Heterocyclic compound

Abstract

The invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein R1, L, R2, and R3 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 COMPOUNDFIELD OF THE INVENTION

[0001] This invention relates to heterocyclic compounds which are inhibitors of the NLRP3 inflammasome, to medicaments which contain them, and to their use to treat diseases, disorders and / or conditions associated with NLRP3, including neurodegenerative diseases, 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. Fernandez-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 aggregation of 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).163020443.1

[0004] Microglia, which are myeloid cells of the CNS, play a major role during innate immune 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-containing domain (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 ofNLRP3 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-KB-dependent transcriptional upregulation ofNLRP3 and pro-IL-1, but also controls post-translational modifications ofNLRP3. See J. Yang, Z. Liu and T. S. Xiao, “Post-translational regulation of inflammasomes,” Cell Mol Immunol 14(l):65-79 (2017). The initial trigger is followed by a second “activation” signal ([3-amyloid, a-synuclein and 263020443.1other 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-ip to their mature inflammatory cytokines, IL-18 and IL-1 p. 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-1 p. 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- 1 P 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 associated with 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 people363020443.1worldwide. 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 inflammasome hyper-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 the proliferating 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,463020443.1inflammation, and insulin resistance” Ann Rev Physiol. 72:219-46 (2010); Shoelson et al. “Obesity, inflammation, and insulin resistance” Gastroenterology 132(6):2169-80 (2007)). In addition, IL- 1 p is thought to be connected with the progression of obesity-associated insulin resistance (Jager et al., “Interleukin- 1 beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression” Endocrinology 148(l):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 predispose individuals to excessive weight gain by impairing the hypothalamic energy homeostasis system (Y oo 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-a” 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- 563020443.1neuronal 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 the NLRP3 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 forthe 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 ofNLRP3 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 for treating 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] W02010 / 103547 and WO2019 / 123482 disclose the following compounds for treating conditions and diseases that are mediated by adenosine receptor activity.63020443.1I

[0015] WO2011 / 055391 disclose the following compounds for treating conditions and diseases that are mediated by adenosine receptor activity.

[0016] The following compounds are disclosed in Bioorganic & Medicinal Chemistry 25 (2017) 1963-1975 as adenosine Ai receptor antagonists.O(Ar = m-CF3C6H4, p-CF3C6H4, m-OMeC6H4, m-COOHC6H4, m-OHC6H4, m-CONH2C6H4)SUMMARY OF THE INVENTION

[0017] This invention provides heterocyclic compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, or hydrates thereof. This invention also provides medicaments that contain imidazopyrimidinone derivatives and provides fortheir use to treat diseases, disorders and / or conditions associated with NLRP3, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, prion disease, other neurodegenerative disorders and obesity.

[0018] One aspect of the invention provides [1] a compound of Formula (I), or a pharmaceutically acceptable salt thereof:63020443.1whereinR1is (1) a halogen atom, (2) an optionally substituted Ci-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C6-10aromatic hydrocarbon ring group, (5) an optionally substituted 4- to 7-membered heterocyclic group or (6) -CONRaRb;L is (1) a bond, (2) -O- or (3) -NRC-;R2is (1) an optionally substituted C1-6 alkyl group, (2) an optionally substituted C3-8cycloalkyl group or (3) an optionally substituted C1-6alkoxy group;R3is (1) a C6-10aromatic hydrocarbon ring group further having at least two substituents or (2) a 5- or 6-membered aromatic heterocyclic ring further having substituent(s);Rais (1) a hydrogen atom or (2) a substituent;Rbis (1) a hydrogen atom or (2) a substituent; andRcis (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group or (3) an optionally substituted C1-6 alkoxy group.

[0019] [2] The compound or a pharmaceutically acceptable salt thereof according to the above [1], wherein R2is (1) an optionally substituted C1-6 alkyl group or (2) an optionally substituted C3-8 cycloalkyl group.

[0020] [3] The compound or a pharmaceutically acceptable salt thereof according to the above [1], whereinR1is(1) a halogen 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 C3-8 cyclopropyl group,(iii) a C1-6 alkoxy group, and(iv) an oxo group,(3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom,(ii) an optionally halogenated C1-6 alkyl group,(iii) a C1-6 alkoxy group, and(iv) a hydroxy group,(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group,863020443.1(5) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom,(ii) a Ci-6 alkyl group,(iii) a Ci -6 alkoxy group and(iv) 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, or(6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a Ci-6 alkyl group, and Rblis a Ci-6 alkyl group);L is(1) a bond,(2) -O-, or(3) -NRcl- (wherein Rclis a Ci-6 alkyl group);R2is (1) an optionally halogenated Ci-6 alkyl group or (2) a Ci-6 alkoxy group; andR3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of(i) a halogen atom,(ii) an optionally halogenated Ci-6 alkyl group,(iii) an optionally halogenated C3-8 cycloalkyl group, and(iv) an optionally halogenated C1-6 alkoxy group.

[0021] [4] The compound or a pharmaceutically acceptable salt thereof according to the above [1], whereinR1is(1) a halogen 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 C3-8 cyclopropyl group, and(iii) a C1-6 alkoxy group,(3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom,(ii) an optionally halogenated C1-6 alkyl group,(iii) a C1-6 alkoxy group, and963020443.1(iv) a hydroxy group,(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group,(5) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom,(ii) a Ci-6 alkyl group, and(iii) a Ci-6 alkoxy group, or(6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a Ci-6 alkyl group, and Rblis a Ci-6 alkyl group);L is(1) a bond,(2) -O-, or(3) -NRcl- (wherein Rclis a Ci-6 alkyl group);R2is an optionally halogenated Ci-6 alkyl group; andR3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of(i) a halogen atom,(ii) an optionally halogenated Ci-6 alkyl group,(iii) an optionally halogenated C3-8 cycloalkyl group, and(iv) an optionally halogenated C1-6 alkoxy group.

[0022] [5] The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR1is a C1-6 alkyl group;L is -O-;R2is a C1-6 alkyl group; andR3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of(i) a halogen atom,(ii) an optionally halogenated C1-6 alkyl group, and(iii) an optionally halogenated C3-8 cycloalkyl group.[6] The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one;1063020443.12-[2,6-dichloro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;2-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;(Ra or Sa)-2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;2-[2-bromo-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;(Ra or Sa)-2-[2-bromo-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;(Ra or Sa)-2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;8-ethoxy-2-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)-1-methyl-1,7-dihydro-6H-purin-6-one;2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one;(Ra or Sa)-2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one;(Sa or Ra)-2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one; and2-(2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one.

[0023] [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 the above [1], wherein the disease, disorder or condition is associated with NLRP3.

[0024] [8] A method of treating a disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or1163020443.1pharmaceutically 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.

[0025] [9] 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 the above [1].

[0026]

[0010] The method according to the above [9], 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).

[0027]

[0011] 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 the above [1].

[0028]

[0012] 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 the above [1].

[0029]

[0013] 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 the above [1].

[0030]

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

[0031]

[0015] The medicament according to the above

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

[0032]

[0016] The medicament according to the above

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

[0033]

[0017] The medicament according to the above

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

[0034]

[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).

[0035]

[0019] The medicament according to the above

[0014] , which is an agent for the treatment of a neurodegenerative disease.1263020443.1

[0036]

[0020] The medicament according to the above

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

[0037]

[0021] The medicament according to the above

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

[0038]

[0022] 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.

[0039]

[0023] Use of a compound or pharmaceutically acceptable salt as defined in the above [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.

[0040]

[0024] Use of a compound or pharmaceutically acceptable salt as defined in the above [1] for the manufacture of a medicament for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

[0041]

[0025] The use according to the above

[0024] , 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).

[0042]

[0026] Use of a compound or pharmaceutically acceptable salt thereof as defined in the above [1] for the manufacture of a medicament for the treatment of a neurodegenerative disease.

[0043]

[0027] Use of a compound or pharmaceutically acceptable salt thereof as defined in the 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

[0044]

[0028] Use of a compound or pharmaceutically acceptable salt thereof as defined in the above [1] for the manufacture of a medicament for the treatment of obesity.

[0045]

[0029] A compound or pharmaceutically acceptable salt as defined in the above [1] for use as a medicament.

[0046]

[0030] A compound or pharmaceutically acceptable salt as defined in the above [1] for use in treating a disease, disorder or condition associated with NLRP3.

[0047]

[0031] 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.1363020443.1

[0048]

[0032] A compound or pharmaceutically acceptable salt as defined in the above [1] for use in treating a cryopyrin-associated periodic syndrome (CAPS).

[0049]

[0033] A Compound or pharmaceutically acceptable salt as defined in the above

[0032] 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).

[0050]

[0034] A compound or pharmaceutically acceptable salt thereof as defined in the above [1] for use in treating a neurodegenerative disease.

[0051]

[0035] A compound or pharmaceutically acceptable salt thereof as defined in the above [1] for use in treating Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

[0052]

[0036] A compound or pharmaceutically acceptable salt thereof as defined in the above [1] for use in treating obesity.

[0053]

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

[0054]

[0038] The combination according to the above

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

[0055] Unless otherwise indicated, this disclosure uses definitions provided below.

[0056] ‘ ‘Substituted,” when used in connection with a chemical substituent or moiety (e.g., a Ci-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.

[0057] “Optional” or “optionally” refers to the subsequently described event or circumstances 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 hydrocarbon1463020443.1group” refers to an unsubstituted hydrocarbon group or a substituted hydrocarbon group substituted with 1 to 3 substituents.”

[0058] ‘ ‘About” or “approximately,” when used in connection with a measurable numerical 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.

[0059] “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, C1-4 alkyl 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-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-l-yl, n-hexyl, and the like.

[0060] “Alkanediyl” refers to divalent alkyl groups, where alkyl is defined above, and generally 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, C1-6 alkanediyl 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-l,3-diyl, isobutane- 1,1 -diyl, isobutane- 1,2-diyl, and the like.

[0061] “Alkenyl” refers to straight chain and branched hydrocarbon groups having one or more 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-l-yl, 1-buten-l-yl, l-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl-l -propen- 1-yl, 2-methyl-2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.

[0062] “Alkynyl” refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms (e.g., C2-6 alkynyl 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-l-yl, 2-propyn-l-yl, 1-butyn-l-yl, 3-butyn-l-yl, 3-butyn-2-yl, 2-butyn-l-yl, and the like.1563020443.1

[0063] “Alkoxy” refers to straight chain and branched saturated hydrocarbon groups attached through an oxygen atom, generally having a specified number of carbon atoms (e.g., Ci-4 alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms,Ci-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-l-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-l-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-l-yloxy, n-hexoxy, and the like.

[0064] “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 methylcarbonyl (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.

