271] Compound (10) can be produced by subjecting compound (9) to a halogenationreaction with phosphoryl halides. Examples of phosphoryl halides to be used include phosphoryl chloride and phosphoryl bromide.

[0272] Compound (I-a) can be produced by subjecting compound (10) to an aromaticnucleophilic substitution reaction with compound (11).

[0273] Compound (I-b) can be produced by subjecting compound (10) to an aromaticnucleophilic substitution reaction with compound (12).

[0274] Compound (I-c) can be produced by subjecting compound (10) to an aromaticnucleophilic substitution reaction with compound (13) or subjecting compound (9) to a deoxyamination reaction with compound (13).

[0275] Compounds of Formula (I), which include compounds named above, and theirpharmaceutically acceptable complexes, salts, solvates and hydrates, should be assessed for their biopharmaceutical properties, such as solubility and solution stability across pH, permeability, and the like, to select an appropriate dosage form and route of administration. Compounds that are intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0276] Compound (I) may be administered alone or in combination with one another orwith one or more pharmacologically active agents which are different than Compound (I). When administering Compound (I) with a pharmacologically active agent (“concomitant drug”), the administration time of Compound (I) and the concomitant drug is not restricted, and Compound (I) or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof can be administered to a subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on a subject, administration route, disease, combination and the like.

[0277] The administration mode of the combination of Compound (I) and the concomitantdrug is not particularly limited, and Compound (I) and the concomitant drug only need to be combined on administration. Examples of such administration mode include the following: (1) administration of a single preparation obtained by simultaneously processing Compound (I) and the concomitant drug, (2) simultaneous administration of two kinds of preparations of Compound (I) and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of Compound (I) and the 70 60230447.1concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of Compound (I) and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of Compound (I) and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of Compound (I) and the concomitant drug, or in the reverse order) and the like.

[0278] The dose of the concomitant drug can be appropriately determined based on thedose employed in clinical situations. The mixing ratio of Compound (I) and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like.

[0279] For example, the content of Compound (I) in the combination with a concomitantdrug differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation.

[0280] The content of the concomitant drug used in the combination with Compound (I)differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation.

[0281] The content of additives such as a carrier and the like used in the combination ofCompound (I) and a concomitant drug differs depending on the form of a preparation, and usually from about 1 to about 99.99 wt%, preferably from about 10 to about 90 wt%, based on the preparation.

[0282] Similar contents may be employed even when Compound (I) and a concomitantdrug are separately formulated into preparations.

[0283] Generally, one or more of these compounds are administered as a pharmaceuticalcomposition (a formulation) in association with one or more pharmaceutically acceptable excipients. The choice of excipients depends on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0284] Compound (I) may be administered orally. Oral administration may involveswallowing in which case the compound enters the bloodstream via the gastrointestinal tract. 71 60230447.1Alternatively, or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.

[0285] Formulations suitable for oral administration include solid, semi-solid and liquidsystems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, e.g., from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents, suspending agents or both. Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).

[0286] Compound (I) may also be used in fast-dissolving, fast-disintegrating dosage formssuch as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0287] For tablet dosage forms, depending on dose, the active pharmaceutical ingredient(API) may comprise from about 1 wt% to about 80 wt% of the dosage form or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets may include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, anti- oxidants, colorants, flavoring agents, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, C1-6 alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.

[0288] Binders are generally used to impart cohesive qualities to a tablet formulation.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. 72 60230447.1

[0289] Tablets may also include surface active agents, such as sodium lauryl sulfate andpolysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0290] Tablets may also contain lubricants such as magnesium stearate, calcium stearate,zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.

[0291] Tablet blends may be compressed directly or by roller compaction to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. If desired, prior to blending one or more of the components may be sized by screening or milling or both. The final dosage form may comprise one or more layers and may be coated, uncoated, or encapsulated. Exemplary tablets may contain up to about 80 wt% of API, from about 10 wt% to about 90 wt% of binder, from about 0 wt% to about 85 wt% of diluent, from about 2 wt% to about 10 wt% of disintegrant, and from about 0.25 wt% to about 10 wt% of lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, as well as a description of alternative techniques for preparing drug products, see A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol.1-3 (2d ed., 1990); and D. K. Parikh & C. K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol.81 (1997).

[0292] Consumable oral films for human or veterinary use are pliable water-soluble orwater-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive. In addition to the API, a typical film includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifying agents, and solvents. Other film ingredients may include anti-oxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste-masking agents. Some components of the formulation may perform more than one function.

[0293] In addition to dosing requirements, the amount of API in the film may depend onits solubility. If water soluble, the API would typically comprise from about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film or from about 20 wt% to about 50 wt% of the solutes in the film. A less soluble API may comprise a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film. 73 60230447.1

[0294] The film-forming polymer may be selected from natural polysaccharides, proteins,or synthetic hydrocolloids and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film.

[0295] Film dosage forms are typically prepared by evaporative drying of thin aqueousfilms coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in lyophilization equipment, or in a vacuum oven.

[0296] Useful solid formulations for oral administration may include immediate releaseformulations and modified release formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. For a general description of suitable modified release formulations, see US Patent No.6,106,864. For details of other useful release technologies, such as high energy dispersions and osmotic and coated particles, see Verma et al, Pharmaceutical Technology On-line (2001) 25(2):1-14.

[0297] Compound (I) may also be administered directly into the blood stream, muscle, oran internal organ of the subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.

[0298] Parenteral formulations are typically aqueous solutions which may containexcipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9). For some applications, however, Compound (I) may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) may be readily accomplished using standard pharmaceutical techniques.

[0299] The solubility of compounds which are used in the preparation of parenteralsolutions may be increased through appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Thus, Compounds (I) may be formulated as a suspension, a solid, a semi-solid, or a thixotropic liquid for administration as an implanted depot providing modified release of the active compound. 74 60230447.1Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.

[0300] Compound (I) may also be administered topically, intradermally, or transdermallyto the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers may include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Topical formulations may also include penetration enhancers. See, e.g., Finnin and Morgan, J. Pharm. Sci.88(10):955-958 (1999).

[0301] Other means of topical administration include delivery by electroporation,iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., PowderjectTMand BiojectTM) injection. Formulations for topical administration may be formulated to be immediate or modified release as described above.

[0302] Compound (I) may also be administered intranasally or by inhalation, typically inthe form of a dry powder, an aerosol spray, or nasal drops. An inhaler may be used to administer the dry powder, which comprises the API alone, a powder blend of the API and a diluent, such as lactose, or a mixed component particle that includes the API and a phospholipid, such as phosphatidylcholine. For intranasal use, the powder may include a bioadhesive agent, e.g., chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer, may be used to generate the aerosol spray from a solution or suspension comprising the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH with or without water), one or more solvents (e.g., 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. An atomizer using electrohydrodynamics may be used to produce a fine mist.

[0303] Prior to use in a dry powder or suspension formulation, the drug product is usuallycomminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles, based on volume, having a largest dimension less than 5 microns). This may be achieved by any appropriate size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0304] Capsules, blisters and cartridges (made, for example, from gelatin orhydroxypropylmethyl cellulose) for use in an inhaler or insufflator may be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The 75 60230447.1lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0305] A suitable solution formulation for use in an atomizer using electrohydrodynamicsto produce a fine mist may contain from about 1 μg to about 20 mg of the API per actuation and the actuation volume may vary from about 1 μL to about 100 μL. A typical formulation may comprise one or more Compound (I), propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents, which may be used instead of propylene glycol, include glycerol and polyethylene glycol.

[0306] Formulations for inhaled administration, intranasal administration, or both, may beformulated to be immediate or modified release using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to formulations intended for inhaled / intranasal administration.

[0307] In the case of dry powder inhalers and aerosols, the dosage unit is determined bymeans of a valve that delivers a metered amount. Units are typically arranged to administer a metered dose or “puff” containing from about 10 μg to about 1000 μg of the API. The overall daily dose will typically range from about 100 μg to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

[0308] The active compounds may be administered rectally or vaginally, e.g., in the formof a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate or modified release as described above.

[0309] Compound (I) may also be administered directly to the eye or ear, typically in theform of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable implants (e.g., absorbable gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes. The formulation may include one or more polymers and a preservative, such as benzalkonium chloride. Typical polymers include crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose), and heteropolysaccharide polymers (e.g., gelan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or aural administration may be formulated to be immediate or modified release as described above. 76 60230447.1

[0310] To improve their solubility, dissolution rate, taste-masking, bioavailability, orstability, Compound (I) may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene glycol-containing polymers. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Alpha-, beta- and gamma-cyclodextrins are commonly used for these purposes. See, e.g., WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0311] As noted above, one or more compounds of Formula (I), including compoundsspecifically named above, and their pharmaceutically active complexes, salts, solvates and hydrates, may be combined with each other or with one or more other pharmaceutically active compounds to treat various diseases, conditions and disorders. In such cases, the compounds may be combined in a single dosage form as described above or may be provided in the form of a kit which is suitable for coadministration of the compositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains Compound (I); and (2) a device for separately retaining the two pharmaceutical compositions, such as a divided bottle or a divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating the different pharmaceutical compositions against one another. To assist with patient compliance, the kit typically comprises directions for administration and may be provided with a memory aid.

[0312] For administration to human patients, the total daily dose of the claimed anddisclosed compounds is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration. For example, oral administration may require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose may only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in single or divided doses and, at the physician’s discretion, may fall outside of the typical ranges given above. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.

[0313] As noted above, Compound (I) may be used to treat diseases, disorders and / orconditions associated with NLRP3, i.e., diseases, disorders and / or conditions for which 77 60230447.1inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, disorders and / or conditions associated with a heterozygous gain of function mutation in the NLRP3 gene, such as a cryopyrin-associated periodic syndrome (CAPS). These may include neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0314] Compound (I) may be used to treat neurodegenerative diseases and / or conditionsassociated with NLRP3. These may include Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, prion disease and other forms of dementia (i.e., major or mild neurocognitive disorders) associated with one or more medical conditions, including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or medication use, HIV infection, prion disease, Parkinson’s disease, and Huntington’s disease. Compound (I) may also be used to treat major or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism. In addition, Compound (I) may also be used to treat obesity with certain additional risk factors for cardiovascular disease.

[0315] The claimed and disclosed compounds may be combined with one or more otherpharmacologically active compounds or therapies to treat one or more disorders, diseases and / or conditions for which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, compounds of Formula (I), which include compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, may be administered simultaneously, sequentially or separately in combination with one or more pharmacologically active compound(s) or therapies for treating Alzheimer’s disease, including beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, such as apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds used to treat Alzheimer’s disease include donepezil, rivastigmine, memantine, and galantamine.

[0316] In addition to drugs used to improve cognition, Compound (I) may be combinedwith sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications 78 60230447.1that are used in the treatment of Alzheimer’s disease. For example, Compound (I) may be combined with one or more pharmacologically active agent(s) for treating depression (antidepressants) and / or schizophrenia (atypical or typical antipsychotics) including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone.

[0317] Likewise, Compound (I) may be combined with one or more pharmaceuticallyactive agent(s) for treating anxiety (anxiolytics) including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone) and buspirone.

[0318] Compound (I) may also be combined with one or more pharmaceutically activeagents for treating epilepsy (antiepileptics or anticonvulsants) including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. EXAMPLES

[0319] The present invention is explained in detail in the following by referring toExamples, Experimental Examples and Formulation Examples, which are not to be construed as limitative, and the invention may be changed within the scope of the present invention.

[0320] In the following Examples, the “room temperature” generally means about 10 °Cto about 35 °C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.

[0321] The elution by column chromatography in the Examples was performed under theobservation by TLC (Thin Layer Chromatography) unless otherwise specified. In the observation by TLC, 60 F254 manufactured by Merck was used as a TLC plate, the solvent 79 60230447.1used as an elution solvent in column chromatography was used as a developing solvent, and UV detector was used for the detection.

[0322] In silica gel column chromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel and the indication of Diol means use of 3-(2,3- dihydroxypropoxy)propylsilane-bonded silica gel.

[0323] 1H Nuclear magnetic resonance (NMR) spectra were obtained for many of thecompounds in the following examples. Characteristic chemical shifts (δ) are given in parts- per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterochloroform), DMSO-d6 (deuterodimethylsulfoxide). For the analysis of1H NMR, ACD / SpecManager (trade name) software and the like were used. Peaks of a hydroxyl group, an amino group and the like, having very mild proton peak, are not sometimes described.