[0065] “Alkylamino” including mono- or di-alkylamino group refers to an alkyl group as defined 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.

[0066] “Alkyl-carbamoyl” including mono- or di-alkyl-carbamoyl group refers to an alkyl group 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.

[0067] “Alkyl-carbonylamino” refers to an alkyl-carbonyl as defined above, which is attached 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., 1,1663020443.12, 3, 4, 5 or 6) carbon atoms, excluding the carbonyl moiety, and so on). Examples of Ci-6 alkyl-carbonylamino groups include methylcarbonylamino (acetylamino), ethylcarbonylamino, and the like.

[0068] “Alkoxy-carbonyl” refers to an alkoxy group as defined above, which is attached through a carbonyl (C(O)) group, and generally having a specified number of carbon atoms (e.g., Ci-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 Ci-6 alkoxycarbonyl groups include methoxy carbonyl, ethoxy carbonyl, and the like.

[0069] ‘ ‘Halo,” “halogen” and “halogeno” may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0070] “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, chloromethyl, dichloromethyl, trichloromethyl, 1 -fluoroethyl, 1,1 -difluoroethyl, 1-chloroethyl, 1,1 -dichloroethyl, 1 -fluoro- 1 -methylethyl, 1 -chloro- 1 -methylethyl, and the like.

[0071] “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., C3-8 cycloalkyl 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.

[0072] 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-l-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. l.l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo [3. l.l]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,1763020443.1bicyclo [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.

[0073] “Cycloalkanediyl” refers to divalent cycloalkyl groups, where cycloalkyl is defined above, and generally having a specified number of carbon atoms (e.g., C3-8 cycloalkanediyl 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.

[0074] “Cycloalkylidene” refers to divalent monocyclic cycloalkyl groups, where cycloalkyl is defined above, which are attached through a single carbon atom of the group, and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-8 cycloalkylidene 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.

[0075] “Cycloalkenyl” refers to partially unsaturated monocyclic and bicyclic hydrocarbon 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-l-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0076] “Cycloalkyl-carbonyl” or “cycloalkylsulfonyl” refers to a cycloalkyl 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., 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)1863020443.1carbon atoms as ring members of cycloalkyl group, and so on). Examples of cycloalkylcarbonyl groups include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and the like. Examples of cycloalkylsulfonyl groups include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, and the like.

[0077] “Aryl” refers to fully unsaturated monocyclic aromatic hydrocarbons and to polycyclic 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., Ce-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.

[0078] “Acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a Ce-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 hydrocarbonsulfinyl 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.

[0079] Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkylcarbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a Ce-i4 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 C1-6 alkoxy-carbonyl group, a Ce-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1963020443.1naphthyloxycarbonyl), a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16aralkyl-carbamoyl group, a 5-to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C1-6alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10cycloalkyl-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 group, a C1-6alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C1-6 alkylsulfonyl group, a C6-14arylsulfonyl group, a phosphono group and a mono- or di-C1-6alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0080] “Aralkyl” refers to an alkyl group as defined above, wherein one of its hydrogens is 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.

[0081] “Aralkyloxy” refers to a hydroxy group whose hydrogen is substituted by an aralkyl group as defined above, and generally having a specified number of carbon atoms (e.g., C7-16 aralkyloxy 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.

[0082] “Aralkyloxy-carbonyl” refers to an aralkyloxy group as defined above, which is attached through a carbonyl (C(O)) group, and generally having a specified number of carbon atoms (e.g., C7-I6 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, phenylpropyloxy carbonyl, and the like.2063020443.1

[0083] “Arylene” refers to divalent aryl groups, where aryl is defined above, and generally having a specified number of carbon atoms that comprise their ring members (e.g.,C6-14 arylene 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).

[0084] “Heterocycle”, “heterocyclic” and “heterocyclyl” may be used interchangeably and refer 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., C2-6 heterocyclyl 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 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 or result in a chemically unstable compound. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-l-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.

[0085] “Heterocycle-diyl” refers to heterocyclyl groups which are attached through two ring 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., C2-6 heterocycle-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-l,2-diyl, 1 -pyrrolidinyl -2 -ylidene, l-pyridinyl-2-ylidene, l-(4 / / )-pyrazolyl-5-ylidene, l-(3 / / )-imidazolyl -2-ylidene, 3-oxazolyl-2-ylidene, l-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.2163020443.1

[0086] ‘ ‘Heteroaromatic”, “aromatic heterocyclyl / heterocyclic” and “heteroaryl” may be used 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-l-yl, pyrrol-2-yl, and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, l-oxa-3,4-diazolyl, l-thia-2,3-diazolyl, l-thia-2,4-diazolyl, l-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0087] 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[l,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- 2263020443.1d]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[l,5-a]pyrazinyl.

[0088] “Heteroarylene” refers to heteroaryl groups which are attached through two ring atoms of the group, where heteroaryl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C3-5 heteroarylene 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.

[0089] ‘ ‘Non-aromatic heterocyclic / heterocyclyl” (including “3- to 8-membered nonaromatic heterocyclic group”) refers to heterocyclic group other than heteroaryl groups as mentioned above. Preferable examples of the “non-aromatic heterocyclic group” include 3- to 8-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

[0090] 9- to 14-membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic 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-P-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[0091] In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ringconstituting atom.2363020443.1

[0092] In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the substituent group A as described later.

[0093] ‘ ‘Oxo” refers to a double bonded oxygen (=0).

[0094] Examples of the “substituent” (including “hetero-containing substituents”) include a 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.

[0095] Examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a Ce-14 aryl group and a C7-I6 aralkyl group.

[0096] “Hetero-containing substituents” refers to substituents containing at least one heteroatom. 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.

[0097] Examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following substituent group A.

[0098] [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 C1-6 alkoxy group,(7) a Ce-14 aryloxy group (e.g., phenoxy, naphthoxy),(8) a C7-16 aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy),2463020443.1(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy),(11) a Ci-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a Ce-i4 aryl-carbonyloxy group (e.g., benzoyloxy, 1 -naphthoyloxy, 2-naphthoyloxy), (13) a Ci -6 alkoxy-carbonyloxy group (e.g., methoxy carbonyloxy, ethoxycarbonyloxy, propoxy carbonyloxy, butoxycarbonyloxy),(14) a mono- or di-Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),(15) a Ce-i4 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 Ci-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a Ce-i4 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated Ci-6 alkylthio 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 Ci-6 alkyl-carbonyl group,(26) a Ce-i4 aryl-carbonyl group,(27) a 5 - to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a Ci-6 alkoxy-carbonyl group,(30) a Ce-i4 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1 -naphthyloxycarbonyl, 2-naphthyloxy carbonyl),(31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-Ci-6 alkyl-carbamoyl group,(35) a Ce-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl),2563020443.1(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 Ci-6 alkylsulfonyl group,(39) a Ce-i4 arylsulfonyl group,(40) a 5 - to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated Ci-6 alkylsulfmyl group,(42) a Ce-i4 arylsulfmyl group (e.g., phenylsulfmyl, 1-naphthylsulfinyl, 2-naphthylsulfmyl), (43) a 5- to 14-membered aromatic heterocyclylsulfmyl group (e.g., pyridylsulfinyl, thienylsulfmyl),(44) an amino group,(45) a mono- or di-Ci-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -methylamino),(46) a mono- or di-Ce-14 arylamino group (e.g., phenylamino),(47) a 5- to 14-membered heterocyclylamino group (e.g., pyridylamino) optionally substituted by 1 to 3 Ci-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 C3-10 cycloalkyl-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 (C1-6 alkyl)(Ci-6 alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (54) a Ce-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (55) a C1-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxy carbonylamino),(56) a C7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino),(57) a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino),2663020443.1(58) a Ce-i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(59) aN-Ci-6 alkoxy- N-CI-6 alkyl-ureido group (e.g., N-methoxy-N-methyl-ureido), (60) a Ci-6 alkyl 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 Ce-io aryl group optionally substituted by 1 to 3 C1-6 alkoxy 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 C3-10 cycloalkyl group,(64) a C3-10 cycloalkenyl group,(65) a Ce-14 aryl group,(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 C1-6 alkoxy-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.

[0099] The number of the above-mentioned substituents in the “optionally substituted hydrocarbon 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.

[0100] “Leaving group” refers to any group that leaves a molecule during a fragmentation process, 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,2763020443.1carboxylate 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.

[0101] “Opposite enantiomer” refers to a molecule that is a non-superimposable mirror image 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.

[0102] ‘ ‘Stereoisomer” and “stereoisomers” of a compound with given stereochemical configuration 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 stereochemical 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.

[0103] “Substantially pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.

[0104] ‘ ‘Pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.

[0105] ‘ ‘Axial chirality” refers to a stereochemical property in which two substituents within a molecule share a rotatable bond axis, and the rotation is restricted by steric hindrance, resulting in the formation of enantiomers.

[0106] “Subject” refers to a mammal, including a human.

[0107] “Pharmaceutically acceptable” substances refer to those substances which are suitable for administration to subjects.

[0108] “Treating” refers to reversing, alleviating, inhibiting the progress of, or preventing a 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.2863020443.1

[0109] ‘ ‘Treatment” refers to the act of “treating,” as defined immediately above.

[0110] “Drug,” “drug substance,” “active pharmaceutical ingredient,” and the like, refer to a 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.

[0111] ‘ ‘Effective amount” of a drug, “therapeutically effective amount” of a drug, and the like, 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.

[0112] “Excipient” refers to any diluent or vehicle for a drug.

[0113] ‘ ‘Medicament” refers to the combination of one or more drug substances and one or more excipients. Sometimes such combination is also described as “formulation” or “pharmaceutical composition”.

[0114] “Drug product,” “pharmaceutical dosage form,” “dosage form,” “final dosage form” 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, sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.

[0115] ‘ ‘Disease, disorder or condition associated with NLRP3” and similar phrases relate to a disease, disorder or condition in a subject for which inhibition of the NLRP3 inflammasome pathway may provide a therapeutic or prophylactic benefit.

[0116] 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)-l,r-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-trichloroethoxy carbonyl); dba (dibenzylideneacetone); DBU (l,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1 -dichloroethane); DCM (dichloromethane); DEA (diethylamine); DIAD (diisopropyl azodicarboxylate); DIPEA (A'. A'-diisopropylcthylaminc. Hiinig’s Base); DMA ( '. '-dimcthylacctamidc): DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF ( '. '-dimcthylformamidc):2963020443.1DMP (Dess-Martin periodinane); DMSO (dimethylsulfoxide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC50 (effective concentration at half maximal response); EDA (ethoxylated dodecyl alcohol, Bq®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-l -ethanesulfonic acid); HO Ac (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 (A-methylmorpholine); NMP (l-methylpyrrolidin-2-one); OTf (triflate); PE (petroleum ether); Ph (phenyl); pEC’50 (-logio(ECso), where EC50 is given in molar (M) units); pICso (-logio(ICso), where IC50 is given in molar (M) units); PMB (p-methoxylbenzyl); Pr (propyl); c-Pr (cyclopropyl), z-Pr (isopropyl); PTFE (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-l,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); and XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1, 1 ’-biphenyl) [2-(2’ -amino- 1,1 ’-biphenyl)]palladium (II)).

[0117] As described below, this disclosure concerns compounds of Formula (I), or pharmaceutically 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 3063020443.1lateral sclerosis, prion disease and other diseases, disorders and / or conditions associated with NLRP3 such as obesity.

[0118] The definition of each variable in Formula (I) is explained in detail in the following.

[0119] R1is (1) a halogen atom, (2) an optionally substituted Ci-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C6-10aromatic hydrocarbon ring group, (5) an optionally substituted 4- to 7-membered heterocyclic group or (6) -CONRaRb(wherein Rais (i) a hydrogen atom or (ii) a substituent, and Rbis (i) a hydrogen atom or (ii) a substituent.).

[0120] As one embodiment, R1is preferably(1) a halogen atom (e.g., chlorine, bromine),(2) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C3-8 cyclopropyl group (e.g., cyclopropyl),(iii) a C1-6 alkoxy group (e.g., methoxy), and(iv) an oxo group,(3) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, spiro[3.3]heptanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) an optionally halogenated C1-6 alkyl group (e.g., trifluoromethyl),(iii) a C1-6 alkoxy group (e.g., methoxy), and(iv) a hydroxy group,(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group (e.g., phenyl, fluorophenyl),(5) a 4- to 7-membered heterocyclic group (e.g. azetidinyl, oxetanyl, tetrahydrofuryl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C1-6 alkyl group (e.g., methyl),(iii) a C1-6 alkoxy group (e.g., methoxy, isobutoxy) and,(iv) 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 (e.g., -O-(CH2)2-), or3163020443.1(6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a Ci-6 alkyl group (e.g., methyl), and Rblis a Ci-6 alkyl group (e.g., methyl)).

[0121] R1is more preferably a Ci-6 alkyl group (e.g., methyl, ethyl).

[0122] L is (1) a bond, (2) -O- or (3) -NRC- (wherein Rcis (1) a hydrogen atom, (2) an optionally substituted Ci-6 alkyl group or (3) an optionally substituted Ci-6 alkoxy group.).

[0123] As one embodiment, L is preferably(1) a bond,(2) -O-, or(3) -NRcl- (wherein Rclis (1) a hydrogen atom or (2) Ci-6 alkyl group (e.g., methyl)).

[0124] L is more preferably -O-.

[0125] R2is (1) an optionally substituted Ci-6 alkyl group, (2) an optionally substituted C3-8cycloalkyl group or (3) an optionally substituted C1-6alkoxy group.

[0126] As one embodiment, R2is preferably (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl, ethyl, difluoroethyl (2,2-difluoroethyl), trifluoroethyl (2,2,2-trifluoroethyl)) or (2) a C1-6 alkoxy group (methoxy).

[0127] As one embodiment, R2is (1) an optionally substituted C1-6 alkyl group or (2) an optionally substituted C3-8 cycloalkyl group.

[0128] As one embodiment, R2is preferably an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl).

[0129] R2is more preferably, a C1-6 alkyl group (e.g., methyl).

[0130] R3is (1) a C6-10aromatic hydrocarbon ring group further having at least two substituents or (2) a 5- or 6-membered aromatic heterocyclic ring further having substituent(s).

[0131] As one embodiment, R3is preferably a Ce-io aromatic hydrocarbon ring group (e.g., phenyl) further having two or three substituents selected from the group consisting of (i) a halogen atom (e.g., fluorine, chlorine, bromine),(ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl (1,1 -difluoroethyl, 2,2-difluoroethyl)), (iii) an optionally halogenated C3-8 cycloalkyl group (e.g., cyclopropyl, fluorocyclopropyl, chlorocyclopropyl), and(iv) an optionally halogenated C1-6 alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy (2,2-difluoroethoxy), trifluoroethoxy (2,2,2-trifluoroethoxy)).3263020443.1

[0132] R3is more preferably, a Ce-io aromatic hydrocarbon ring group (e.g., phenyl) further having two or three substituents selected from the group consisting of(i) a halogen atom (e.g., fluorine, chlorine, bromine),(ii) an optionally halogenated Ci-6 alkyl group (e.g., methyl, difluoromethyl), and (iii) an optionally halogenated C3-8 cycloalkyl group (e.g., fluorocyclopropyl).

[0133] Preferable embodiment of a compound of Formula (I) includes the following compounds.

[0134] [Compound A]R1is (1) a halogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C6-10aromatic hydrocarbon ring group, (5) an optionally substituted 4- to 7-membered heterocyclic group or (6) -CONRaRb(wherein Rais (i) a hydrogen atom or (ii) a substituent, and Rbis (i) a hydrogen atom or (ii) a substituent.);L is (1) a bond, (2) -O- or (3) -NRC- (wherein Rcis (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group or (3) an optionally substituted C1-6 alkoxy group.);R2is (1) an optionally substituted C1-6 alkyl group, (2) an optionally substituted C3-8 cycloalkyl group, or (3) an optionally substituted C1-6 alkoxy group; andR3is (1) a C6-10aromatic hydrocarbon ring group further having at least two substituents or (2) a 5- or 6-membered aromatic heterocyclic ring further having substituent(s).

[0135] [Compound B]R1is (1) a halogen atom, (2) an optionally substituted C1-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C6-10aromatic hydrocarbon ring group, (5) an optionally substituted 4- to 7-membered heterocyclic group or (6) -CONRaRb(wherein Rais (i) a hydrogen atom or (ii) a substituent, and Rbis (i) a hydrogen atom or (ii) a substituent.);L is (1) a bond, (2) -O- or (3) -NRC- (wherein Rcis (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group or (3) an optionally substituted C1-6 alkoxy group.);R2is (1) an optionally substituted C1-6 alkyl group or (2) an optionally substituted C3-8 cycloalkyl group; andR3is (1) a C6-10aromatic hydrocarbon ring group further having at least two substituents or (2) a 5- or 6-membered aromatic heterocyclic ring further having substituent(s).

[0136] [Compound C]R1is(1) a halogen atom (e.g., chlorine, bromine),3363020443.1(2) a Ci-6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C3-8 cyclopropyl group (e.g., cyclopropyl),(iii) a C1-6 alkoxy group (e.g., methoxy), and(iv) an oxo group,(3) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, spiro[3.3]heptanyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) an optionally halogenated C1-6 alkyl group (e.g., trifluoromethyl),(iii) a C1-6 alkoxy group (e.g., methoxy), and(iv) a hydroxy group,(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group (e.g., phenyl, fluorophenyl),(5) a 4- to 7-membered heterocyclic group (e.g., azetidinyl, oxetanyl, tetrahydrofuryl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C1-6 alkyl group(s) (e.g., methyl),(iii) a C1-6 alkoxy group (e.g., methoxy, isobutoxy), and(iv) 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 (e.g., -O-(CH2)2-), or (6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a C1-6 alkyl group (e.g., methyl), and Rblis a C1-6 alkyl group (e.g., methyl));L is(1) a bond,(2) -O-, or(3) -NRcl- (wherein Rclis (1) a hydrogen atom or (2) a C1-6 alkyl group (e.g., methyl)); R2is (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl, ethyl, difluoroethyl (2,2-difluoroethyl), trifluoroethyl (2,2,2-trifluoroethyl)) or (2) a C1-6 alkoxy group (e.g, methoxy); andR3is a Ce-io aromatic hydrocarbon ring group (e.g., phenyl) further having two or three substituents selected from the group consisting of3463020443.1(i) a halogen atom (e.g., fluorine, chlorine, bromine),(ii) an optionally halogenated Ci-6 alkyl group (e.g., methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl (1,1 -difluoroethyl, 2,2-difluoroethyl), (iii) an optionally halogenated C3-8 cycloalkyl group (e.g., cyclopropyl, fluorocyclopropyl, chlorocyclopropyl), and(iv) an optionally halogenated C1-6 alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy (2,2- difluoroethoxy), trifluoroethoxy (2,2,2- trifluoroethoxy)).

[0137] [Compound D]R1is(1) a halogen atom (e.g., chlorine, bromine),(2) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C3-8 cyclopropyl group (e.g., cyclopropyl), and(iii) a C1-6 alkoxy group (e.g., methoxy),(3) a C3-8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) an optionally halogenated C1-6 alkyl group (e.g., trifluoromethyl),(iii) a C1-6 alkoxy group (e.g., methoxy), and(iv) a hydroxy group,(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group (e.g., phenyl, fluorophenyl),(5) a 4- to 7-membered heterocyclic group (e.g. oxetanyl, tetrahydrofuryl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) optionally substituted by 1 to 3 substituent(s) selected from the group consisting of(i) a halogen atom (e.g., fluorine),(ii) a C1-6 alkyl group(s) (e.g., methyl), and(ii) a C1-6 alkoxy group (e.g., methoxy, isobutoxy), or(6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a C1-6 alkyl group (e.g., methyl), and Rblis a C1-6 alkyl group (e.g., methyl));L is3563020443.1(1) a bond,(2) -O-, or(3) -NRcl- (wherein Rclis a Ci-6 alkyl group (e.g., methyl));R2is an optionally halogenated Ci-6 alkyl group (e.g., methyl, difluoromethyl); and R3is a Ce-io aromatic hydrocarbon ring group (e.g., phenyl) further having two or three substituents selected from the group consisting of(i) a halogen atom (e.g., fluorine, chlorine),(ii) an optionally halogenated Ci-6 alkyl group (e.g., methyl, difluoromethyl, trifluoromethyl, ethyl),(iii) an optionally halogenated C3-8 cycloalkyl group (e.g., cyclopropyl, fluorocyclopropyl), and(iv) an optionally halogenated C1-6 alkoxy group (e.g., methoxy, difluoromethoxy).

[0138] [Compound E]R1is a C1-6 alkyl group (e.g., methyl);L is -O-;R2is a C1-6 alkyl group (e.g., methyl); andR3is a Ce-io aromatic hydrocarbon ring group (e.g., phenyl) further having two or three substituents selected from the group consisting of(i) a halogen atom (e.g., fluorine, chlorine, bromine),(ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl), and (iii) an optionally halogenated C3-8 cycloalkyl group (e.g., fluorocyclopropyl).

[0139] Specific examples of a compound of Formula (I) include the compounds of Examples 1 to 189.