[0324] MS was measured by LC / MS. As the ionization method, ESI method, or APCImethod was used. The data indicates actual measured value (found). While molecular ion peak is generally observed, a fragment ion is sometimes observed. For example, in the case of a compound having a tert-butoxycarbonyl group, a peak after elimination of a tert- butoxycarbonyl group or a tert-butyl group may be observed as a fragment ion. In the case of a compound having a hydroxy group, a peak after elimination of H2O may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.

[0325] In Examples, the following abbreviations are used.APCI: atmospheric pressure chemical ionization Ar: argon CDCl3: deuterochloroform CH2Cl2: dichloromethane CH3CN: acetonitrile CuBr: copper(I) bromide DMA: dimethyl acetamide DME: 1,2-dimethoxyethane DMSO-d6: deuterodimethyl sulfoxide ESI: electrospray ionization Et2O : diethyl ether EtOAc: ethyl acetate 80 60230447.1HCl: hydrogen chloride1H NMR: proton nuclear magnetic resonance IPE: diisopropyl ether KOAc: potassium acetate K3PO4: potassium triphosphate LC / MS: liquid chromatograph mass spectrometer M: mol concentration MgSO4: magnesium sulfate MS: mass spectrum N2: nitrogen NaHCO3: sodium hydrogen carbonate Na2SO4: sodium sulfate NBS: N-bromosuccinimide NIS: N-iodosuccinimide NH4Cl: ammonium chloride THF: tetrahydrofuran XPhos-Pd-G4: methanesulfonato(2-dicyclohexylphosphino-2’,4’,6’-tri-i-propyl-1,1’- biphenyl)(2’-methylamino-1,1’-biphenyl-2-yl)palladium(II). Zn: zinc Example 38

[0326] 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0327] A) 2-hydroxy-8-methoxy-pyrimido[1,2-a]pyrimidin-4-one

[0328] To a suspension of 4-methoxypyrimidin-2-amine (28.0 g) in toluene (538 mL) wasadded bis(2,4,6-trichlorophenyl) propanedioate (104 g) at room temperature. The mixture was stirred at 100 ℃ for 12 hours. The resulting solid was collected by filtration using EtOAc to give the title compound (40.5 g). MS: [M+H]+193.9.

[0329] B）(8-methoxy-4-oxo-pyrimido[1,2-a]pyrimidin-2-yl) trifluoromethanesulfonate

[0330] To a mixture of 2-hydroxy-8-methoxy-pyrimido[1,2-a]pyrimidin-4-one (40.5 g)and pyridine (85 mL) in CH3CN (600 mL) was added trifluoromethanesulfonic anhydride (53 mL) at 0 ℃. The mixture was stirred at 0 ℃ under N2 for 3 hours. The mixture was poured into a mixture of EtOAc and saturated aqueous NH4Cl at 0 ℃ and extracted with EtOAc. The organic layer was separated, washed with 1 M HCl aqueous solution, water, and 81 60230447.1brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. MS: [M+H]+325.9.

[0331] C) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0332] To a mixture of (8-methoxy-4-oxo-pyrimido[1,2-a]pyrimidin-2-yl)trifluoromethanesulfonate (934 mg), 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methyl-phenyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 g) and XPhos-Pd-G4 (371 mg) in THF (30 mL) were added K3PO4 (1.86 g) and water (1.5 mL) at 0 °C . The mixture was stirred at room temperature under N2 for 14 hours. To the mixture was added saturated aqueous NH4Cl at 0 °C. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by diol silica gel column chromatography (EtOAc / hexane) to give the title compound including some impurities (533 mg). The residue was stirred in EtOAc (5 mL) at 80 °C for 15 minutes. To the solution was added heptane (25 mL) at 80 °C. The mixture was stirred at 80 °C for 30 minutes and then cooled to room temperature over 1 hour. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with EtOAc / heptane (1:5), and dried to give the title compound (383 mg). The title compound (805 mg) was stirred in EtOAc (20 mL) at 80 °C for 30 minutes. To the solution was added heptane (100 mL) at 80 °C. The mixture was stirred at 80 °C for 30 minutes and then cooled to room temperature over 1 hour. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with EtOAc / heptane (1:5), and dried to give the title compound.1H NMR (300 MHz, DMSO-d6) δ 1.22-1.29 (2H, m), 1.47-1.61 (2H, m), 2.27 (3H, s), 4.05 (3H, s), 6.37 (1H, s), 6.98 (1H, d, J = 7.6 Hz), 7.03 (1H, d, J = 10.8 Hz), 7.08 (1H, s), 9.07 (1H, d, J = 7.6 Hz).

[0333] Example 54

[0334] 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one

[0335] A) 2-bromo-5-ethenyl-1-fluoro-3-methylbenzene

[0336] Potassium tert-butoxide (3.15 g) was added to a mixture ofmethyl(triphenyl)phosphonium bromide (10.0 g) in THF (75 mL) at 0 °C. The mixture was stirred at 0 °C under Ar for 30 minutes. A mixture of 4-bromo-3-fluoro-5- methylbenzaldehyde (5 g) in THF (50 mL) was added to the mixture at 0 °C. The mixture was stirred at room temperature under Ar overnight. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with Et2O. The organic layer was 82 60230447.1separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was suspended in Et2O (50 mL) and hexane (100 mL), and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and washed with Et2O / hexane (1:2). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (4.77 g).1H NMR (300 MHz, DMSO-d6) δ 2.38 (3H, s), 5.37 (1H, d, J = 10.9 Hz), 5.96 (1H, d, J = 16.9 Hz), 6.68 (1H, dd, J = 17.7, 10.9 Hz), 7.25-7.45 (2H, m).

[0337] B) 2-bromo-5-(2-bromo-1-fluoroethyl)-1-fluoro-3-methylbenzene

[0338] NBS (823 mg) was added to a mixture of 2-bromo-5-ethenyl-1-fluoro-3-methylbenzene (497 mg) in CH2Cl2(10 mL) at 0 °C. The mixture was stirred at 0 °C for 5 minutes. Triethylamine trihydrofluoride (1.13 mL) was added to the mixture at 0 °C. The mixture was stirred at room temperature under N2overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaHCO3and water, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (523 mg).1H NMR (300 MHz, DMSO-d6) δ 2.41 (3H, s), 3.91 (1H, d, J = 5.3 Hz), 3.97-4.01 (1H, m), 5.68-5.98 (1H, m), 7.21-7.40 (2H, m).

[0339] C) 2-bromo-1-fluoro-5-(1-fluoroethenyl)-3-methylbenzene

[0340] A mixture of 2-bromo-5-(2-bromo-1-fluoroethyl)-1-fluoro-3-methylbenzene (513.0mg) and potassium tert-butoxide (275 mg) in THF (10 mL) was refluxed for 1 hour. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with Et2O. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give the title compound (344.1 mg).1H NMR (300 MHz, DMSO-d6) δ 2.43 (3H, s), 5.07 (1H, dd, J = 18.8, 4.1 Hz), 5.43-5.72 (1H, m), 7.37-7.57 (2H, m).

[0341] D) 2-bromo-1-fluoro-5-(1-fluorocyclopropyl)-3-methylbenzene

[0342] Zn (289 mg) was added to a mixture of chloromethyl benzoate (753 mg),5,10,15,20-tetraphenyl-21H,23H-porphine iron monochloride (104 mg) and sodium iodide (662 mg) in THF (25 mL) at room temperature. The mixture was stirred at room temperature under Ar for 10 minutes. To the mixture was added a mixture of 2-bromo-1-fluoro-5-(1- fluoroethenyl)-3-methylbenzene (343 mg) in THF (5 mL) at room temperature. The mixture was stirred at 60 °C under Ar for 48 hours. To the mixture were added chloromethyl benzoate (753 mg), 5,10,15,20-tetraphenyl-21H,23H-porphine iron monochloride (104 mg), sodium iodide (662 mg) and Zn (289 mg) at room temperature. The mixture was stirred at 60 °C 83 60230447.1under Ar for 48 hours. To the mixture were added chloromethyl benzoate (753 mg), 5,10,15,20-tetraphenyl-21H,23H-porphine iron monochloride (104 mg), sodium iodide (662 mg) and Zn (289 mg) at room temperature. The mixture was stirred at 60 °C under Ar overnight. To the mixture were added chloromethyl benzoate (753 mg), 5,10,15,20- tetraphenyl-21H,23H-porphine iron monochloride (104 mg), sodium iodide (662 mg) and Zn (289 mg) at room temperature. The mixture was stirred at 60 °C under Ar overnight. The insoluble material was removed by filtration, and washed with Et2O. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (286 mg).1H NMR (300 MHz, DMSO-d6) δ 1.14-1.29 (2H, m), 1.42-1.58 (2H, m), 2.40 (3H, s), 7.08 (1H, dd, J = 9.6, 2.1 Hz), 7.13 (1H, s).

[0343] E) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0344] To a mixture of 2-bromo-1-fluoro-5-(1-fluorocyclopropyl)-3-methylbenzene (127mg) in THF (5 mL) was added 1.3 M isopropylmagnesium chloride lithium chloride complex in THF (0.791 mL) at 0 °C. The mixture was stirred at room temperature under N2for 30 minutes. To the mixture was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.262 mL) at 0 °C. The mixture was stirred at 0 °C and then at room temperature under N2overnight. To the mixture was added saturated aqueous NH4Cl at 0 °C and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (99.1 mg). MS: [M+H]+295.1.

[0345] F) 2-(2-aminopyrimidin-4-yl)propan-2-ol

[0346] 28% ammonia (4.84 mL) was added to a mixture of 2-(2-chloropyrimidin-4-yl)propan-2-ol (247 mg) in CH3CN (1 mL) in a microwave vessel. The mixture was stirred at 90 °C under Ar for 16 hours. Three other reactions were conducted on the same scale and under the same conditions. After the four reactions were combined, EtOAc and THF were added to the mixture at room temperature. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (851 mg).1H NMR (400 MHz, CDCl3) δ 1.47 (6H, s), 4.49 (1H, s), 5.05 (2H, br s), 6.67 (1H, d, J = 5.3 Hz), 8.27 (1H, d, J = 5.3 Hz).

[0347] G) 2-hydroxy-8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one

[0348] To a mixture of 2-(2-aminopyrimidin-4-yl)propan-2-ol (0.57 g) in Et2O (30 ml)was added bis(2,4,6-trichlorophenyl) propanedioate (1.72 g) at room temperature. The 84 60230447.1mixture was stirred at room temperature for 12 hours. The precipitate was collected by filtration, washed with Et2O and dried to give the title compound (0.67 g). MS: [M+H]+222.0.

[0349] H) 8-(2-hydroxypropan-2-yl)-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate

[0350] To a mixture of 2-hydroxy-8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one (330 mg) and pyridine (0.362 mL) in CH3CN (10 mL) was added trifluoromethanesulfonic anhydride (0.302 mL) at 0 °C. The mixture was stirred at 0 °C under N2 for 2 hours, and then quenched with saturated aqueous NH4Cl at 0 °C. The mixture was extracted with EtOAc. The organic layer was separated, washed with 1 M HCl aqueous solution, water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (299 mg). MS: [M+H]+354.1.

[0351] I) 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one A mixture of 8-(2-hydroxypropan-2-yl)-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (65.0 mg), 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.9 mg), K3PO4(117 mg), (s)- (dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)-l5-phosphaneyl)(2'-(methylamino)- [1,1'-biphenyl]-2-yl)palladium(III) methanesulfonate (15.9 mg), THF (1 mL) and water (0.1 mL) was stirred at room temperature under N2overnight. To the mixture was added water at room temperature. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound including some impurities (52.2 mg). The residue was suspended in EtOAc (0.5 mL) and IPE (0.5 mL), and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration, washed with EtOAc / IPE (1:1), and dried to give the title compound (34.1 mg).1H NMR (300 MHz, DMSO-d6) δ 1.21-1.32 (2H, m), 1.46-1.61 (8H, m), 2.27 (3H, s), 5.78 (1H, s), 6.49 (1H, s), 6.99-7.15 (2H, m), 7.72 (1H, d, J = 7.5 Hz), 9.30 (1H, d, J = 7.5 Hz). Example 230 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3- methylbenzonitrile 85 60230447.1A) 2-amino-5-iodo-3-methylbenzonitrile To a solution of 2-amino-3-methylbenzonitrile (50.0 g) in DMF (1000 mL) was added NIS (102 g). The mixture was stirred at 60 °C for 2 hours. Two reactions (50.0 g + 50.0 g) were combined for work-up. The mixture was added into water. The resulting mixture was extracted with EtOAc twice. The combined organic layers were washed with brine four times, dried over anhydrous Na2SO4, filtered and concentratedunder reduced pressure to give a residue. The residue was purified by silica gel columnchromatography (hexanes / CH2Cl2) to give a crude solid. The product was triturated with CH2Cl2 at 20 °C for 30 minutes to afford a suspension. After filtration, the solid was dried under reduced pressure to give the title compound (142 g).