[0140] More preferable examples of a compound of Formula (I) include2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 14);2-[2,6-dichloro-4-(l-fluorocyclopropyl)phenyl]-8-methoxy-l-methyl-l,7-dihydro-6H-purin-6-one (Example 88);2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8-methoxy-l-methyl-l,7-dihydro-6H-purin-6-one (Example 105);2-[2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 108);3663020443.1(Ra or Sa)-2-[2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (Example 109);2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 116);(Ra or Sa)-2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 117);2-[4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl] -8 -methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 128);2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 139);(Ra or Sa)-2-[2-chloro-6-(difluoromethyl)-4-( 1 - fluorocyclopropyl)phenyl] -8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (Example 140);8-ethoxy-2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 182);2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 183);(Ra or Sa)-2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-ethoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (Example 184);(Sa or Ra)-2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-ethoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (Example 185); and2-(2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl)-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (Example 186).

[0141] Compounds of Formula (I) include embodiments described in the preceding paragraphs 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.

[0142] 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,3763020443.1benzoate, 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.

[0143] Pharmaceutically acceptable base salts include salts derived from bases, including metal 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, and 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).

[0144] Pharmaceutically acceptable salts may be prepared using various methods. For example, 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.

[0145] Compounds of Formula (I) may exist in a continuum of solid states ranging from fully 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 3863020443.1peaks. 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”).

[0146] Compounds of Formula (I) may also exist in unsolvated and solvated forms. The term “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).

[0147] A currently accepted classification system for solvates and hydrates of organic compounds 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 solvent (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.

[0148] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry 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.

[0149] Compounds of Formula (I) may also exist as multi-component complexes (other than 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. Cocrystals 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.

[0150] When subjected to suitable conditions, compounds of Formula (I) may exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state lies between the 3963020443.1true 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., -COO~Na+, -COO”K+, -SO3~Na+) or polar non-ionic moiety (such as -N~N+(CH3)3). See, e.g., N. H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0151] 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.

[0152] “Prodrugs” refer to compounds having little or no pharmacological activity that can, when metabolized in vivo, undergo conversion to compounds having desired pharmacological activity. Prodrugs may be prepared by replacing appropriate functionalities present 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., Bioreversihle Carriers in Drug Design (1987).

[0153] ‘ ‘Metabolites” refer to compounds formed in vivo upon administration of pharmacologically 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.

[0154] Compounds of Formula (I) may exist as stereoisomers that result from the presence of 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.

[0155] Compounds of Formula (I) may exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, ketoenol, oxime-nitroso, and amide-imidic acid tautomerism.

[0156] Compounds of Formula (I) may have an axial chirality. That is Compounds of Formula (I) may exist as atropisomers.4063020443.1

[0157] Compounds of Formula (I) may exhibit more than one type of isomerism.

[0158] Geometrical (.cis! trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0159] Conventional techniques for preparing or isolating a compound having a specific stereochemical 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).

[0160] Compounds of Formula (I) may possess isotopic variations, in which at least one atom 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 as36C1, 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.

[0161] Compound (I) may be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation,4163020443.1chromatography, 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).

[0162] In the methods and examples below, certain compounds may be prepared using protecting 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 useful 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).

[0163] Generally, the chemical transformations described throughout the specification may 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.

[0164] Many of the chemical transformations may also employ one or more compatible solvents, 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);4263020443.1aliphatic alcohols (e.g., methanol, ethanol, propan-l-ol, propan-2 -ol, butan-l-ol, 2-methyl-propan-l-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-l-ol, 3 -methyl -butan-l-ol, hexan-l-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, l-methoxy-2-(2-methoxy-ethoxy)-ethane, l-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).

[0165] In the schemes, below, substituent identifiers (e.g., R1, L, R2and R3) 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) and 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.

[0166] The production method of the compound of the present invention is explained below.

[0167] The raw material compound and reagent used and the compound obtained in each step 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.

[0168] When the compound obtained in each step is a free form, it can be converted to the objective 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.

[0169] The compound obtained in each step can be used directly as the reaction mixture or as 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.4363020443.1

[0170] When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly.

[0171] In the reaction in each step, 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 10 minutes to 8 hours, unless otherwise specified.

[0172] In 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 -78 °C to 300 °C, preferably -78 °C to 150 °C, unless otherwise specified.

[0173] In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.

[0174] Microwave synthesizer such as Initiator manufactured by Biotage and the like may be 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, preferably 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.

[0175] In the reaction in each step, the reagent is used in an amount of 0.5 equivalents to 20 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.

[0176] 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;4463020443.1sulfoxides: 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.

[0177] The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio.

[0178] When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like;organic 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.

[0179] When an acid or an acid catalyst is used for the reaction in each step, examples thereof 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.

[0180] Unless otherwise specified, the reaction in each step is carried out according to a method 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.4563020443.1Tietze, 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.); Modem Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.l -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.

[0181] In each step, the protection or deprotection reaction of a functional group is carried out 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.

[0182] Examples of the protecting group for a hydroxy group of an alcohol and the like and 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.

[0183] Examples of the protecting group for a carbonyl group of an aldehyde include acetal -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.

[0184] 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.

[0185] Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; amide-type protecting groups such as N, N-dimethylamide and the like, and the like.

[0186] Examples of the protecting group for a thiol include ether-type protecting groups such as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.4663020443.1

[0187] Examples of the protecting group for an amino group and an aromatic heterocycle such 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 methane sulfonamide and the like, and the like.

[0188] The protecting groups can be removed according to a method known per se, for example, 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.

[0189] When reduction reaction is carried out in each step, examples of the reducing agent to 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 as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; iron; zinc and the like.

[0190] 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.

[0191] When oxidation reaction is carried out in each step, examples of the oxidizing agent 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-l,4-benzoquinone (DDQ) and the like.

[0192] When radical reaction is carried out in each step, examples of the radical initiator to 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 4763020443.1the radical reagent to be used include tributylstannane, tristrimethylsilylsilane, 1, 1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like.

[0193] When Wittig reaction is carried out in each step, examples of the Wittig reagent to be 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.

[0194] When Homer-Emmons reaction is carried out in each step, examples of the reagent to 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.

[0195] When Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid 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 an 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.

[0196] When aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (e.g., an amine, imidazole, alcohol etc.) and abase (e.g., an inorganic base, an organic base etc.) are used as a reagent.

[0197] When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-addition reaction (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.

[0198] When Grignard reaction is carried out in each step, examples of the Grignard reagent 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.

[0199] When Knoevenagel condensation reaction is carried out in each step, a compound having 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.4863020443.1

[0200] When Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (e.g., N, N-dimethylformamide etc.) are used as a reagent.

[0201] When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in 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.

[0202] When reductive amination reaction or reductive alkylation reaction is carried out in each 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 ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like.

[0203] When Mitsunobu reaction is carried out in each step, a cyanomethylenetrialkyl phosphorane (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.

[0204] When esterification reaction, amidation reaction or urea formation reaction is carried 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-l,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-l -methyl -pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-l-yl)-N, N, N’, N’-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; combinations thereof and the like. When 4963020443.1carbodiimide 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.

[0205] When coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladinm(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.

[0206] When deoxyamination reaction is carried out in each step, examples of the reagent to be used include phosphonium salt such as PyBOP, PyBroP and the like.

[0207] When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a l,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent) etc.) can also be used instead of phosphorus pentasulfide.

[0208] When Wohl-Ziegler reaction is carried out in each step, examples of the halogenating 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.

[0209] 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 the5063020443.1corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed.

[0210] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0211] When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methane sulfonic anhydride, p-toluenesulfonic anhydride and the like.

[0212] When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For acid hydrolysis reaction of the tert-butyl ester, formic acid, triethyl silane 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.

[0213] When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N, N’-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0214] When Chan-Lam reaction is carried out in each step, examples of the metal catalyst 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.

[0215] When Ullmann reaction is carried out in each step, examples of the metal catalyst to 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.

[0216] When alkylation reaction is carried out in each step, examples of the base to be used 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.

[0217] When deoxofluorination reaction is carried out in each step, examples of the fluorinating agent to be used include bis(2-methoxyethyl)aminosulfur trifluoride,5163020443.1diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, N, N-diethyl-S, S-difluorosulfiliminium tetrafluoroborate, difluoro-4-morpholinylsulfonium tetrafluoroborate and the like.

[0218] When Hofmann rearrangement reaction is carried out in each step, examples of the reagent to be used include lead tetraacetate, iodobenzene diacetate and the like.

[0219] When thiourea formation reaction or thiocarbamation reaction is carried out in each 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.

[0220] When cyclopropanation reaction is carried out in each step, examples of the reagent to be used include diiodomethane, dibromomethane, dibromodifluoromethane, dibromofluoromethane, (trifluoromethyl)trimethylsilane, (bromodifluoromethyl)trimethylsilane, (dibromofluoromethyl)trimethylsilane, carbon tetrafluoride, sodium trifluoroacetate and the like.

[0221] When compound (I) and intermediate for the production of compound (I) have a convertible functional group (e.g., a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a mercapto group, a Ci-6 alkoxy-carbonyl group, a Ce-14 aryloxy-carbonyl group, a C7-16 aralkyloxy-carbonyl group, a sulfo group, a sulfide group, a halogen atom, an optionally halogenated C1-6 alkylsulfonyloxy 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.

[0222] Carboxyl group can be converted, for example, by reactions such as esterification, reduction, amidation, conversion reaction to optionally protected amino group and the like.

[0223] Amino group can be converted, for example, by reactions such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.

[0224] Hydroxy group can be converted, for example, by reactions such as esterification, carbamoylation, sulfonylation, alkylation, fluorination, arylation, oxidation, halogenation and the like.

[0225] 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.

[0226] Mercapto group can be converted, for example, by reactions such as alkylation, oxidation and the like.5263020443.1

[0227] Ci-6 alkoxy-carbonyl group, Ce-14 aryloxy-carbonyl group and C7-16 aralkyloxycarbonyl group can be converted, for example, by reactions such as reduction, hydrolysis and the like.

[0228] Sulfo group can be converted, for example, by reactions such as sulfonamidation, reduction and the like.

[0229] Sulfide group can be converted, for example, by reactions such as oxidation and the like.

[0230] Halogen atom can be converted, for example, by various nucleophilic substitution reactions, various coupling reactions and the like.

[0231] Optionally halogenated C1-6 alkylsulfonyloxy group can be converted, for example, by various nucleophilic substitution reactions, various coupling reactions and the like.

[0232] Cyano group can be converted, for example, by reactions such as reduction, hydrolysis and the like.

[0233] Aminocarbonyl group can be converted, for example, by reactions such as dehydration, reduction and the like.

[0234] Boryl group can be converted, for example, by oxidation, various coupling reactions and the like.

[0235] In each of the above-mentioned reactions, when the compound is obtained in a free form, 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.

[0236] The conversion of these functional group can be carried out according to a method known per se, for example, the method described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock, or the like.

[0237] Compound (I) obtained in each reaction scheme can be isolated and purified by known 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.

[0238] When compound (I) has isomers such as an optical isomer, a stereoisomer, a regioisomer 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 5363020443.1can 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).

[0239] Compound (I) may be a crystal, and the crystal form may be single or a mixture of crystal forms, both of which are encompassed in compound (I). The crystal can be produced according to a crystallization method known per se.

[0240] The compound (I) may be a solvate (e.g., hydrate) or a non-solvate (e.g., nonhydrate etc.) and both are encompassed in compound (I).

[0241] The compounds labeled with isotopes (e.g.,3H,14C,35S,125I etc.) and the like are also encompassed in compound (I).

[0242] A deuterium conversion form wherein1H is converted to2H(D) is also encompassed in compound (I).

[0243] Compound (I) labeled or substituted with an isotope can be used as, for example, a tracer (PET tracer) used for Positron Emission Tomography (PET), and therefore, it is useful in the fields of medical diagnosis and the like.

[0244] Compound (I) of the present invention can be synthesized according to the production method described below.

[0245] Each variable in the formulas of the reaction schemes is as defined above, unless otherwise specified.

[0246] In the schemes, PG is a protecting group for aromatic heterocycle and LG is a leaving group. Examples of the protecting group for aromatic heterocycle include a methoxy methyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, 4-methoxybenzyl, tert-butoxycarbonyl, and the like. Examples of the leaving group include halogen atoms, optionally halogenated Ci-6 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl), optionally halogenated Ci-6 alkylsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), Ce-14 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0247] Compound (I-a), wherein L is O, and compound (I-b), wherein L is N, can be produced from compound (1) according to the following scheme 1.5463020443.1

[0248] Scheme 1

[0249] Compounds (1), (2), (7) and (10) may be commercially available or can be produced according to a method known per se.

[0250] Compound (3) can be produced by subjecting compound (1) to an oxidative cyclization reaction with the corresponding aldehyde (2) and an oxidant. Examples of the oxidant to be used include iodine, and the like.

[0251] Compound (4) can be produced by subjecting compound (3) to a halogenation reaction with halogenating agents. Examples of halogenating agents to be used include N-iodosuccinimide, N-bromosuccinimide, and the like.

[0252] Compounds (5) and / or (6) can be produced by subjecting compound (4) to a protection reaction.

[0253] Compounds (8) and / or (9) can be produced by subjecting compounds (5) and / or (6) to an aromatic nucleophilic substitution reaction with the corresponding alcohol (7).

[0254] Compound (I-a) can be produced by subjecting compounds (8) and / or (9) to a deprotection reaction.

[0255] Compounds (11) and / or (12) can be produced by subjecting compounds (5) and / or (6) to an aromatic nucleophilic substitution reaction with the corresponding amine (10).

[0256] Compound (I-b) can be produced by subjecting compounds (11) and / or (12) to a deprotection reaction.

[0257] Compound (4) can also be produced from compound (13) according to the following scheme 2. In the scheme, R4is an optionally substituted Ci-6 alkyl group. Examples of the optionally substituted Ci-6 alkyl group include methyl, ethyl, and the like.5563020443.1

[0258]

[0259] Compounds (13) and (17) may be commercially available or can be produced according to a method known per se.

[0260] Compound (14) can be produced by subjecting compound (13) to a halogenation reaction.

[0261] Compounds (15) and / or (16) can be produced by subjecting compound (14) to a protection reaction.

[0262] Compounds (18) and / or (19) can be produced by subjecting compounds (15) and / or (16) to an amidation reaction with the corresponding amine (17).

[0263] Compounds (20) and / or (21) can be produced by subjecting compounds (18) and / or (19) to a reduction reaction.

[0264] Compound (4) can be produced by subjecting compounds (20) and / or (21) to an oxidative cyclization reaction with the corresponding aldehyde (2).

[0265] Compound (I-c), wherein L is a bond, can be produced from compound (22) according to the following scheme 3. In the scheme, Z is a dihydroxyboryl or a pinacolboryl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl).

[0266] Scheme 3

[0267] Compounds (22), (23), (25), (26) and (29) may be commercially available or can be produced according to a method known per se.

[0268] Compound (27) can be produced by subjecting compound (22) to an amidation reaction with the corresponding carboxylic acid (25) or acyl halide (26).5663020443.1

[0269] Compound (24) can be produced by subjecting compound (22) to an oxidative cyclization reaction with the corresponding aldehyde (23), or by subjecting compound (27) to a cyclization reaction with an acid or a base. Examples of the acid to be used include acetic acid, trifluoroacetic acid, and the like. Examples of the base to be used include sodium hydroxide, sodium methoxide, cesium fluoride, and the like.

[0270] Compound (28) can be produced by subjecting compound (24) to a halogenation reaction.

[0271] Compounds (30) and / or (31) can be produced by subjecting compound (28) to a protection reaction.

[0272] Compounds (32) and / or (33) can be produced by subjecting compounds (30) and / or (31) to a coupling reaction with the corresponding compound (29).

[0273] Compound (I-c) can be produced by subjecting compound (28) to a coupling reaction with the corresponding compound (29), or by subjecting compounds (32) and / or (33) to a deprotection reaction.

[0274] Compound (I-c) can also be produced from compound (34) according to the following scheme 4. In the scheme, Z is dihydroxyboryl or pinacolboryl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl), PG1and PG2are protecting groups for the aromatic amine and LG1, LG2and LG3are leaving groups. Examples of the protecting group for the aromatic amine include tert-butyloxy carbonyl, benzyloxy carbonyl, 4-methoxybenzyl, and the like. Examples of the leaving group include halogen atoms, optionally halogenated Ci-6 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl), optionally halogenated Ci-6 alkylsulfonyloxy gruop (e.g., methanesulfonyloxy, ethane sulfonyloxy, trifluoromethanesulfonyloxy), Ce-14 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0275] Scheme 463020443.1

[0276] Compounds (34) and (35) may be commercially available or can be produced according to a method known per se.

[0277] Compound (36) can be produced by subjecting compound (34) to an aromatic nucleophilic substitution reaction with the corresponding amine (35).

[0278] Compound (37) can be produced by subjecting compound (36) to a protection reaction.

[0279] Compound (38) can be produced by subjecting compound (37) to a hydrolysis reaction.

[0280] Compound (39) can be produced by subjecting compound (38) to a coupling reaction with the corresponding compound (29).

[0281] Compound (40) can be produced by subjecting compound (39) to an alkylation reaction.

[0282] Compound (41) can be produced by subjecting compound (40) to a reduction reaction.

[0283] Compound (42) can be produced by subjecting compound (41) to a deprotection reaction.

[0284] Compound (43) can be produced by subjecting compound (42) to an amidation reaction with the corresponding carboxylic acid (25) or acyl halide (26).

[0285] Compound (I-c) can be produced by subjecting compound (42) to an oxidative cyclization reaction with the corresponding aldehyde (23), or by subjecting compound (43) to a cyclization reaction.

[0286] Compound (I-d), wherein R1is -CONRaRband L is a bond, and compound (I-a) can be produced from compound (42) according to the following scheme 5. In the scheme, R4’ is an optionally substituted Ci-6 alkyl group. Examples of the optionally substituted Ci-6 alkyl group include methyl, ethyl, and the like.

[0287] 63020443.1

[0288] Compounds (44) and (48) may be commercially available or can be produced according to a method known per se.

[0289] Compound (45) can be produced by subjecting compound (42) to an oxidative cyclization reaction with the corresponding aldehyde (44).

[0290] Compounds (46) and / or (47) can be produced by subjecting compound (45) to a protection reaction.

[0291] Compounds (49) and / or (50) can be produced by subjecting compounds (46) and / or (47) to an amidation reaction with the corresponding amine (48).

[0292] Compound (I-d) can be produced by subjecting compounds (49) and / or (50) to a deprotection reaction.

[0293] Compound (51) can be produced by subjecting compound (42) to a urea formation reaction.

[0294] Compound (I-a) can be produced by subjecting compound (51) to an alkylation reaction.

[0295] Compound (I-a) can also be produced from compound (52) according to the following scheme 6. In the schemes, PG3is a protecting group for aromatic hydroxyl group. Examples of the protecting group for the aromatic hydroxyl group include benzyl, 4-methoxybenzyl, and the like.Scheme 6

[0296] Compounds (55) may be commercially available or can be produced according to a method known per se.

[0297] Compounds (53) and / or (54) can be produced by subjecting compound (52) to a protection reaction.5963020443.1

[0298] Compounds (56) and / or (57) can be produced by subjecting compounds (53) and / or (54) to an aromatic nucleophilic substitution reaction with the corresponding alcohol (55).

[0299] Compounds (58) and / or (59) can be produced by subjecting compounds (56) and / or (57) to a halogenation reaction.

[0300] Compounds (60) and / or (61) can be produced by subjecting compounds (58) and / or (59) to an aromatic nucleophilic substitution reaction with the corresponding alcohol (7).

[0301] Compounds (62) and / or (63) can be produced by subjecting compounds (60) and / or (61) to a coupling reaction with the corresponding compound (29).

[0302] Compounds (64) and / or (65) can be produced by subjecting compounds (62) and / or (63) to a deprotection reaction.

[0303] Compounds (66) and / or (67) can be produced by subjecting compounds (64) and / or (65) to an alkylation reaction.

[0304] Compound (I-a) can be produced by subjecting compounds (66) and / or (67) to a deprotection reaction.

[0305] Compound (66) and / or (67) can also be produced from compound (56) and / or (57) according to the following scheme 7.

[0306] Compounds (68) and / or (69) can be produced by subjecting compound (56) and / or (57) to a deprotection reaction.6063020443.1

[0307] Compounds (70) and / or (71) can be produced by subjecting compound (68) and / or (69) to an alkylation reaction.

[0308] Compounds (72) and / or (73) can be produced by subjecting compound (70) and / or (71) to a halogenation reaction.

[0309] Compounds (74) and / or (75) can be produced by subjecting compound (72) and / or (73) to an aromatic nucleophilic substitution reaction with the corresponding alcohol (7).

[0310] Compounds (66) and / or (67) can be produced by subjecting compound (74) and / or (75) to a coupling reaction with the corresponding compound (29).

[0311] Compounds of Formula (I), which include compounds named above, and their pharmaceutically 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 fdms by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0312] Compound (I) may be administered alone or in combination with one another or with 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.

[0313] The administration mode of the combination of Compound (I) and the concomitant drug 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 concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of6163020443.1Compound (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.

[0314] The dose of the concomitant drug can be appropriately determined based on the dose 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.