[0352] 1H NMR (400 MHz, DMSO-d6) δ 2.07 (3H, s), 5.93 (2H, s), 7.49 (1H, d, J = 0.8Hz), 7.57 (1H, d, J = 2.0 Hz). B) 2-bromo-5-iodo-3-methylbenzonitrileTo a mixture of 2-amino-5-iodo-3- methylbenzonitrile (50.0 g) and CuBr (33.4 g) in CH3CN (500 mL) was added dropwise tert- butyl nitrite (39.9 g) at 20 °C and the mixture was stirred at 60 °C for 16 hours. The mixturewas filtered using CH2Cl2. The filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexanes / CH2Cl2) to give the title compound (35 g).

[0353] 1H NMR (400 MHz, DMSO-d6) δ 2.37 (3H, s), 8.09 (1H, d, J = 2.0 Hz), 8.14 (1H,d, J = 2.0 Hz)

[0354] C) 2-bromo-5-(1-fluorocyclopropyl)-3-methylbenzonitrile

[0355] To a mixture of 2-bromo-5-iodo-3-methylbenzonitrile (20.0 g), (1,3-dioxoisoindolin-2-yl) 1-fluorocyclopropanecarboxylate (23.2 g) and Zn (32.5 g) in anhydrous DMA (200 mL) was added diaquabis(2,2’-bipyridine-κN1,κN1’)di-μ-chlorodichlorodinickel, stereoisomer (CAS No: 1012368-96-5) (3.77 g). The mixture was degassed and purged with N2for 3 times. The mixture was cooled to -10 °C, then TMSCl (20.3 g) was added dropwise over 10 minutes below -10 °C and -5 °C to the mixture. The mixture was stirred at -10 °C for 1 hour. The mixture was diluted with EtOAc, and quenched with saturated aqueous NaHCO3at 0 °C. The insoluble material was removed by filtration through celite and washed with EtOAc. The combined organic layers were washed with brine four times, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes / CH2Cl2) to afford the title compound (8.3 g).

[0356] 1H NMR (400 MHz, DMSO-d6) δ 1.22-1.32 (2H, m), 1.46-1.60 (2H, m), 2.43 (3H,s), 7.57-7.64 (2H, m). 86 60230447.1

[0357] D) 5-(1-fluorocyclopropyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile To a mixture of 2-bromo-5-(1-fluorocyclopropyl)-3-methylbenzonitrile (15.0 g) and Et2O (150 mL) was added 2.5 M n-BuLi in hexane (28.3 mL) over 10 minutes at -78 °C under N2. The mixture was stirred at -78 °C for 10 minutes, followed by addition of 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.0 g) over 10 minutes. After the mixture was stirred at -78 °C for 0.5 hour under N2, saturated aqueous NH4Cl was slowly added to the mixture at -78 °C under N2. The mixture was extracted with CH2Cl2 twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc) to give the title compound (13.3 g).

[0358] MS: [M+H]+ 302.0.

[0359] E) 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3-methylbenzonitrile To a mixture of (8-methoxy-4-oxo-pyrimido[1,2-a]pyrimidin-2-yl) trifluoromethanesulfonate (750 mg) and 5-(1-fluorocyclopropyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (882 mg) in toluene (12 mL) and DMF (3 mL) were added K3PO4(1468 mg) and XPhos-Pd-G4 (794 mg) and the mixture was stirred for 6 hours at room temperature under N2. The mixture was poured into H2O at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc / n-heptane to give the title compound (404 mg).

[0360] To a solution of 803 mg of the title compound in EtOAc (50 mL) was addeddropwise n-heptane (50 mL) at 75°C. The mixture was stirred at 75°C for 15 minutes, then cooled to room temperature, and further stirred at 0°C for 15 minutes. The precipitate was collected by filtration, washed with EtOAc / n-heptane (1:2), and dried to give the title compound (730 mg).1H NMR (300 MHz, DMSO-d6) δ 1.25-1.39 (2H, m), 1.49-1.64 (2H, m), 2.30 (3H, s), 4.06 (3H, s), 6.48 (1H, s), 7.02 (1H, d, J = 7.53 Hz), 7.59 (1H, s), 7.64 (1H, d, J = 1.88 Hz), 9.11 (1H, d, J = 7.53 Hz).

[0361] Example 302

[0362] 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0363] A) 2-chloro-4-iodo-6-methylaniline87 60230447.1

[0364] To a solution of 2-chloro-6-methylaniline (50.0 g) in DMF (250 mL) was addedNIS (87.4 g) at 0 °C over 10 minutes. After being stirred at 0 °C for 1 hour, themixture was added into water. The resulting mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (101 g, crude).1H NMR (400 MHz, DMSO-d6) δ 2.09 (3H, s), 5.20 (2H, brs), 7.23 (1H, s), 7.35 (1H, d, J = 2.0 Hz).

[0365] B) 2-bromo-1-chloro-5-iodo-3-methylbenzene

[0366] To a mixture of 2-chloro-4-iodo-6-methylaniline (69.0 g) and CuBr (55.5 g) inCH3CN (525 mL) was added tert-butyl nitrite (79.8 g). After the reaction mixture was stirred at 60 °C for 2 hours, the insoluble material was removed by filtration and the filtrate was added into water. The resulting mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes) to give the title compound (53.3 g).1H NMR (400 MHz, DMSO- d6) δ 2.38 (3H, s), 7.73 (1H, d, J = 1.2 Hz), 7.83 (1H, d, J = 1.2 Hz).

[0367] C) 2-bromo-1-chloro-5-(1-fluorocyclopropyl)-3-methylbenzene

[0368] Diaquabis(2,2’-bipyridine-κN1,κN1’)di-μ-chlorodichlorodinickel, stereoisomer(CAS No: 1012368-96-5) (1.83 g) in anhydrous DMA (50 mL) was dispersed in sonication for 1 hour. The above suspension was added to a mixture of 2-bromo-1-chloro-5-iodo-3- methylbenzene (10.0 g), (1,3-dioxoisoindolin-2-yl) 1-fluorocyclopropanecarboxylate (11.3 g) and Zn (16.1 g) in DMA (100 mL) at -10 °C under N2. The mixture was degassed and purged with N2 for 3 times. TMSCl (11.5 mL) was added dropwise over 13 minutes below -12 °C and -7 °C to the mixture. The mixture was stirred at -10 °C for 2 hours. The mixture was diluted with EtOAc, and quenched with saturated aqueous NaHCO3 at 0 °C. The insoluble material was removed by filtration through celite and washed with EtOAc. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexanes at 25 °C for 10 minutes to afford a suspension. The suspension was filtered by basic silica gel with hexanes and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes) to give the title compound (5.00 g).1H NMR (400 MHz, DMSO-d6) δ 1.22-1.27 (2H, m), 1.44-1.57 (2H, m), 2.43 (3H, s), 7.24 (1H, d, J = 1.6 Hz), 7.32 (1H, d, J = 2.0 Hz).

[0369] D) 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 88 60230447.1

[0370] To a solution of 2-bromo-1-chloro-5-(1-fluorocyclopropyl)-3-methylbenzene (15.0g), KOAc (22.3 g) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (36.1 g) in DMSO (300 mL) was added Pd(dppf)Cl2(4.16 g) and the mixture was degassed and purged with N2 for 3 times. The mixture was heated to 100 °C and stirred for 16 hours under N2. The mixture was diluted with EtOAc and water. The mixture was filtered and the filtrate was extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound (8.5 g).1H NMR (400 MHz, CDCl3) δ 0.98-1.08 (2H, m), 1.41 (12H, s), 1.43-1.53 (2H, m), 2.39 (3H, s), 6.89 (1H, s), 7.01 (1H, s).

[0371] E) 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0372] (8-methoxy-4-oxo-pyrimido[1,2-a]pyrimidin-2-yl) trifluoromethanesulfonate (1.10g), XPhos-Pd-G4 (0.89 g) and K3PO4(2.20 g) were added to a mixture of 2-[2-chloro-4-(1- fluorocyclopropyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 g) in THF (30 mL). Then water (6 mL) was added to the suspension to form a clear solution. After being stirred at 40 °C for 1.5 hours under Ar, the mixture was quenched with water at 0 °C and extracted with EtOAc / THF (ca.2:1). The organic layer was separated, washed with saturated aqueous NH4Cl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by diol silica gel column chromatography (EtOAc / hexane) to give the title compound (620 mg).

[0373] 1.24 g of the title compound was suspended in EtOAc (5 mL) and IPE (30 mL).The mixture was stirred at 50 °C for 1 hour, gradually cooled to room temperature and stirred overnight. The resulting precipitate was collected by filtration and washed with IPE to give an off-white solid. To the obtained solid was added EtOAc (12 mL), and the mixture was heated at 80 °C for 15 minutes to afford a clear yellow solution. After n-heptane (60 mL) was added to the solution, the solution was stirred at 80 °C for 1 hour, and then gradually cooled to room temperature. The mixture was stirred at room temperature overnight. The resulting solid was collected, washed with EtOAc / n-heptane, and dried to give the title compound (0.75 g).1H NMR (300 MHz, DMSO-d6) δ 1.19-1.33 (2H, m), 1.45-1.62 (2H, m), 2.20 (3H, s), 4.05 (3H, s), 6.30 (1H, s), 7.00 (1H, d, J = 7.5 Hz), 7.21 (1H, s), 7.27 (1H, d, J = 1.5 Hz), 9.09 (1H, d, J = 7.5 Hz).

[0374] Example 30589 60230447.1

[0375] 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0376] A) 3-methyl-2-nitrobenzaldehyde

[0377] To a solution of (3-methyl-2-nitrophenyl)methanol (25.0 g), TEA (45.4 g) inDMSO (175 mL) was added pyridine sulfur trioxide (47.6 g) over 10 min at 0 ℃. The mixture was stirred at 25 ℃ for 0.5 hour. Two reactions (each 25 g scale) were combined to work up. The reaction mixture was added into water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (46.2 g).1H NMR (400 MHz, DMSO-d6) δ 2.30 (3H, s), 7.75-7.83 (2H, m), 7.96 (1H, d, J = 7.2 Hz), 9.95 (1H, s).

[0378] B) 1-(difluoromethyl)-3-methyl-2-nitrobenzene

[0379] To a solution of 3-methyl-2-nitrobenzaldehyde (25.0 g) in CH2Cl2 (260 mL) wasadded diethylaminosulfur trifluoride (61.0 g) at 0 ℃ over 10 minutes. The mixture was stirred at 0 ℃ for 1 hour. The mixture was added dropwise to saturated aqueous NaHCO3at 0 ℃. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (20.0 g).1H NMR (400 MHz, DMSO-d6) δ 2.34 (3H, s), 7.20 (1H, t, J = 54.0 Hz), 7.63-7.68 (3H, m).

[0380] C) 2-(difluoromethyl)-4-iodo-6-methylaniline

[0381] A solution of 4-(4-pyridyl)pyridine (1.67 g) in DMF (80 mL) was degassed withN2 for 3 times. After the mixture was cooled to 0 ℃, hypoboric acid (38.3 g) was added to the mixture at 0 ℃ under N2. The mixture was stirred at 0 ℃ for 10 minutes. Then 1- (difluoromethyl)-3-methyl-2-nitrobenzene (20.0 g) in DMF (20 mL) was added dropwise to the mixture over 20 minutes below 10 and 25 ℃. After addition, the resulting mixture was stirred at 10 ℃ for 0.5 hour under N2. The mixture was poured into water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. To a solution of the residue in DMF (170 mL) was added NIS (26.8 g) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour under N2. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column 90 60230447.1chromatography (EtOAc / hexane) to give the title compound (26.0 g).1H NMR (400 MHz, DMSO-d6) δ 2.07 (3H, s), 5.29 (2H, br s), 7.03 (1H, t, J = 54.8 Hz), 7.38 (1H, s), 7.40 (1H, s).

[0382] D) 2-bromo-1-(difluoromethyl)-5-iodo-3-methylbenzene

[0383] To a solution of 2-(difluoromethyl)-4-iodo-6-methylaniline (26.0 g) in CH3CN(260 mL) was added CuBr (19.8 g) and tert-butyl nitrite (28.4 g). The mixture was stirred at 60 ℃ for 1 hour. The reaction mixture was added to water, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (23.0 g).1H NMR (400 MHz, DMSO-d6) δ 2.36 (3H, s), 7.11 (1H, t, J = 54.0 Hz), 7.74 (1H, s), 7.95 (1H, s).

[0384] E) 2-bromo-1-(difluoromethyl)-5-(1-fluorocyclopropyl)-3-methylbenzene

[0385] Diaquabis(2,2’-bipyridine-κN1,κN1’)di-μ-chlorodichlorodinickel, stereoisomer(CAS No: 1012368-96-5) (3.50 g) in anhydrous DMA (80 mL) was dispersed in sonication for 1 hour. The above suspension was added to a mixture of 2-bromo-1-(difluoromethyl)-5- iodo-3-methylbenzene (20.0 g), (1,3-dioxoisoindolin-2-yl) 1-fluorocyclopropanecarboxylate (21.6 g) and Zn (32.2 g) in anhydrous DMA (200 mL) at -10 °C. The mixture was degassed and purged with N2for 3 times. TMSCl (2.0 mL) was added dropwise between -10 °C and - 5 °C over 5 minutes. Then TMSCl (20 mL) was added dropwise over 25 minutes below - 10 °C and - 5 °C to the mixture. The mixture was stirred at -10 °C for 1 hour. The mixture was diluted with EtOAc, and quenched with saturated aqueous NaHCO3at 0 °C. The insoluble material was removed by filtration through celite and washed with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexane at 20 °C for 30 minutes. The suspension was filtered by basic silica gel using hexane and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (10.5 g).1H NMR (400 MHz, DMSO- d6) δ 1.22-1.24 (2H, m), 1.49-1.54 (2H, m), 2.41 (3H, s), 7.17 (1H, t, J = 54.0 Hz), 7.38 (1H, s), 7.42 (1H, s).

[0386] F) 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0387] A mixture of 2-bromo-1-(difluoromethyl)-5-(1-fluorocyclopropyl)-3-methylbenzene (7.80 g), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (14.2 g), Pd(dppf)Cl2(2.04 g) and KOAc (11.0 g) in DME (62 mL) and 91 60230447.1H2O (21 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 16 hours under N2. The mixture was added to water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.6 g).1H NMR (400 MHz, DMSO-d6) δ 1.19-1.23 (2H, m), 1.33 (12H, s), 1.48-1.54 (2H, m), 2.42 (3H, s), 6.90-7.21 (2H, m), 7.28 (1H, s).

[0388] G) 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one

[0389] (8-methoxy-4-oxo-pyrimido[1,2-a]pyrimidin-2-yl) trifluoromethanesulfonate (500mg), K3PO4 (1000 mg) and XPhos-Pd-G4 (264 mg) were added to a mixture of 2-[2- (difluoromethyl)-4-(1-fluorocyclopropyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (676 mg) in THF (25 mL). Water (5 mL) was added to the suspension and the system was immediately purged with Ar. The mixture was stirred at room temperature under Ar for 20 hours. The mixture was diluted with EtOAc at 0 ℃. Water was added to the mixture and the mixture was transferred to the separating funnel. Saturated aqueous NH4Cl and THF were added. The extracted organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by diol silica gel column chromatography (EtOAc / hexane) to obtain the title compound (327 mg). 624 mg of the title compound was dissolved in EtOAc (3 mL) at room temperature. The mixture was stirred at 60 ℃. Heptane (4.5 mL) was added dropwise to form precipitates. The mixture was stirred at 60 ℃ for 1 hour and at room temperature overnight. Additional heptane (4.5 mL) was added to the mixture and the mixture was stirred at room temperature overnight. Then the mixture was stirred at 0 ℃ for 1 hour. The resulting precipitates were collected by filtration, washed with cold EtOAc / heptane (1:4) and dried in vacuo to give the title compound (441 mg).1H NMR (400 MHz, DMSO-d6) δ 1.21-1.32 (2H, m), 1.49-1.63 (2H, m), 2.23 (3H, s), 4.05 (3H, s), 6.27 (1H, s), 6.71-7.05 (2H, m), 7.36 (1H, s), 7.45 (1H, s), 9.10 (1H, d, J = 7.6 Hz).

[0390] The compounds of Examples are shown in Table 1-1 to Table 1-29. MS in thetables means actual measured value. The compounds of Examples 1-317 in the following tables were produced according to the methods described in the above mentioned Examples, or methods analogous thereto. 92 60230447.1

[0391] Table 1-1ExampleCompounMS numberd name Structure[M+H] 2-(4-cyclopropyl-2,6-dimethylphenyl)-8-methyl-4H-pyrimido[1,2- 1 306.1 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-methyl-4H- 2 310.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-ethyl-4H- 3 324.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-7-methyl-4H- 4 310.1 pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4H- 5 336.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-methoxy-4H- 6 325.9 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,6-difluorophenyl)-8-methyl-4H-pyrimido[1,2- 7 314.0 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6,8-dimethyl-4H- 8 324.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-7-methoxy-4H- 9 326.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(4- 10 methoxyphenyl)methyl](methyl)amino}-4H-pyrimido[1,2- 445.2 a]pyrimidin-4-one 93 60230447.1

[0392] Table 1-22-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(methylamino)-4H- 11 325.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-methoxyethoxy)- 12 370.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,6-difluorophenyl)-8-methoxy-4H-pyrimido[1,2- 13 330.0 a]pyrimidin-4-one 2-(4-cyclopropyl-2-methylphenyl)-8-methoxy-4H-pyrimido[1,2- 14 308.1 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-oxo-1,3- 15 381.1 oxazolidin-3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-hydroxy-4H- 16 312.2 pyrimido[1,2-a]pyrimidin-4-one 8-methoxy-2-(4-methoxy-2-methylphenyl)-4H-pyrimido[1,2- 17 297.9 a]pyrimidin-4-one 4-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3- 18 293.0 methylbenzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(dimethylamino)- 19 339.0 4H-pyrimido[1,2-a]pyrimidin-4-one 8-(3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)-2-(4- 20 cyclopropyl-2-fluoro-6-methylphenyl)-4H-pyrimido[1,2- 495.3 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3- 21 381.0 hydroxypyrrolidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 94 60230447.1

[0393] Table 1-32-[4-cyclopropyl-2-(2,2-difluoroethyl)-6-fluorophenyl]-8- 22 376.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-hydroxypropan- 23 354.0 2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-fluoro-6-(methoxymethyl)phenyl]-8-methoxy- 24 356.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(2-chloro-4-cyclopropyl-6-fluorophenyl)-8-methoxy-4H- 25 345.9 pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-fluoro-6-(hydroxymethyl)phenyl]-8-methoxy- 26 342.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2- 27 395.1 hydroxycyclopentyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(difluoromethoxy)-2-fluoro-6-methylphenyl]-8-methoxy-4H- 28 351.9 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-fluoropropan-2- 29 356.0 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 8-methoxy-2-[2-methyl-4-(trifluoromethyl)phenyl]-4H- 30 336.0 pyrimido[1,2-a]pyrimidin-4-one 2-(2,4-dimethylphenyl)-8-methoxy-4H-pyrimido[1,2-a]pyrimidin- 31 282.0 4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2- 32 355.0 hydroxyethyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 95 60230447.1

[0394] Table 1-42-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(morpholin-4-yl)- 33 381.1 4H-pyrimido[1,2-a]pyrimidin-4-one 8-methoxy-2-(2,4,6-trimethylphenyl)-4H-pyrimido[1,2- 34 296.0 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2- 35 369.0 hydroxypropyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(oxolan-3- 36 381.0 yl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-{4-cyclopropyl-2-[(difluoromethoxy)methyl]-6-fluorophenyl}-8- 37 392.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 38 344.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(2,2-difluoroethyl)-6-fluorophenyl]-8-(2- 39 404.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1,4-oxazepan-4- 40 395.1 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(3R,4R)-4- 41 hydroxytetrahydro-2H-pyran-3-yl]amino}-4H-pyrimido[1,2- 411.1 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(3S,4S)-4- 42 hydroxytetrahydro-2H-pyran-3-yl]amino}-4H-pyrimido[1,2- 411.1 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(pyrrolidin-1-yl)- 43 365.0 4H-pyrimido[1,2-a]pyrimidin-4-one 96 60230447.1

[0395] Table 1-55-cyclopropyl-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin- 44 333.0 2-yl)-3-methylbenzonitrile 2-[4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl]-8-(2- 45 390.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(oxolan-3-yl)oxy]- 46 382.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(3- 47 369.1 hydroxypropyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-3-fluoro-2-(8-methoxy-4-oxo-4H-pyrimido[1,2- 48 337.0 a]pyrimidin-2-yl)benzonitrile 2-(2-chloro-4-cyclopropyl-6-fluorophenyl)-8-(2-hydroxypropan-2- 49 374.0 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-3-fluoro-2-[8-(2-hydroxypropan-2-yl)-4-oxo-4H- 50 365.0 pyrimido[1,2-a]pyrimidin-2-yl]benzonitrile 5-cyclopropyl-2-[8-(2-hydroxypropan-2-yl)-4-oxo-4H- 51 361.0 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-hydroxybutan-2- 52 368.0 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(2-hydroxybutan-2-yl)-4-oxo-4H- 53 375.1 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(2- 54 372.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 97 60230447.1

[0396] Table 1-62-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-methoxy-3-methyl- 55 340.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-methylphenyl)-8-methoxy-3-methyl-4H- 56 322.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-hydroxyethoxy)- 57 356.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-hydroxypropoxy)- 58 370.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,6-dimethylphenyl)-8-methoxy-4H- 59 322.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1,1-difluoro-2- 60 390.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(1,1-difluoro-2-hydroxypropan-2-yl)-4-oxo- 61 397.1 4H-pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 5-cyclopropyl-2-(8-cyclopropyl-4-oxo-4H-pyrimido[1,2- 62 343.0 a]pyrimidin-2-yl)-3-methylbenzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(oxolan-3-yl)-4H- 63 366.0 pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-(8-cyclopropyl-4-oxo-4H-pyrimido[1,2- 64 347.0 a]pyrimidin-2-yl)-3-fluorobenzonitrile 2-(4-cyclopropyl-2,6-difluorophenyl)-8-methoxy-3-methyl-4H- 65 344.0 pyrimido[1,2-a]pyrimidin-4-one 98 60230447.1

[0397] Table 1-72-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-methoxy-7-methyl- 66 340.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(oxetan-3-yl)-4H- 67 352.0 pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(difluoromethoxy)-6-fluorophenyl]-8-(2- 68 406.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1-hydroxyethyl)- 69 340.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(3-methyloxetan-3- 70 381.1 yl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-hydroxyazetidin- 71 367.1 1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3,3- 72 387.0 difluoroazetidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(oxetan-3- 73 367.1 yl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(1-methyl-1H- 74 391.1 pyrazol-3-yl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(4- 75 409.1 methoxypiperidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3,3- 76 401.1 difluoropyrrolidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 99 60230447.1

[0398] Table 1-82-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-oxa-6- 77 393.0 azaspiro[3.3]heptan-6-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 8-(5-azaspiro[2.3]hexan-5-yl)-2-(4-cyclopropyl-2-fluoro-6- 78 377.1 methylphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 1-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 79 390.1 pyrimido[1,2-a]pyrimidin-8-yl]pyrrolidine-3-carbonitrile 8-(3-cyclopropyl-3-fluoroazetidin-1-yl)-2-(4-cyclopropyl-2-fluoro- 80 409.1 6-methylphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 1-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 81 390.1 pyrimido[1,2-a]pyrimidin-8-yl]-3-methylazetidine-3-carbonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-fluoro-3- 82 383.0 methylazetidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1s,3s)-3-hydroxy- 83 395.1 3-methylcyclobutyl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-oxa-8- 84 407.1 azabicyclo[3.2.1]octan-8-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 1-({[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 85 pyrimido[1,2-a]pyrimidin-8-yl]amino}methyl)cyclopropane-1- 390.1 carbonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2- 86 381.0 hydroxycyclobutyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(8-oxa-3- 87 407.1 azabicyclo[3.2.1]octan-3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 100 60230447.1

[0399] Table 1-92-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[3- 88 401.1 (difluoromethyl)azetidin-1-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 1-{[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 89 376.1 pyrimido[1,2-a]pyrimidin-8-yl]amino}cyclopropane-1-carbonitrile 8-(5-azaspiro[2.4]heptan-5-yl)-2-(4-cyclopropyl-2-fluoro-6- 90 391.1 methylphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[3- 91 (difluoromethyl)pyrrolidin-1-yl]-4H-pyrimido[1,2-a]pyrimidin-4- 415.2 one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1RS,2RS)-2- 92 409.1 hydroxycyclohexyl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-7-fluoro-8- 93 343.0 (methylamino)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(6- 94 hydroxyspiro[3.3]heptan-2-yl)amino]-4H-pyrimido[1,2- 421.2 a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(ethylamino)-4H- 95 339.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(4-methyl-3- 96 408.1 oxopiperazin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1s,3s)-3- 97 381.0 hydroxycyclobutyl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(oxetan-2- 98 381.0 yl)methyl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 101 60230447.1