[0315] For example, the content of Compound (I) in the combination with a concomitant drug 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.

[0316] 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.

[0317] The content of additives such as a carrier and the like used in the combination of Compound (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.

[0318] Similar contents may be employed even when Compound (I) and a concomitant drug are separately formulated into preparations.

[0319] Generally, one or more of these compounds are administered as a pharmaceutical composition (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 fortheir preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0320] Compound (I) may be administered orally. Oral administration may involve swallowing in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively, or additionally, oral administration may involve mucosal administration (e.g.,6263020443.1buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.

[0321] Formulations suitable for oral administration include solid, semi-solid and liquid systems 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).

[0322] Compound (I) may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0323] 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, antioxidants, 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, Ci-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.

[0324] 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.

[0325] Tablets may also include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active 6363020443.1agents 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.

[0326] 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.

[0327] 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).

[0328] Consumable oral films for human or veterinary use are pliable water-soluble or water-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, 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.

[0329] In addition to dosing requirements, the amount of API in the film may depend on its 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.6463020443.1

[0330] 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.

[0331] Film dosage forms are typically prepared by evaporative drying of thin aqueous films 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.

[0332] Useful solid formulations for oral administration may include immediate release formulations 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.

[0333] Compound (I) may also be administered directly into the blood stream, muscle, or an internal organ of the subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.

[0334] Parenteral formulations are typically aqueous solutions which may contain excipients 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.

[0335] The solubility of compounds which are used in the preparation of parenteral solutions 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.6563020443.1Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug -loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.

[0336] Compound (I) may also be administered topically, intradermally, or transdermally to 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).

[0337] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., Powdeiject™ and Bioject™) injection. Formulations for topical administration may be formulated to be immediate or modified release as described above.

[0338] Compound (I) may also be administered intranasally or by inhalation, typically in the 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.

[0339] Prior to use in a dry powder or suspension formulation, the drug product is usually comminuted 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.

[0340] Capsules, blisters and cartridges (made, for example, from gelatin or hydroxypropylmethyl 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 6663020443.1lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0341] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 pg to about 20 mg of the API per actuation and the actuation volume may vary from about 1 pL to about 100 pL. 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.

[0342] Formulations for inhaled administration, intranasal administration, or both, may be formulated 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.

[0343] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units are typically arranged to administer a metered dose or “puff’ containing from about 10 pg to about 1000 pg of the API. The overall daily dose will typically range from about 100 pg to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

[0344] The active compounds may be administered rectally or vaginally, e.g., in the form of 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.

[0345] Compound (I) may also be administered directly to the eye or ear, typically in the form 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.6763020443.1

[0346] To improve their solubility, dissolution rate, taste-masking, bioavailability, or stability, Compound (I) may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene gly col-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.

[0347] As noted above, one or more compounds of Formula (I), including compounds specifically 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.

[0348] For administration to human patients, the total daily dose of the claimed and disclosed 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.

[0349] As noted above, Compound (I) may be used to treat diseases, disorders and / or conditions associated with NLRP3, i.e., diseases, disorders and / or conditions for which 6863020443.1inhibition 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).

[0350] Compound (I) may be used to treat neurodegenerative diseases and / or conditions associated 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.

[0351] The claimed and disclosed compounds may be combined with one or more other pharmacologically 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.

[0352] In addition to drugs used to improve cognition, Compound (I) may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications 6963020443.1that 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, 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.

[0353] Likewise, Compound (I) may be combined with one or more pharmaceutically active 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.

[0354] Compound (I) may also be combined with one or more pharmaceutically active agents 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, rufmamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.EXAMPLES

[0355] The present invention is explained in detail in the following by referring to Examples, 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.

[0356] In the following Examples, the “room temperature” generally means about 10 °C to about 35 °C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.

[0357] The elution by column chromatography in the Examples was performed under the observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the observation by TLC, 60 F254manufactured by Merck was used as a TLC plate, the solvent7063020443.1used as an elution solvent in column chromatography was used as a developing solvent, and UV detector was used for the detection.

[0358] In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel and the indication of Diol means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel.

[0359] 1H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (5) 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: CDCT (deuterochloroform), DMSO-dr, (deuterodimethylsulfoxide). For the analysis of 'H 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.

[0360] MS was measured by LC / MS. As the ionization method, ESI method, or APCI method 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 tertbutoxycarbonyl 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.

[0361] In Examples, the following abbreviations are used.APCI: atmospheric pressure chemical ionizationAr: argonCDCI3: deuterochloroformCS2CO3: cesium carbonateCH2CI2: dichloromethaneCH3CN: acetonitrileCuBr: copper(I) bromideCui: copper(I) iodideDMA: dimethyl acetamideDME: 1,2-dimethoxyethaneDMSO-dr,: deuterodimethyl sulfoxide7163020443.1ESI: electrospray ionizationEtiO: diethyl etherEtOAc: ethyl acetateEtOH: ethanolHC1: hydrogen chloride1H NMR: proton nuclear magnetic resonanceIPE: diisopropyl etherKOAc: potassium acetateK3PO4: potassium triphosphateLC / MS: liquid chromatograph mass spectrometerM: mol concentrationMeOH: methanolMgSC: magnesium sulfateMS: mass spectrumN2: nitrogenNaHCCE: sodium hydrogen carbonateNa SO4: sodium sulfateNBS: N-bromosuccinimideNIS: N-iodosuccinimideNH4CI: ammonium chloridePd dppQCh’CEECh: l,l'-bis(diphenylphoshino)ferrocene- palladium (II) dichloride dichloromethane complexPE: petroleum etherTHF: tetrahydrofuranTFA: trifluoroacetic acidZn: zinc

[0362] Example 14

[0363] 2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0364] A) 2-fluoro-4-(l-fluorocyclopropyl)-6-methyl -aniline

[0365] Trimethylchlorosilane (1.6 mb) was added to a mixture of 2-fluoro-4-iodo-6-methylaniline (1.03 g), (l,3-dioxoisoindolin-2-yl)-l-fluorocyclopropanecarboxylate (2.00 g), Zn (2.00 g), bis(dichloronickel) bis(2-(2-pyridyl)pyridine) dihydrate (250 mg) and DMA (257263020443.1mL) at -10 °C. The mixture was stirred at -10 °C under N2 for 3 hours. To the mixture were added EtOAc and saturated aqueous NaHCOi solution at 0 °C. The insoluble materials were removed by filtration through a pad of Celite, and washed with EtOAc. The organic layer of the filtrate was separated, washed with water and brine, dried over NaiSO4 and concentrated in vacuo. The residue was purified by column chromatography (basic silica gel, eluted with EtOAc in hexane) to give the title compound (321 mg). MS: [M+H]+184.0.

[0366] B) 2-bromo-l-fhioro-5-(l-fluorocyclopropyl)-3 -methylbenzene

[0367] Pentyl nitrite (0.35 mL) was added to a mixture of 2-fluoro-4-(l-fluorocyclopropyl)-6-methyl-aniline (315 mg) and copper(II) bromide (461 mg) in CH3CN (10 mL) at 0 °C. The mixture was stirred at 0 °C under N2 for 30 minutes and at room temperature overnight. To the mixture was added 1 M HC1 aqueous solution at 0 °C. The mixture was stirred at 0 °C for 10 minutes. The mixture was extracted with EtiO. The organic layer was separated, washed with water and brine, dried over NaiSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (291 mg). 'H NMR (400 MHz, DMSO-dr,) 5 1.16-1.27 (2H, m), 1.44-1.57 (2H, m), 2.40 (3H, s), 7.08 (1H, dd, J = 9.7, 2.0 Hz), 7.13 (1H, s).

[0368] C) 2-fluoro-4-(l-fluorocyclopropyl)-6-methyl -benzaldehyde

[0369] 1.6 M n-Butyllithium in hexane (0.90 mL) was added to a mixture of 2-bromo-l-fluoro-5-(l-fluorocyclopropyl)-3 -methylbenzene (287 mg) in THF (6 mL) at -78 °C. The mixture was stirred at -78 °C under Ar for 30 minutes. To the mixture was added DML (0.12 mL) at -78 °C. The mixture was stirred at -78 °C under Ar for 1 hour. To the mixture was added saturated aqueous NH4CI solution and water at -78 °C. The whole mixture was extracted with EtOAc at room temperature. The organic layer was separated, washed with brine, dried over NaiSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (171 mg). MS: [M+H]+197.0.

[0370] D) 2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] - 1 -methyl-7H-purin-6-one

[0371] A mixture of 5-amino-N-methyl-lH-imidazole-4-carboxamide (189 mg), 2-fluoro-4-(l-fhrorocyclopropyl)-6-methyl-benzaldehyde (255 mg), and iodine (166 mg) in DMSO (4.5 mL) was stirred at 120 °C under N2 for 5 hours. To the mixture was added 10% Na2S2O3 aqueous solution at room temperature, and the mixture was extracted with EtOAc / THL. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (165 mg). MS: [M+H]+317.0.7363020443.1

[0372] E) 2- [2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0373] NBS (100 mg) was added to a mixture of 2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methylphenyl]-l-methyl-7H-purin-6-one (114 mg) in CH3CN (2.5 mL) at room temperature. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give a mixture (147.3 mg) of 8-bromo-2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-l -methyl -7H-purin-6-one and succinimide.

[0374] To the mixture (146.4 mg) of 8-bromo-2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-l-methyl-7H-purin-6-one and succinimide in DMF (3 mL) was added sodium hydride (46.5 mg, 60% dispersion in paraffin liquid) at 0 °C. The mixture was stirred at 0 °C under N2 for 10 minutes. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (0.19 mL) at 0 °C. The mixture was stirred at room temperature under N2 for 30 minutes. To the mixture was added saturated aqueous NH4CI solution at 0 °C, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give a mixture (191.1 mg) of 8-bromo-2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] - 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one, 8-bromo-2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methylphenyl] - 1 -methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one and 1 -(2-trimethylsilylethoxymethyl)pyrrolidine-2, 5-dione.

[0375] To the mixture (190.4 mg) of 8-bromo-2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methyl -phenyl] - 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one, 8-bromo-2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methyl-phenyl] - 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one and l-(2-trimethylsilylethoxymethyl)pyrrolidine-2, 5-dione in THF (4 mL) was added 28% sodium methoxide in MeOH (0.40 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a mixture of EtOAc and saturated aqueous NH4CI solution at 0 °C. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methylphenyl] -8-methoxy- l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one or 2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one (51.1 mg) and 2-[2-fhioro-4-(l-fluorocyclopropyl)-6-methylphenyl] -8-methoxy- l-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one or 2-[2- 7463020443.1fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one (27.6 mg).