[0400] Table 1-102-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[3-(difluoromethyl)- 99 431.0 3-hydroxypyrrolidin-1-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2,2-difluoro-3- 100 405.1 hydroxypropyl)amino]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(2R)-1- 101 369.0 hydroxypropan-2-yl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(3-hydroxyoxetan- 102 397.0 3-yl)methyl]amino}-4H-pyrimido[1,2-a]pyrimidin-4-one 3-{[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 103 390.1 pyrimido[1,2-a]pyrimidin-8-yl]amino}cyclobutane-1-carbonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-oxa-7- 104 421.1 azaspiro[4.4]nonan-7-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(2S)-2- 105 (methoxymethyl)pyrrolidin-1-yl]-4H-pyrimido[1,2-a]pyrimidin-4- 409.1 one 8-(azetidin-1-yl)-2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4H- 106 351.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-methoxyazetidin- 107 381.0 1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(oxan-4-yl)-4H- 108 380.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-chloro-2-fluoro-6-methylphenyl)-8-(2-hydroxypropan-2-yl)- 109 347.9 4H-pyrimido[1,2-a]pyrimidin-4-one 102 60230447.1

[0401] Table 1-112-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(difluoromethoxy)- 110 361.9 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2,6-difluoro-4-(1-fluorocyclopropyl)phenyl]-8-(2- 111 376.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(1-fluorocyclopropyl)-4-oxo-4H-pyrimido[1,2- 112 361.0 a]pyrimidin-2-yl]-3-methylbenzonitrile N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 113 395.1 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}acetamide 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1H-pyrazol-1-yl)- 114 362.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-fluoro-6-(trifluoromethyl)phenyl]-8-(2- 115 408.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{1-[(oxan-2- 116 436.2 yl)oxy]cyclopropyl}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(4-hydroxyoxan-4- 117 396.0 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-3-methyl-2-[8-(1-methyl-1H-pyrazol-3-yl)-4-oxo- 118 383.2 4H-pyrimido[1,2-a]pyrimidin-2-yl]benzonitrile 2-[4-cyclopropyl-2-(2,2-difluoroethyl)-6-fluorophenyl]-8-(1- 119 426.1 methyl-1H-pyrazol-3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-fluoro-6-(methoxymethyl)phenyl]-8-(1- 120 406.1 methyl-1H-pyrazol-3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 103 60230447.1

[0402] Table 1-122-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1-methyl-1H- 121 376.1 pyrazol-3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-[2,6-difluoro-4-(1-fluorocyclopropyl)phenyl]-4H- 122 358.0 pyrimido[1,2-a]pyrimidin-4-one 1-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 123 361.1 pyrimido[1,2-a]pyrimidin-8-yl]cyclopropane-1-carbonitrile 2-(4-cyclopropyl-2,6-dimethylphenyl)-8-(2-hydroxypropan-2-yl)- 124 350.1 4H-pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-[4-cyclopropyl-2-(difluoromethoxy)-6- 125 388.1 fluorophenyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-methyl-8-(oxetan- 126 366.1 3-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-(2- 127 392.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(1-methoxycyclopropyl)-4-oxo-4H- 128 373.2 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1-methyl-1H- 129 376.2 pyrazol-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-hydroxyoxolan-3- 130 382.1 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2,2- 131 379.1 dimethylazetidin-1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 104 60230447.1

[0403] Table 1-132-(2-bromo-4-cyclopropyl-6-fluorophenyl)-8-(2-hydroxypropan-2- 132 418.0 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-bromo-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 133 349.9 a]pyrimidin-4-one 5-cyclopropyl-2-(8-cyclopropyl-6-methyl-4-oxo-4H-pyrimido[1,2- 134 357.1 a]pyrimidin-2-yl)-3-methylbenzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2,2- 135 372.0 difluorocyclopropyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(2-methoxypropan-2-yl)-4-oxo-4H- 136 375.1 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 5-cyclopropyl-3-methyl-2-[4-oxo-8-(propan-2-yl)-4H- 137 345.1 pyrimido[1,2-a]pyrimidin-2-yl]benzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-ethoxy-4H- 138 340,2 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 139 312.0 a]pyrimidin-4-one 2-[4-(difluoromethoxy)-2-(difluoromethyl)-6-methylphenyl]-8-(2- 140 412.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-fluorooxolan-3- 141 384.1 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(8-cyclopropyl-6-methyl-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2- 142 375.0 yl)-5-(1-fluorocyclopropyl)-3-methylbenzonitrile 105 60230447.1

[0404] Table 1-142-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8- 143 408.2 (2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-(1-fluorocyclopropyl)-2-[8-(1-fluorocyclopropyl)-4-oxo-4H- 144 379.1 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(oxan-4- 145 398.1 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-8-methoxy-4H- 146 346.1 pyrimido[1,2-a]pyrimidin-4-one 5-(1-fluorocyclopropyl)-2-[8-(2-hydroxypropan-2-yl)-4-oxo-4H- 147 379.1 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile tert-butyl (2-{2-[2-(difluoromethyl)-6-fluoro-4-(1- 148 fluorocyclopropyl)phenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8- 507.2 yl}propan-2-yl)carbamate 2-(5-bromo-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 149 349.9 a]pyrimidin-4-one 2-(3-bromo-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 150 349.9 a]pyrimidin-4-one N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4- 151 413.2 oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan-2-yl)acetamide N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4- 152 427.1 oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan-2-yl)propanamide N-(2-{2-[2-(difluoromethyl)-6-fluoro-4-(1- 153 fluorocyclopropyl)phenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8- 449.1 yl}propan-2-yl)acetamide 106 60230447.1

[0405] Table 1-152-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-8-(2-hydroxypropan- 154 374.1 2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1- 155 366.2 hydroxycyclobutyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-cyclopropyl-2-[8-(3-hydroxyoxolan-3-yl)-4-oxo-4H- 156 389.2 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 8-cyclopropyl-2-[4-(difluoromethoxy)-2-fluoro-6-methylphenyl]- 157 362.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(8-cyclopropyl-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-5-(1- 158 361.2 fluorocyclopropyl)-3-methylbenzonitrile 8-cyclopropyl-2-[2-cyclopropyl-4-(difluoromethoxy)-6- 159 388.1 fluorophenyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(2-hydroxy-4,6-dimethylphenyl)-8-(2-hydroxypropan-2-yl)-4H- 160 326.1 pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-(2-hydroxy-4,6-dimethylphenyl)-4H- 161 308.1 pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8- 162 434.2 (oxan-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 5-(1-fluorocyclopropyl)-3-methyl-2-[8-(oxan-4-yl)-4-oxo-4H- 163 405.1 pyrimido[1,2-a]pyrimidin-2-yl]benzonitrile 5-cyclopropyl-2-[8-(1,1-difluoroethyl)-4-oxo-4H-pyrimido[1,2- 164 367.1 a]pyrimidin-2-yl]-3-methylbenzonitrile 107 60230447.1

[0406] Table 1-165-cyclopropyl-2-[8-(3-fluorooxolan-3-yl)-4-oxo-4H-pyrimido[1,2- 165 391.1 a]pyrimidin-2-yl]-3-methylbenzonitrile 5-(1-fluorocyclopropyl)-2-[8-(2-fluoropropan-2-yl)-4-oxo-4H- 166 381.1 pyrimido[1,2-a]pyrimidin-2-yl]-3-methylbenzonitrile 2-(5-cyclopropyl-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 167 312.0 a]pyrimidin-4-one 2-(3-cyclopropyl-2-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 168 312.0 a]pyrimidin-4-one 2-[4-(1,1-difluoroethyl)-2-fluoro-6-methylphenyl]-8-(2- 169 378.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-8-(2-hydroxypropan-2- 170 390.1 yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(2-cyclopropyl-4,6-dimethylpyrimidin-5-yl)-8-methoxy-4H- 171 324.0 pyrimido[1,2-a]pyrimidin-4-one 8-(bicyclo[1.1.1]pentan-1-yl)-2-(4-cyclopropyl-2-fluoro-6- 172 362.1 methylphenyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-bromo-2-(difluoromethoxy)-6-methylphenyl]-8-(2- 173 440.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-4-(difluoromethoxy)-6-fluorophenyl]-8-cyclopropyl-4H- 174 382.0 pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(difluoromethoxy)-6-methylphenyl]-8-(2- 175 402.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 108 60230447.1

[0407] Table 1-171-{4-[8-(2-hydroxypropan-2-yl)-4-oxo-4H-pyrimido[1,2- 176 a]pyrimidin-2-yl]-3,5-dimethylphenyl}cyclopropane-1- 375.1 carbonitrile 1-[4-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3,5- 177 347.0 dimethylphenyl]cyclopropane-1-carbonitrile 2-(2-cyclopropyl-4,6-dimethylpyrimidin-5-yl)-8-(2- 178 352.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one methyl {2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 179 411.2 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}carbamate N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 180 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}-1- 439.2 fluorocyclopropane-1-carboxamide N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 181 409.2 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}-N-methylacetamide 2-(4-cyclopropyl-2,5-difluorophenyl)-8-(2-hydroxypropan-2-yl)- 182 358.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8- 183 380.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,5-difluorophenyl)-8-methoxy-4H- 184 330.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,6-difluorophenyl)-8-(2-hydroxypropan-2-yl)- 185 358.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy- 186 364.0 4H-pyrimido[1,2-a]pyrimidin-4-one 109 60230447.1

[0408] Table 1-188-cyclopropyl-2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 187 354.1 methylphenyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethyl)-6-fluoro-4-(propan-2-yl)phenyl]-8-(2- 188 392.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]- 189 404.1 8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 190 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}pyridine-2- 458.2 carboxamide 2-[2-fluoro-6-methyl-4-(propan-2-yl)phenyl]-8-(2- 191 356.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 192 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}-2,2- 431.2 difluoroacetamide 2-(2-chloro-6-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 193 306.0 a]pyrimidin-4-one 2-[2-chloro-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-6,8- 194 362.0 dimethyl-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,3-difluorophenyl)-8-(2-hydroxypropan-2-yl)- 195 358.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[1-(oxan-2-yl)-1H- 196 446.2 pyrazol-5-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(2-cyclopropyl-6-fluorophenyl)-8-methoxy-4H-pyrimido[1,2- 197 312.0 a]pyrimidin-4-one 110 60230447.1

[0409] Table 1-192-[2-fluoro-6-methyl-4-(propan-2-yl)phenyl]-8-methoxy-4H- 198 328.1 pyrimido[1,2-a]pyrimidin-4-one 2-(6-cyclopropyl-2,4-dimethylpyridin-3-yl)-8-(2-hydroxypropan- 199 351.1 2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-8-methoxy-4H- 200 362.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2-hydroxy-2- 201 368.1 methylpropyl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(2-fluoropropan-2-yl)-6-methylphenyl]-8-(2- 202 374.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[8-(bicyclo[1.1.1]pentan-1-yl)-4-oxo-4H-pyrimido[1,2- 203 387.1 a]pyrimidin-2-yl]-5-(1-fluorocyclopropyl)-3-methylbenzonitrile 2-(4-cyclopropyl-2,3-difluorophenyl)-8-methoxy-4H- 204 330.0 pyrimido[1,2-a]pyrimidin-4-one 2-(6-cyclopropyl-2,4-dimethylpyridin-3-yl)-8-methoxy-4H- 205 323.1 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1H-pyrazol-5-yl)- 206 362.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-7,8-dimethyl-4H- 207 324.0 pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-7,8- 208 342.0 dimethyl-4H-pyrimido[1,2-a]pyrimidin-4-one 111 60230447.1

[0410] Table 1-202-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(3-fluoroazetidin- 209 369.0 1-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 210 384.1 methylphenyl]-7-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-methoxy-6-methylphenyl)-8-(2- 211 366.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-[(1s,3s)- 212 3-hydroxy-3-methylcyclobutyl]-4H-pyrimido[1,2-a]pyrimidin-4- 398.1 one 2-(4-cyclopropyl-2-methoxyphenyl)-8-methoxy-4H-pyrimido[1,2- 213 323.9 a]pyrimidin-4-one 2-(4-cyclopropyl-2-methoxy-6-methylphenyl)-8-methoxy-4H- 214 338.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1RS,2RS)-2- 215 382.1 hydroxycyclobutyl]oxy}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1RS,2SR)-2- 216 382.1 hydroxycyclobutyl]oxy}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethoxy)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]- 217 396.0 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 218 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}-2,2- 445.2 difluoropropanamide N-{2-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 219 425.3 pyrimido[1,2-a]pyrimidin-8-yl]propan-2-yl}-2-methoxyacetamide 112 60230447.1