[0376] TFA (1.5 mL) was added to a mixture of 2-[2-fhioro-4-(l-fluorocyclopropyl)-6-methylphenyl] -8-methoxy- l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one or 2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one (50.0 mg) and 2-[2-fhioro-4-(l-fluorocyclopropyl)-6-methylphenyl] -8-methoxy- l-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one or 2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one (26.7 mg) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was poured into a mixture of EtOAc and saturated aqueous NaHCCE solution at 0 °C, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was stirred in THF (2 mL) and 9% NEE aqueous solution (1 mL) at room temperature for 15 minutes. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (37.9 mg), which was stirred in Et2O (1 mL) and IPE (1 mL) at room temperature for 30 minutes. The precipitated solid was collected, washed with EtiO / IPE (1:1), and dried to give the title compound (32.0 mg).1H NMR (400 MHz, DMSO-d6) 5 1.25-1.36 (2H, m), 1.50-1.63 (2H, m), 2.16 (3H, s), 3.25 (3H, s), 4.04 (3H, s), 7.11 (1H, d, J = 10.5 Hz), 7.17 (1H, s), 12.70-13.02 (1H, m).

[0377] Example 882-[2,6-dichloro-4-(l-fhiorocyclopropyl)phenyl]-8-methoxy-l-methyl-l,7-dihydro-6H-purin-6-one

[0378] A) 2,6-dichloro-4-iodo-aniline

[0379] To a mixture of 2,6-dichloroaniline (6.4 mL) in EtOH (200 mL) were added Ag2SO4(16.5 g) and iodine (13.44 g). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and the insoluble material was removed by filtration though a pad of Celite, and the fdter cake was washed with EtOAc. The fdtrate was washed with 20% Na2S2O2aqueous solution and brine, dried over anhydrous Na2SO4and concentrated in vacuo to give the title compound (14.55 g). MS: [M+H]+287.8.

[0380] B) 2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) benzaldehyde

[0381] Pentyl nitrite (5.7 mL) was added to a mixture of 2,6-dichloro-4-iodo-aniline (8.0 g) in anhydrous CH3CN (120 mL) at room temperature. The mixture was stirred for 57563020443.1minutes, and copper(I) bromide (5.98 g) was added portionwise at room temperature. The mixture was stirred at 60 °C for 2.5 hours under Ar. The mixture was diluted with EtOAc and quenched with saturated aqueous NH4CI solution. The organic layer was separated, washed with water and brine, dried over anhydrous MgSC>4, and filtered through a short pad of basic silica gel. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give crude 2-bromo-l,3-dichloro-5-iodo-benzene (4.52 g).

[0382] Trimethylchlorosilane (4.9 mL) was added dropwise over 20 minutes to a mixture of crude 2-bromo-l,3-dichloro-5-iodo-benzene (4.52 g) obtained above, (1,3-dioxoisoindolin-2-yl) 1 -fluorocyclopropanecarboxylate (4.80 g), bis(2,2-bipyridine)Ni2(p-Cl)2(Cl)2(H2O)2 (CAS No: 1012368-96-5) (781 mg) and zinc (6.72 g) in DMA (85 mL) at -5 °C under Ar. The mixture was stirred at -5 °C to -10 °C under Ar for 1.5 hours. The mixture was diluted with EtOAc and quenched with saturated aqueous NaHCOa solution at 0 °C. The insoluble material was removed by filtration through a pad of Celite, and the filter cake was washed with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give crude 2-bromo-l,3-dichloro-5-(l-fluorocyclopropyl)benzene (1.65 g).

[0383] To a mixture of crude 2-bromo-l,3-dichloro-5-(l-fluorocyclopropyl)benzene (1.65 g) in THF (60 mL) at -78 °C was added dropwise n-butyllithium (1.6 M in hexane, 4.4 mL). The mixture was stirred at -78 °C under Ar for 20 minutes. Then DMF (675 pL) was added to the mixture at -78 °C. The mixture was stirred at -78 °C under Ar for 15 minutes. The mixture was quenched with saturated aqueous NH4CI solution at -78 °C and extracted with EtOAc at room temperature. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (573 mg). MS: [M+H]+233.0.

[0384] C) 2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl]- 1 -methyl-7H-purin-6-one

[0385] A mixture of 2,6-dichloro-4-(l-fluorocyclopropyl)benzaldehyde (573 mg), 5-amino-N -methyl- lH-imidazole-4-carboxamide (362 mg) and iodine (312 mg) in DMSO (40 mL) was stirred at 120 °C under Ar overnight. To the mixture was added 10% Na2S2O3 aqueous solution at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4 and7663020443.1concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give the title compound (386 mg). MS: [M+H]+352.9.

[0386] D) 8-bromo-2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl]- 1 -methyl-7H-purin-6-one

[0387] A mixture of 2-[2,6-dichloro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-7H-purin-6-one (386 mg) and NBS (292 mg) in CH3CN (90 mb) was stirred at reflux for 4.5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (400 mg). MS: [M+H]+430.9.

[0388] E) 8-bromo-2- [2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one or 8-bromo-2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one

[0389] Sodium hydride (111 mg, 60% purity in mineral oil) was added to the mixture of 8-bromo-2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl]- 1 -methyl-7H-purin-6-one (400 mg) in DMF (20 mL) at 0 °C. The mixture was stirred at 0 °C under Ar for 10 minutes. Then 2-(trimethylsilyl)ethoxymethyl chloride (0.49 mL) was added to the mixture at 0 °C. The mixture was stirred at 0 °C under Ar for 30 minutes. The mixture was quenched with saturated aqueous NH4CI solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compounds (309 mg). MS: [M+H]+561.0.

[0390] F) 2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0391] To a solution of 8-bromo-2-[2,6-dichloro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one or 8-bromo-2-[2,6-dichloro-4-( 1 -fluorocyclopropyl)phenyl]- l-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one (309 mg) in THF (50 mL) was added 28% sodium methoxide in MeOH (4.0 mL) at 0°C. The mixture was stirred 0 °C for 1 hour, and then poured into a mixture of EtOAc and saturated aqueous NH4CI solution at 0 °C. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue (280 mg).

[0392] To the residue (280 mg) was added TFA (2 mL), and the mixture was stirred at 0 °C for 1 hour. The mixture was concentrated in vacuo and azeotroped with toluene. The mixture was dissolved in THF (4 mL), and 9% NH3 aqueous solution (2 mL) was added. The mixture was stirred for 15 minutes and then partitioned between water and EtOAc. The 7763020443.1organic layer was separated, washed with brine, dried over anhydrous NaiSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The obtained solid was triturated with IPE to give the title compound (103 mg).1HNMR (400 MHz, DMSO-ok) 5 1.34-1.46 (2H, m), 1.55-1.69 (2H, m), 3.26 (3H, s), 4.03-4.08 (3H, m), 7.55 (2H, s), 12.84-13.05 (1H, m).

[0393] Example 105

[0394] 2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8-methoxy-l-methyl- 1,7-dihydro-6H-purin-6-one

[0395] A) 2,6-dichloro-N-[(2,4-dimethoxyphenyl) methyl] -5 -nitro-pyrimidin-4-amine

[0396] To a mixture of 2,4,6-trichloro-5-nitro-pyrimidine (25.0 g) and N, N-diisopropylethylamine (21.2 g) in THF (300 mL) was added a solution of (2,4-dimethoxyphenyl)methanamine (18.3 g) in THF (60 mL) dropwise and the mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSO-i, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (30 g). 'H NMR (400 MHz, DMSO- d) 53.78 (3H, s), 3.84 (3H, s), 4.55 (2H, d, J= 6.0 Hz), 6.51 (1H, dd, J= 8.0, 2.4 Hz), 6.61 (1H, d, J= 2.4 Hz), 7.13 (1H, d, J= 8.4 Hz), 9.13 (1H, t, J= 5.6 Hz).

[0397] B) tert-butyl N-(2,6-dichloro-5-nitro-pyrimidin-4-yl)-N-[(2,4-dimethoxyphenyl) methyl] carbamate

[0398] To a solution of 2,6-dichloro-N-[(2,4-dimethoxyphenyl) methyl]-5-nitro-pyrimidin-4-amine (19.0 g) in THF (500 mL) was added NaH (4.23 g, 60% purity in mineral oil) at 0 °C for 30 minutes and the mixture was degassed and purged with N2 for three times. Then di -tert-butyl dicarbonate (17.3 g) was added dropwise to the mixture at 0 °C, and the mixture was stirred at 20 °C for 30 minutes under N2. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSO-i, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (22.5 g). ’H NMR (400 MHz, DMSO-de) 5 1.29 (9H, s), 3.66 (3H, s), 3.74 (3H, s), 4.94 (2H, s), 6.47 (1H, d, J= 8.0 Hz), 6.55 (1H, s),7.14 (1H, d, J= 8.4 Hz).

[0399] C) tert-butyl N-(2-chloro-5-nitro-6-oxo-lH-pyrimidin-4-yl)-N-[(2,4-dimethoxyphenyl) methyl] carbamate

[0400] To a solution of tert-butyl N-(2,6-dichloro-5-nitro-pyrimidin-4-yl)-N-[(2,4-dimethoxyphenyl) methyl] carbamate (19.0 g) in DME (300 mL) was added dropwise 2 M 7863020443.1NaOH aqueous solution (62.1 mL) at 0°C and the mixture was stirred at 20°C for 1 hour. The mixture was diluted with 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 column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (13.6 g). 'H NMR (400 MHz, DMSO-t / e) 5 1.28 (9H, s), 3.66 (3H, s), 3.73 (3H, s), 4.70 (2H, s), 6.44 (1H, dd, J= 8.4, 2.4 Hz), 6.47 (1H, d, J= 2.4 Hz), 7.23 (1H, d, J= 8.4 Hz).

[0401] D) tert-butyl N-[2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-5-nitro-6-oxo-lH-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate

[0402] To a solution of tert-butyl N-(2-chloro-5-nitro-6-oxo-lH-pyrimidin-4-yl)-N-[(2,4-dimethoxyphenyl)methyl]carbamate (500 mg) and 2-[2-(difhioromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (562 mg) in DME (5 mL) and H2O (1 mL) were added Pd(dppf)Ch-CH2C12 (92.6 mg) and CS2CO3 (554 mg) at 25 °C. The mixture was stirred at 110 °C for 6 hours under N2. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (380 mg). MS: [M+H]+609.3.