[0411] Table 1-212-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1r,3r)-3- 220 382.1 hydroxycyclobutyl]oxy}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-fluoro-6-(trifluoromethyl)phenyl]-8-methoxy- 221 380.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(2-chloro-4-cyclopropyl-6-fluoro-3-methylphenyl)-8-methoxy- 222 360.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(6-chloro-4-cyclopropyl-2-fluoro-3-methylphenyl)-8-methoxy- 223 360.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-methyl-6-(1H-pyrazol-1-yl)phenyl]- 224 392.1 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 8-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-2,3- 225 356.1 dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 8-(4-cyclopropyl-2-fluoro-6-methylphenyl)-2,3-dihydro-6H- 226 338.0 furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[(1s,3s)-3- 227 382.0 hydroxycyclobutyl]oxy}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-(1H-pyrazol-1-yl)phenyl]-8- 228 378.1 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-8-methoxy-4H- 229 360.0 pyrimido[1,2-a]pyrimidin-4-one 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2- 230 351.0 a]pyrimidin-2-yl)-3-methylbenzonitrile 113 60230447.1

[0412] Table 1-222-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy- 231 362.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-5-fluoro-2-methylphenyl)-8-methoxy-4H- 232 326.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-3-fluoro-2-methylphenyl)-8-methoxy-4H- 233 326.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,3-dimethylphenyl)-8-methoxy-4H- 234 322.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-5-fluoro-2-methylphenyl)-8-(2-hydroxypropan- 235 354.1 2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-methoxy-6-(trifluoromethyl)phenyl]- 236 410.1 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-3-fluoro-2-methylphenyl)-8-(2-hydroxypropan- 237 354.1 2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,3-dimethylphenyl)-8-(2-hydroxypropan-2-yl)- 238 350.1 4H-pyrimido[1,2-a]pyrimidin-4-one tert-butyl (2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 239 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 471.2 2-yl)carbamate 2-[2-fluoro-6-methyl-4-(1-methylcyclopropyl)phenyl]-8- 240 340.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-6-methyl-4-(1-methylcyclopropyl)phenyl]-8-(2- 241 368.0 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 114 60230447.1

[0413] Table 1-232-[4-cyclopropyl-2-(2-hydroxypropan-2-yl)phenyl]-8-methoxy- 242 352.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-methyl-6-(oxetan-3-yl)phenyl]-8- 243 382.1 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,5-dimethylphenyl)-8-methoxy-4H- 244 322.0 pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2,5-dimethylphenyl)-8-(2-hydroxypropan-2-yl)- 245 350.1 4H-pyrimido[1,2-a]pyrimidin-4-one 8-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-2-methyl- 246 370.1 2,3-dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 2,2-difluoro-N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 247 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 463.1 2-yl)propanamide N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4- 248 oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan-2-yl)-2- 457.2 methoxypropanamide 8-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]- 249 392.0 2,3-dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 8-(2-aminopropan-2-yl)-2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 250 371.1 methylphenyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-6-methyl-2-oxopyridin-1(2H)-yl)-8-methoxy- 251 325.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(4-methyl-1H- 252 376.1 pyrazol-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 115 60230447.1

[0414] Table 1-244-fluoro-N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 253 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 501.3 2-yl)oxane-4-carboxamide 3,3,3-trifluoro-N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 254 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 481.2 2-yl)propanamide 2-[2-(azetidin-1-yl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8- 255 381.1 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(3- 256 hydroxybicyclo[1.1.1]pentan-1-yl)-4H-pyrimido[1,2-a]pyrimidin- 396.0 4-one 2-[2-(difluoromethoxy)-4-(1-fluorocyclopropyl)-6-methylphenyl]- 257 392.0 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-[(1- 258 384.1 hydroxycyclopropyl)methyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-(trifluoromethyl)phenyl]-8-methoxy- 259 380.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-{[1-(oxan-2-yl)- 260 476.3 1H-pyrazol-5-yl]methoxy}-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[(1H-pyrazol-5- 261 392.1 yl)methoxy]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-7-methyl-8-(1H- 262 376.1 pyrazol-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 3,3-difluoro-N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 263 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 463.2 2-yl)propanamide 116 60230447.1

[0415] Table 1-258-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]- 264 388.1 2,3-dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-(trifluoromethyl)phenyl]-8- 265 398.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-3-fluoro-2-(trifluoromethyl)phenyl]-8-methoxy- 266 380.1 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-3-fluoro-2-(trifluoromethyl)phenyl]-8-(2- 267 408.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(2,2-difluoroethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]- 268 394.0 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 7-fluoro-2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8- 269 390.1 (2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[5-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl]-8-methoxy-4H- 270 363.0 pyrimido[1,2-a]pyrimidin-4-one ethyl {5-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 271 448.3 pyrimido[1,2-a]pyrimidin-8-yl]-1H-pyrazol-1-yl}acetate 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 272 410.2 7-(1H-pyrazol-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8,9- 273 370.1 dihydro-4H,7H-pyrano[2,3-d]pyrimido[1,2-a]pyrimidin-4-one 8-cyclopropyl-2-[4-(1-fluorocyclopropyl)-2-(methanesulfonyl)-6- 274 414.1 methylphenyl]-4H-pyrimido[1,2-a]pyrimidin-4-one 117 60230447.1

[0416] Table 1-262-[4-cyclopropyl-5-fluoro-2-(trifluoromethyl)phenyl]-8-methoxy- 275 380.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-5-fluoro-2-(trifluoromethyl)phenyl]-8-(2- 276 408.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one tert-butyl 7-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-9- 277 oxo-2,3-dihydro-1H,9H-pyrimido[1',2':1,2]pyrimido[4,5- 471.2 b][1,4]oxazine-1-carboxylate 2-[4-(1-fluorocyclopropyl)-2-(methanesulfonyl)-6- 278 404.0 methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 7-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-2,3- 279 dihydro-1H,9H-pyrimido[1',2':1,2]pyrimido[4,5-b][1,4]oxazin-9- 371.1 one 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2- 280 405.0 a]pyrimidin-2-yl)-3-(trifluoromethyl)benzonitrile {5-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo-4H- 281 420.3 pyrimido[1,2-a]pyrimidin-8-yl]-1H-pyrazol-1-yl}acetic acid 2-[4-cyclopropyl-5-methoxy-2-(trifluoromethyl)phenyl]-8- 282 392.0 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-cyclopropyl-5-methoxy-2-(trifluoromethyl)phenyl]-8-(2- 283 420.1 hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(2,2-difluoroethyl)-4-(1-fluorocyclopropyl)-6- 284 390.1 methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2,2,2-trifluoro-N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6- 285 methylphenyl]-4-oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan- 467.1 2-yl)acetamide 118 60230447.1

[0417] Table 1-27N-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4- 286 oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan-2-yl)-2- 443.2 methoxyacetamide 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-[2-(1H- 287 422.2 pyrazol-3-yl)propan-2-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one N'-(2-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4- 288 oxo-4H-pyrimido[1,2-a]pyrimidin-8-yl}propan-2-yl)-N-methoxy- 458.2 N-methylurea 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-{2-[(1- 289 methyl-1H-pyrazol-3-yl)amino]propan-2-yl}-4H-pyrimido[1,2- 451.2 a]pyrimidin-4-one 3-chloro-5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H- 290 370.9 pyrimido[1,2-a]pyrimidin-2-yl)benzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[1-(oxan-4-yl)-1H- 291 446.2 pyrazol-5-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(2,2-difluorocyclopropyl)-4-(1-fluorocyclopropyl)-6- 292 402.1 methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[4-(1-fluorocyclopropyl)-2-methyl-6-(trifluoromethyl)phenyl]- 293 394.1 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(methoxyamino)- 294 341.2 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-(difluoromethoxy)-3-fluoro-4-(1-fluorocyclopropyl)-6- 295 410.1 methylphenyl]-8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-cyclopropyl-5-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin- 296 387.1 2-yl)-4-(trifluoromethyl)benzonitrile 119 60230447.1

[0418] Table 1-283-(difluoromethoxy)-5-(1-fluorocyclopropyl)-2-(8-methoxy-4- 297 403.1 oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)benzonitrile 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(1-methyl-1H- 298 376.1 pyrazol-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-(1- 299 394.2 methyl-1H-pyrazol-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-6-(difluoromethoxy)-4-(1-fluorocyclopropyl)phenyl]- 300 412.1 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-6-(difluoromethoxy)-4-(1-fluorocyclopropyl)phenyl]- 301 440.1 8-(2-hydroxypropan-2-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 302 360.0 4H-pyrimido[1,2-a]pyrimidin-4-one 2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8- 303 396.1 methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one 3-(difluoromethyl)-5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo- 304 387.1 4H-pyrimido[1,2-a]pyrimidin-2-yl)benzonitrile 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]- 305 376.0 8-methoxy-4H-pyrimido[1,2-a]pyrimidin-4-one tert-butyl 5-[2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-4-oxo- 306 4H-pyrimido[1,2-a]pyrimidin-8-yl]-2,5-diazaspiro[3.4]octane-2- 506.3 carboxylate 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[2-(oxetan-3-yl)- 307 2,5-diazaspiro[3.4]octan-5-yl]-4H-pyrimido[1,2-a]pyrimidin-4- 462.3 one 120 60230447.1

[0419] Table 1-291-acetyl-7-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-2,3- 308 413.0 dihydro-1H,9H-pyrimido[1',2':1,2]pyrimido[4,5-b][1,4]oxazin-9-one 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-[1-(oxetan- 309 436.1 3-yl)-1H-pyrazol-5-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 8-[2-(6-chloropyridazin-4-yl)-2,5-diazaspiro[3.4]octan-5-yl]-2-(4- 310 cyclopropyl-2-fluoro-6-methylphenyl)-4H-pyrimido[1,2-a]pyrimidin- 518.3 4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-(2,5- 311 406.3 diazaspiro[3.4]octan-5-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-8-[2-(pyridazin-4-yl)- 312 484.2 2,5-diazaspiro[3.4]octan-5-yl]-4H-pyrimido[1,2-a]pyrimidin-4-one 7-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-2,3-dihydro- 313 372.1 9H-[1,4]dioxino[2,3-d]pyrimido[1,2-a]pyrimidin-9-one 8-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-3-hydroxy- 314 372.0 2,3-dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one 4-(5-{2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-4-oxo- 315 4H-pyrimido[1,2-a]pyrimidin-8-yl}-1H-pyrazol-1-yl)-1lambda~6~- 512.2 thiane-1,1-dione 5-(1-fluorocyclopropyl)-3-methyl-2-(6-oxo-2,3-dihydro-6H- 316 363.2 furo[2,3-d]pyrimido[1,2-a]pyrimidin-8-yl)benzonitrile 8-[2-(difluoromethoxy)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]- 317 408.1 2,3-dihydro-6H-furo[2,3-d]pyrimido[1,2-a]pyrimidin-6-one

[0420] BIOLOGICAL ACTIVITY

[0421] The biological activity of the compound of Formula 1 with respect to NLRP3 wasdetermined using the following in vitro method.

[0422] IL-1β TR-FRET Assay (reported as percentage of inhibition at 6 μM or 30 μM)121 60230447.1

[0423] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in accordance with theprovider’s instructions in RPMI media (Thermo Fisher Scientific, Cat # A10491-01); RPMI was supplemented with 10% heat inactivated fetal bovine serum (NICHIREI BIOSCIENCES, Cat # 175012). The cells were differentiated into macrophages by the addition of 25 ng / mL IFN-γ (PeproTech, Cat # AF-300-02-100UG) for 24 hours at 37 °C / 5% CO2. Media was exchanged with fresh media with no FBS, and the cells were treated with 50 ng / mL LPS (priming step) (LPS-EK: Invivogen, Cat # tlrl-peklps). The cells were plated at 20,000 cells per well in 384-well flat-bottom cell culture plates (Greiner Bio-One, Cat # 781091) and were incubated for 24 hours at 37 °C / 5% CO2. Compounds were serially diluted (5-fold dilutions) with DMSO and were finally diluted with Media with no FBS. The compounds were added to the cells in 384-well plates and then the plates were incubated for 30 minutes at 37 °C / 5% CO2. The NLRP3 inflammasome was activated with the addition of 20 mM ATP (Sigma Cat # A3377-25G) and the cells were incubated for 2 hours at 37 °C / 5% CO2. At the end of the incubation period, 30 µL supernatant was transferred to another 384- well plate and mixed on a plate shaker for 1 minute. The supernatant was mixed with HTRF Antibody (Human IL1 beta kit, Cisbio, Cat # 62HIL1BPEH) in assay plates (Greiner Bio- One, Cat # 784075) and the assay plates were incubated in shading box at room temperature for 16-24 hours. HTRF signal was measured by EnVision (Perkinelmer) in accordance with the manufacturer’s instructions.

[0424] TNF-α Assay (reported as IC50)

[0425] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in accordance with theprovider’s instructions in RPMI media (Thermo Fisher Scientific, Cat # A10491-01); RPMI was supplemented with 10% heat inactivated fetal bovine serum (NICHIREI BIOSCIENCES, Cat # 175012). The cells were differentiated into macrophages by the addition of 25 ng / mL IFN-γ for 24 hours at 37 °C / 5% CO2. Media was exchanged with fresh media with no FBS. The cells were plated at 40,000 cells per well in 384-well flat-bottom cell culture plates (Corning, Cat # 3764) containing compounds in a 5-fold serial dilution in DMSO and were incubated for 30 minutes at 37 °C / 5% CO2. The NF-κB pathway was activated with the addition of 600 ng / mL LPS and the cells were incubated for 3 hours at 37 °C / 5% CO2. At the end of the incubation period, supernatant (40 μL) was removed, and TNF- alpha were monitored using an ELISA (Human TNF-α ELISA, R&D systems, Cat # DY210) according to the manufacturer’s instructions.100% inhibition is determined with positive control, TPCA-1.

[0426] Data Interpretation122 60230447.1The percentage of inhibition at 6 μM or 30 μM in the IL-1β TR-FRET assay was calculated by the following formula: Percentage of inhibition = [1 – (HTRF signaltest – HTRF signalLow) / (HTRF signalHigh– HTRF signalLow)] *100, where HTRF signaltestis the HTRF signal in the well to which test compound is added, HTRF signalLow is the HTRF signal in the well to which 3 μM MCC-950 is added, and the HTRF signalHighis the HTRF signal in the well to which DMSO is added.

[0427] The IC50 values in the TNF-α assay were calculated from a plot of percentage of inhibition versus the inhibitor concentration by a logistics curve fit according to: Y = [Bottom + (Top- Bottom)] / (1 + 10^ [(Log IC50– X) ∙ Hill Slope], where Y was the % inhibition at the inhibitor concentration, X, “Bottom” was the lowest inhibition value, i.e., 0 %, “Top” was the maximum inhibition value, i.e., 100 %, and the “Hill Slope” described the slope of the sigmoidal curve between the “Bottom” and “Top” values. The curve fitting was conducted with internally developed software.

[0428] Table 2 lists in vitro biological assay data (IL-1β and TNF-α assay) for thecompounds shown in the examples. These assays are described in the section entitled Biological Activity, above.

[0429] Table 2: Biological Assay DataIL-1β TNF-α IC50 Example inhibitory rate (μM) No. at 6 μM (%) 1 105 2 95 3 97 4 98 5 105 >30 6 97 >30 7 98 8 103 9 96 >30 10 98 11 105 >30 12 100 >30 123 60230447.113 96 >30 14 100 >30 15 101 >30 16 101 >30 17 98 >30 18 64 (30μM) 19 103 >30 20 103 >30 21 100 >30 22 97 >30 23 105 >30 24 97 >30 25 102 >30 26 97 >30 27 100 >30 28 99 >30 29 99 >30 30 102 >30 31 58 32 104 >30 33 101 >30 34 90 >30 35 105 >30 36 100 >30 37 101 >30 38 103 >30 39 97 >30 40 98 >30 41 102 >30 42 100 >30 43 99 >30 44 103 >30 124 60230447.145 100 >30 46 99 >30 47 101 >30 48 102 >30 49 98 >30 50 99 >30 51 102 >30 52 100 >30 53 101 >30 54 101 >30 55 95 >30 56 84 >30 57 101 >30 58 98 >30 59 100 >30 60 99 >30 61 98 >30 62 101 >30 63 99 >30 64 98 >30 65 97 >30 66 101 >30 67 102 >30 68 97 >30 69 99 >30 70 99 >30 71 102 >30 72 100 >30 73 99 >30 74 99 >30 75 99 >30 76 95 >30 125 60230447.177 99 >30 78 100 >30 79 99 >30 80 99 >30 81 99 >30 82 100 >30 83 98 >30 84 95 >30 85 99 >30 86 99 >30 87 99 >30 88 98 >30 89 100 >30 90 99 91 102 >30 92 97 >30 93 95 >30 94 98 >30 95 99 >30 96 101 >30 97 96 >30 98 101 >30 99 99 >30 100 96 >30 101 98 >30 102 99 >30 103 101 >30 104 98 >30 105 96 >30 106 96 >30 107 99 >30 108 98 >30 126 60230447.1109 101 >30 110 99 >30 111 101 >30 112 104 >30 113 98 >30 114 100 >30 115 101 >30 116 100 >30 117 100 >30 118 98 >30 119 96 >30 120 98 >30 121 101 >30 122 98 >30 123 101 >30 124 99 >30 125 101 >30 126 97 >30 127 99 >30 128 101 >30 129 101 >30 130 99 >30 131 104 >30 132 97 >30 133 67 >30 134 97 >30 135 100 >30 136 101 >30 137 101 >30 138 98 >30 139 100 >30 140 98 >30 127 60230447.1141 94 >30 142 103 >30 143 100 >30 144 98 >30 145 100 >30 146 99 >30 147 99 >30 148 99 >30 151 102 152 100 >30 153 102 154 99 >30 155 101 >30 156 101 >30 157 99 >30 158 100 >30 159 103 >30 160 103 >30 161 100 >30 162 100 >30 163 100 >30 164 100 >30 165 100 >30 166 95 >30 168 33 169 103 >30 170 102 >30 171 60 >30 172 97 >30 173 98 >30 174 100 >30 175 99 >30 128 60230447.1176 101 >30 177 100 >30 178 61 >30 179 98 >30 180 104 >30 181 21 (30μM) 182 101 >30 183 102 >30 184 100 >30 185 102 >30 186 100 >30 187 97 >30 188 102 >30 189 102 >30 190 95 >30 191 100 >30 192 102 >30 193 28 (30μM) 194 95 >30 195 101 >30 196 96 >30 198 101 >30 199 102 >30 200 102 >30 201 103 >30 202 101 >30 203 105 >30 204 100 >30 205 88 >30 206 98 >30 207 104 >30 208 100 >30 129 60230447.1209 98 >30 210 99 >30 211 95 >30 212 102 >30 213 100 >30 214 94 >30 215 98 >30 216 96 >30 217 99 >30 218 98 >30 219 98 >30 220 103 >30 221 100 >30 222 100 >30 223 101 >30 224 100 >30 225 100 >30 226 98 >30 227 104 >30 228 100 >30 229 102 >30 230 99 >30 231 98 >30 232 96 >30 233 97 >30 234 101 >30 235 98 >30 236 98 >30 237 99 >30 238 99 >30 239 93 >30 240 102 >30 130 60230447.1241 97 >30 242 74 (30μM) 243 96 >30 244 100 >30 245 100 >30 246 100 >30 247 98 >30 248 100 >30 249 100 >30 250 54 251 74 >30 252 102 >30 253 100 >30 254 99 >30 255 82 >30 256 99 >30 257 98 >30 258 102 >30 259 101 >30 260 100 >30 261 96 >30 262 96 >30 263 98 >30 264 99 >30 265 101 >30 266 102 >30 267 101 >30 268 101 >30 269 101 >30 270 100 >30 271 98 >30 272 101 >30 131 60230447.1273 98 >30 274 101 >30 275 99 >30 276 99 >30 277 98 >30 278 102 >30 279 100 >30 280 102 >30 281 57 282 66 >30 283 95 >30 284 103 >30 285 103 >30 286 100 >30 287 102 >30 288 103 >30 289 100 >30 290 101 >30 291 99 >30 292 100 >30 293 98 >30 294 102 >30 295 99 >30 296 45 297 94 >30 298 101 >30 299 102 >30 300 98 >30 301 100 >30 302 98 >30 303 97 >30 304 102 >30 132 60230447.1305 96 >30 306 84 (30μM) 307 41 308 98 >30 309 99 >30 310 52 (30μM) 311 40 (30μM) 312 66 >30 313 97 >30 314 99 >30 315 95 >30 316 99 >30 317 99

[0430] The results showed that compounds of the present invention suppress theproduction of IL-1β. It was also confirmed that the compounds of the present invention show more selective to IL-1β than TNF-α. These indicate that the compounds inhibit the targeted NLRP3 inflammasome activation pathway with little or no interference of the NF-κB - dependent priming pathway. Considering the diversity of pro-inflammatory factors, often with opposing functions, specific inhibition of the NLRP3 inflammasome pathway is required to achieve the most desired outcome without impeding the tissue repair process.

[0431] The following in vitro assays may be used to assess the ability of a compound ofFormula 1 to enter the CNS through the blood-brain barrier.

[0432] Multidrug Resistance Protein 1 (MDR1) Substrate Screening Assay

[0433] Method 1

[0434] Human MDR1-expressing Madine-Darby Canine Kidney (MDCK) cells werecultured, and the transcellular transport study was performed. The cells were cultured in Transwell 96-well permeable support (pore size 0.4 μm, 0.143 cm2surface area) with polycarbonate membrane (Corning Life Sciences, Lowell, MA). The cells were preincubated with Hanks’ Balanced Salt Solution (HBSS) for 10 minutes at 37 °C. Subsequently, transcellular transport was initiated by the addition of HBSS either to apical compartments (75 μL) or to basolateral compartments (250 μL) containing 1 or 10 μmol / L of each test compound. The assay was terminated by separating each assay plate after 1 hour. Aliquots 133 60230447.1(25 μL) from the opposite compartments were mixed with acetonitrile. After centrifugation, the compound concentrations in the supernatant were measured by LC-MS / MS and an Unison UK-C18 HT column (3.0 μm, 2.0 × 20 mm). The apparent permeability (Papp) in the receiver wells was determined and the Papp and efflux ratio (ER) for the membrane permeability test was calculated from two-point standard curve (the concentration corresponding to 10 and 100 nm / sec) using the following equations: Papp = (R – y-axis intercept of R,STD100 and R, STD10) / Slope of R,STD100 and R,STD10 where R is ratio of peak area of test compound to that of internal standard, and R,STD10 and R,STD100 are ratio of peak area of standard sample corresponding to 10 and 100 nm / sec to that of internal standard. ER = Papp,BtoA / Papp,AtoB where Papp,AtoB and Papp,BtoA represent the apparent permeability in the apical-to-basal direction and the basal-to-apical direction, respectively.

[0435] Method 2

[0436] 1. Cell Culture

[0437] MDR1-MDCK I cells were seeded onto polyethylene membranes (PET) in 96-wellCorning insert systems at 2.5 x 105 cells / mL until to 4-7 days for confluent cell monolayer formation.

[0438] 2. Experimental Procedures

[0439] For control compounds, the transport buffer in the study was HBSS with 10.0 mMHEPES at pH 7.40±0.05. For test compounds, the transport buffer in the study was HBSS with 10.0 mM HEPES and 1% BSA at pH 7.40±0.05. Test compounds were tested at 1.00 μM bi-directionally in duplicate. Digoxin was tested at 10.0 μM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 μM in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1%. The plate was incubated for 1 hour in CO2incubator at 37±1 °C, with 5% CO2at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3220 xg for 10 minutes. For all samples, 150 µL supernatant solution was diluted with 150 µL ultra-pure water for LC-MS / MS analysis. In addition, the efflux ratio of each compound was also determined. Test and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / IS. After transport assay, Lucifer yellow rejection assay was applied to determine the cell monolayer integrity. Buffers were removed from both apical and basolateral chambers, 134 60230447.1followed by the addition of 75 µL of 100 µM lucifer yellow in transport buffer and 250 µL transport buffer in apical and basolateral chambers, respectively. The plate was incubated for 30 minutes at 37 °C with 5% CO2and 95% relative humidity without shaking. After 30 minutes incubation, 20 µL of lucifer yellow samples were taken from the apical sides, followed by the addition of 60 µL of Transport Buffer. And then 80 µL of lucifer yellow samples were taken from the basolateral sides. The relative fluorescence unit (RFU) of lucifer yellow was measured at 425 / 528 nm (excitation / emission) with a microplate reader.

[0440] 3. Data Analysis

[0441] The apparent permeability coefficient Papp (cm / s) was calculated using theequation: Papp = (dCr / dt) x Vr / (A x C0) Where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (µM / s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm2for the area of the monolayer; C0 is the initial concentration in the donor chamber (µM). The efflux ratio was calculated using the equation: Efflux Ratio = Papp (BA) / Papp (AB) Percent recovery was calculated using the equation: %Solution Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x C0) Where Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side); Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively. Percent of lucifer yellow in basolateral well was calculated using the equation: Wherelucifer yellow in the apical and basolateral wells, respectively; VApical and VBasolateral are the volume of apical and basolateral wells (0.075 mL and 0.25 mL), respectively. The %Lucifer Yellow should be less than 1.0.

[0442] Breast Cancer Resistance Protein (BCRP) Substrate Screening Assay

[0443] Human BCRP-expressing MDCKII cells were cultured, and the transcellulartransport study was performed. The cells were cultured in Transwell 96-well permeable support (pore size 0.4 μm, 0.143 cm2surface area) with polycarbonate membrane (Corning 135 60230447.1Life Sciences, Lowell, MA). The cells were preincubated with M199 for 10 minutes at 37 °C. Subsequently, transcellular transport was initiated by the addition of M199 either to apical compartments (75 μL) or to basolateral compartments (250 μL) containing 1 μmol / L of each test compound. The assay was terminated by separating each assay plate after 1 hour. Aliquots (25 μL) from the opposite compartments were mixed with acetonitrile. After centrifugation, the compound concentrations in the supernatant were measured by LC- MS / MS and an Unison UK-C18 HT column (3.0 μm, 2.0 × 20 mm). The apparent permeability (Papp) in the receiver wells was determined and the Papp and efflux ratio (ER) for the membrane permeability test was calculated from two-point standard curve (the concentration corresponding to 10 and 100 nm / sec) using the following equations: Papp = (R – y-axis intercept of R,STD100 and R, STD10) / Slope of R,STD100 and R,STD10 where R is ratio of peak area of test compound to that of internal standard, and R,STD10 and R,STD100 are ratio of peak area of standard sample corresponding to 10 and 100 nm / sec to that of internal standard. ER = Papp,BtoA / Papp,AtoB where Papp,AtoB and Papp,BtoA represent the apparent permeability in the apical-to-basal direction and the basal-to-apical direction, respectively.

[0444] Formulation Example 1 (production of capsule)1) compound of Example 1 30 mg 2) crystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg 1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

[0445] Formulation Example 2 (production of tablet)1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4) calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000 tablets 140 g in total The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is 136 60230447.1punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

[0446] As used in this specification and the appended claims, singular articles such as“a,” “an,” and “the,” may refer to a single object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing “a compound” may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the invention should be determined with reference to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references cited in the disclosure, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes. 137 60230447.1

Claims

WHAT IS CLAIMED IS 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:substituted C1-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted 4- to 7-membered heterocyclic group, (5) -ORa, or (6) -NRbRc; R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) an optionally substituted C1-6alkyl group, (5) an optionally substituted C3-8cycloalkyl group, (6) an optionally substituted C1-6 alkoxy group, (7) -NRbRc, or (8) an optionally substituted 5- or 6- membered aromatic heterocyclic group; R1and R2may bind to form an optionally substituted 5- or 6-membered heterocyclic ring with the adjacent carbon atoms; R3is (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C1-6 alkoxy group, (5) -NRbRc, or (6) an optionally substituted 4- to 7-membered heterocyclic group; R4is (1) a hydrogen atom, (2) a fluorine atom, (3) a chlorine atom, (4) a bromine atom, or (5) an optionally substituted C1-6alkyl group; Ring A is a 6-membered ring wherein X1is (i) =C(R5)-, (ii) -C(R5)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X2is (i) =C(R6)-, (ii) -C(R6)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X3is (i) =C(R7)-, (ii) -C(R7)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X4is (i) =C(R8)-, (ii) -C(R8)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X5is (i) =C(R9)-, (ii) -C(R9)=, (iii) -C(=O)-, (iv) =N-, or (v) -N=; X6is (i) C, or (ii) N; R5is (i) a hydrogen atom, or (ii) a substituent; R6is (i) a hydrogen atom, or (ii) a substituent; R7is (i) a hydrogen atom, or (ii) a substituent; R8is (i) a hydrogen atom, or (ii) a substituent; 138 60230447.1R9is (i) a hydrogen atom, or (ii) a substituent; proviso that Ring A has at least one substituent on any one of X1, X2, X3, X4, or X5position; and Rais (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group or (iv) an optionally substituted 4- to 7- membered heterocyclic group; Rbis (i) a hydrogen atom, (ii) an optionally substituted C1-6 alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group, (iv) an optionally substituted C1-6 alkoxy group or (v) an optionally substituted 4- to 7-membered heterocyclic group, in each occurrence; and Rcis (i) a hydrogen atom, (ii) an optionally substituted C1-6alkyl group, (iii) an optionally substituted C3-8 cycloalkyl group or (iv) an optionally substituted 4- to 7- membered heterocyclic group, in each occurrence.

2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1is (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a halogen atom, (ii) a C3-8cycloalkyl group optionally substituted by 1 to 3 hydroxy group, (iii) a C1-6 alkoxy group, (iv) an amino group, (v) a (4- to 7-membered heterocyclic)-amino group optionally substituted by 1 to 3 C1-6alkyl group, (vi) a C1-6 alkyl-carbonyl-amino group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a halogen atom, and(b) a C1-6 alkoxy group,(vii) a C3-8cycloalkyl-carbonyl-amino group optionally substituted by 1 to 3 halogen atom(s), (viii) a (4- to 7-membered heterocyclic group)-carbonyl-amino group optionally substituted by 1 to 3 halogen atom(s), (ix) a C1-6alkoxy-carbonyl-amino group, 139 60230447.1(x) a N-C1-6alkyl- N-C1-6alkyl-carbonyl-amino group, (xi) a N-C1-6 alkoxy- N-C1-6 alkyl-ureido group, (xii) a hydroxy group, and (xiii) a 4- to 7-membered heterocyclic group, (3) a C3-8cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group, (ii) a halogen atom, (iii) a cyano group, (iv) a C1-6alkoxy group, (v) a hydroxy group, and (vi) a 4- to 7-membered heterocyclyloxy group, (4) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (i) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkoxy group, (b) a halogen atom, (c) a C1-6 alkoxy-carbonyl group, and (d) carboxyl group, (ii) a C3-8cycloalkyl group, (iii) a C1-6 alkoxy group, (iv) a halogen atom, (v) a hydroxy group, (vi) a tri-C1-6alkylsilyloxy group, (vii) a cyano group, (viii) –(CH2)l- (wherein l is an integer of 2 to 4), (ix) –(CH2)mO(CH2)n- (wherein m is an integer of 1 or 2, and n is an integer of 1 or 2), (x) an oxo, (xi) a 4- to 7-membered heterocyclyl group, and (xii) –(CH2)pNRd1(CH2)q- (wherein Rd1(a) a hydrogen atom, (b) a C1-6 alkoxy- carbonyl group, or (c) an optionally halogenated 4- to 7-membered heterocyclic group, p is an integer of 1 or 2, and q is an integer of 1 or 2), (5) -ORa1140 60230447.1(Ra1is (i) a hydrogen atom,(ii) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected fromthe group consisting of (a) a hydroxy group, (b) a halogen atom, (c) C1-6 alkoxy group, and (d) a 4- to 7- membered heterocyclic group optionally substituted by 1 to 34- to 7- membered heterocyclic group, (iii) a 4- to 7- membered heterocyclic group, or(iv) a C3-8 cycloalkyl group optionally substituted by 1 to 3 hydroxy group), or(6) -NRb1Rc1(Rb1is (i) a C1-6alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C3-8cycloalkyl group optionally substituted by 1 to 3 cyano group(s), (b) a halogen atom, (c) a hydroxy group, (d) a C6-10 aryl group optionally substituted by 1 to 3 C1-6 alkoxy(s), and (e) a 4- to 7 membered heterocyclic group optionally substituted by a hydroxy group, (ii) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkyl group, (b) a hydroxy group, and (c) a cyano group, (iii) a C1-6alkoxy group or (iv) a 4- to 7-membered heterocylic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (a) a C1-6 alkyl group, and (b) a hydroxy group; Rc1is (i) a hydrogen atom, or(ii) a C1-6 alkyl group);141 60230447.1R2is (1) a hydrogen atom, (2) a fluorine atom, (3) a C1-6 alkyl group, (4) a C1-6alkoxy group, or (5) a 5- or 6-membered aromatic heterocyclic group; or R1and R2may bind to form 5- or 6-membered heterocyclic ring with the adjacent carbon atoms optionally substituted by 1 to 3 substituent(s) selected from the group consisting of (1) a C1-6 alkyl group, (2) a C1-6 alkyl-carbonyl group, (3) a C1-6 alkoxy- carbonyl group, and (4) a hydroxy group. R3is (1) a hydrogen atom, or (2) a C1-6 alkyl group; R4is (1) a hydrogen atom, or (2) a C1-6alkyl group; and Ring A is a benzene ring substituted by 1 to 4 substituent(s) selected from a group consisting of (i) a halogen atom,(ii) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selectedfrom the group consisting of (a) a halogen atom,(b) a hydroxy group, and(c) an optionally halogenated C1-6 alkoxy group,(iii) a C3-6 cycloalkyl group optionally substituted by 1 to 3 substituent(s)selected from the group consisting of (a) a halogen atom,(b) a C1-6 alkyl group, and(c) a cyano group,(iv) an optionally halogenated C1-6 alkoxy group,(v) a hydroxy group,(vi) a cyano group,(vii) a 4- to 7 membered heterocyclic group, and(viii) a C1-6 alkylsulfonyl group.142 60230447.

13. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1is (1) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy group(s) or (2) a C1-6alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is(1) a pyridine ring substituted by 1 to 3 substituent(s) selected from a group consisting of(i) an optionally halogenated C1-6 alkyl group, and(ii) an optionally halogenated C3-6 cycloalkyl group,(2) a pyrimidine ring substituted by 1 to 3 substituent(s) selected from a group consisting of(i) a C1-6 alkyl group, and(ii) a C3-6 cycloalkyl group, or(3) a dihydropyridine ring substituted by 1 to 3 substituent(s) selected from a groupconsisting of (i) a C1-6 alkyl group,(ii) a C3-6 cycloalkyl group, and(iii) an oxo group.

4. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1is a C1-6alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4is a hydrogen atom; and Ring A is a benzene ring optionally substituted by 1 to 3 substituent(s) selected from a group consisting of (i) a halogen atom,(ii) an optionally halogenated C1-6 alkyl group,(iii) an optionally halogenated C3-6 cycloalkyl group, and(iv) a cyano group.143 60230447.

15. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: 2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2- a]pyrimidin-4-one, 5-(1-fluorocyclopropyl)-2-(8-methoxy-4-oxo-4H-pyrimido[1,2-a]pyrimidin-2-yl)-3- methylbenzonitrile, 2-[2-chloro-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H-pyrimido[1,2- a]pyrimidin-4-one, and 2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-4H- pyrimido[1,2-a]pyrimidin-4-one.

6. A method of treating a disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with NLRP3.

7. A method of treating a disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with a heterozygous gain of function mutation in the NLRP3 gene.

8. A method of treating a cryopyrin-associated periodic syndrome (CAPS) in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

9. The method according to claim 8, wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease 144 60230447.1(NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

10. A method of treating a neurodegenerative disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

11. A method of treating Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

12. A method of treating obesity in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

13. A medicament comprising a compound or pharmaceutically acceptable salt as defined in claim 1.

14. The medicament according to claim 13, which is an agent for the treatment of disease, disorder or condition associated with NLRP3.

15. The medicament according to claim 13, which is an agent for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene. 145 60230447.

116. The medicament according to claim 13, which is an agent for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

17. The medicament according to claim 16, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

18. The medicament according to claim 13, which is an agent for the treatment of a neurodegenerative disease.

19. The medicament according to claim 13, which is an agent for the treatment of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

20. The medicament according to claim 18, which is an agent for the treatment of obesity.

21. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of disease, disorder or condition associated with NLRP3.

22. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene. 146 60230447.

123. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

24. The use according to claim 23 wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle- Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

25. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of a neurodegenerative disease.

26. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease 27. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of obesity.

28. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a disease, disorder or condition associated with NLRP3.

29. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene. 147 60230447.

130. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a cryopyrin-associated periodic syndrome (CAPS).

31. The compound according to claim 30, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

32. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a neurodegenerative disease.

33. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

34. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating obesity. 148 60230447.1

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