[0403] E) tert-butyl N-[2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-5-nitro-6-oxo-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate

[0404] To a mixture of tert-butyl N-[2-[2-(difhioromethyl)-6-fluoro-4-(l-fhiorocyclopropyl)phenyl]-5-nitro-6-oxo-lH-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (278 mg), CS2CO3 (447 mg) and 4A molecular sieves (250 mg) in DMF (4 mL) was added methyl iodide (68.1 mg) at 0 °C. The mixture was stirred at 25 °C for 12 hours under N2. A second reaction was performed following the same procedure using tert-butyl N-[2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-5-nitro-6-oxo-lH-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (380 mg), CS2CO3 (610 mg) and 4A molecular sieves (300 mg) and Mel (93.1 mg) in DMF (8 mL). Both reaction mixtures were combined and filtered, and the filter cake was washed with EtOAc. The mixture was diluted with 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 column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (520 mg). MS: [M+H]+623.3.7963020443.1

[0405] F) tert-butyl N-[5-amino-2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-6-oxo-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate

[0406] To a solution of tert-butyl N-[2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-5-nitro-6-oxo-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (520 mg) in EtOH (8 m ) and H2O (1.6 m ) were added Fe (233 mg) and NH4CI (447 mg) at 25 °C. The mixture was stirred at 60 °C for 2 hours under N2. The mixture was filtered and the filter cake was washed with EtOAc. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (430 mg). MS: [M+H]+593.4.

[0407] G) 2-[2-(difluoromethyl)-6-fluoro-4-( l-fluorocyclopropyl)phenyl]-9-[(2,4-dimethoxyphenyl)methyl] - 1 -methyl-7H-purine-6, 8-dione

[0408] To a solution of tert-butyl N-[5-amino-2-[2-(difhroromethyl)-6-fluoro-4-(l-fhiorocyclopropyl)phenyl]-l-methyl-6-oxo-pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (380 mg) in DMF (6 mb) was added sodium methoxide (139 mg, 30% purity in MeOH) at 25 °C. The mixture was stirred at 60 °C for 2 hours under N2. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (320 mg). MS: [M+H]+519.2.

[0409] H) 2-[2-(difluoromethyl)-6-fluoro-4-( l-fluorocyclopropyl)phenyl]-9-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-l-methyl-purin-6-one

[0410] To a solution of 2-[2-(difhioromethyl)-6-fhioro-4-(l-fluorocyclopropyl)phenyl]-9-[(2, 4-dimethoxyphenyl)methyl]-l-methyl-7H-purine-6, 8-dione (320 mg) in toluene (6 mb) were added Ag2CO3 (340 mg) and iodomethane (350 mg) at 25 °C. The mixture was stirred at 50 °C for 14 hours under N2. The mixture was filtered and the filter cake was washed with EtOAc. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (250 mg). MS: [M+H]+533.3.

[0411] I) 2-[2-(difluoromethyl)-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl] -8 -methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0412] To solution of 2-[2-(difluoromethyl)-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-9-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-l-methyl-purin-6-one (250 mg) in CH2Q2 (18063020443.1mL) was added TFA (2 mL) at 25 °C. The mixture was stirred at 60 °C for 6 hours under N2. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: 55-Boston Prime C18 150x30 mm, 5 pm; Mobile phase: [H2O (0.05%NH3H20+10mMNH4HC03)-ACN]; Gradient: 30%-50% ACN over 10 minutes) to give the title compound (64.2 mg). 'H NMR (400 MHz, DMSO-de) 5 1.38-1.41 (2H, m), 1.60-1.66 (2H, m), 3.25 (3H, s), 4.04 (3H, s), 7.03 (1H, t, J= 54.0 Hz), 7.49-7.53 (2H, m), 12.95 (1H, brs).

[0413] Example 108

[0414] 2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0415] A) 6-(benzyloxy)-2-chloro-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

[0416] To a stirred 1HF (50 mL) was added lithium diisopropylamide (2 M in 1HF, 33.2 mL) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 5 minutes. Then 6-(benzyloxy)-2-chloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine (20 g) in THF (50 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 30 minutes. To the above mixture was added l,2-dibromo-l,l,2,2-tetrachloroethane (33.2 g) in THF (100 mL) dropwise at -78 °C. The mixture was stirred at 25 °C for 16 hours and quenched with saturated aqueous NH4CI solution at 25 °C. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in PE) to give 6-(benzyloxy)-8-bromo-2-chloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine (18.6 g). To a mixture of 6-(benzyloxy)-8-bromo-2-chloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine (18.6 g) in MeOH (300 mL) was added silver(I) oxide (27.3 g) in portions at 25 °C under N2. The mixture was stirred at 60 °C for 16 hours, and then cooled to room temperature. The mixture was filtered, and the filter cake was washed with CH2C12. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in PE) to give the title compound (8.71 g). MS: [M+H]+421.2.

[0417] B) 6-(benzyloxy)-2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

[0418] To a solution of 6-(benzyloxy)-2-chloro-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1.26 g) and 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (970 mg) in 8163020443.1DME (18 mL) and H2O (4.3 mL) were added l,l-bis(di-tert-butylphosphino)ferrocene palladium dichloride (193 mg) and K2CO3 (1.23 g) at 25 °C. The mixture was stirred at 90 °C for 4 hours under N2. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (910 mg). MS: [M+H]+585.2.

[0419] C) 2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one

[0420] To a mixture of 6-(benzyloxy)-2-(2-(difluoromethyl)-4-(l -fluorocyclop ropyl)-6-methylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1 g) in MeOH (13.4 mL) was added Pd / C (10% palladium on carbon) (269 mg). The mixture was placed under H2 (1 atm). The mixture was stirred at room temperature for 30 minutes, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound (698 mg). MS: [M+H]+495.1.

[0421] D) 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-methoxy-l-methyl-9-((2-(trimethylsilyl)ethoxy)methyl)-l,9-dihydro-6H-purin-6-one

[0422] To a mixture of 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-l,9-dihydro-6H-purin-6-one (698 mg) and K2CO3 (585 mg) in DMF (25.6 mL) was added methyl iodide (0.176 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (369 mg). MS: [M+H]+509.1.

[0423] E) 2-[2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-l-methyl- 1,7-dihydro-6H-purin-6-one

[0424] TFA (5 mL) was added to 2-(2-(difhroromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-methoxy- 1 -methyl-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one (369 mg) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was quenched with saturated aqueous NaHCO3 solution at 0 °C, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (195 mg).1HNMR(400 MHz, DMSO-d6) 5 1.26-1.35 (2H, m), 1.52-1.67 (2H,8263020443.1m), 2.09 (3H, s), 3.13 (3H, s), 4.04 (3H, s), 6.69-7.04 (1H, m), 7.44 (1H, s), 7.48 (1 H, s), 12.70-13.00 (1H, m).

[0425] Example 109

[0426] (Raor. S'„)-2-|2-(difluoromcthyl)-4-( l-fliiorocyclopropyl)-6-mcthylphcnyl |-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0427] 2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (195 mg) was separated by chiral SFC (Column:CHIRALPAK IJ(FPOOl) (20 mmID x 250 mmL, 5 pm); Mobile phase: CO2 / 2 -propanol = 90 / 10 (v / v)). The desired fraction (shorter retention time) was concentrated under vacuum by oil pump at 10 °C to give the title compound (95.3 mg, shorter retention time). 'H NMR (400 MHz, DMSO-d6) 5 1.28-1.35 (2H, m), 1.53-1.63 (2H, m), 2.08 (3H, s), 3.13 (3H, s), 4.04 (3H, s), 6.86 (1H, t, J= 54.8 Hz), 7.44 (1H, s), 7.48 (1H, s), 12.83 (1 H, brs).

[0428] Example 110

[0429] (Saor / ? J-2-|2-(difluoromcthyl)-4-( l-fluorocyclopropyl)-6-methylphenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0430] 2-(2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methylphenyl)-8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (195 mg) was separated by chiral SFC (Column:CHIRALPAK IJ(FPOOl) (20 mmID x 250 mmL, 5 pm); Mobile phase: CO2 / 2 -propanol = 90 / 10 (v / v)). The desired fraction (longer retention time) was concentrated under vacuum by oil pump at 10 °C to give the title compound (96.1 mg, longer retention time). 'H NMR (400 MHz, DMSO-d6) 5 1.28-1.34 (2H, m), 1.54-1.61 (2H, m), 2.08 (3H, s), 3.13 (3H, s), 4.04 (3H, s), 6.86 (1H, t, J= 54.4 Hz), 7.44 (1H, s), 7.48 (1H, s), 12.65 (1 H, brs).

[0431] Example 116

[0432] 2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0433] A) 2-bromo-6-fluoro-4-iodo-aniline

[0434] To a solution of 2-bromo-6-fluoro-aniline (50 g) in DMF (500 mL) was added NIS (74 g) at 0 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was added into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (79 g). ‘HNMR (400 MHz, DMSO-d6) 55.52 (2H, brs), 7.41 (1H, d, J= 10.0 Hz), 7.51 (1H, s).8363020443.1

[0435] B) 2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) aniline

[0436] To a mixture of 2-bromo-6-fluoro-4-iodo-aniline (20 g), (l,3-dioxoisoindolin-2-yl) 1 -fluorocyclopropanecarboxylate (31.6 g), bis(2,2-bipyridine) Ni2(p-C1)2(C1)2(H2O)2 (CAS No: 1012368-96-5) (3.9 g) was added Zn (33.1 g) in DMA (200 mL). The mixture was degassed and purged with N2 for three times and cooled to -10 °C ~ -5 °C, then trimethylchlorosilane (20.6 g) was added dropwise slowly between -10 °C ~ -5 °C. The mixture was stirred at -10 °C for 2 hours. The mixture was diluted with EtOAc, and quenched with saturated aqueous NaHCCh solution at 0 °C. The insoluble material was removed by filtration through a pad of 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 purified by column chromatography (basic silica gel, eluted with EtOAc in hexane) to give the title compound (6.3 g). 'H NMR (400 MHz, DMSO-de) 5 1.05-1.07 (2H, m), 1.30-1.39 (2H, m), 5.41 (2H, brs), 7.07 (1H, dd, J = 12.0, 1.2 Hz), 7.20 (1H, s).

[0437] C) l-bromo-3-fluoro-5-(l-fluorocyclopropyl)-2-iodobenzene

[0438] A mixture of 2-bromo-6-fluoro-4-(l -fluorocyclopropyl) aniline (13.5 g), CuI (15.6 g), and diiodomethane (72.9 g) in CH3CN (250 mL) was added pentyl nitrite (9.6 g) at 20 °C and the mixture was stirred at 60 °C for 5 hours. The mixture was added into saturated aqueous NH4CI solution 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 column chromatography (silica gel, eluted with hexane) to give the title compound (12.2 g). 'H NMR (400 MHz, CDCh) 5 1.06-1.12 (2H, m), 1.54-1.62 (2H, m), 6.87 (1H, dd, J= 8.4, 2.0 Hz), 7.29 (1H, s).

[0439] D) 2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) benzaldehyde

[0440] To a mixture of l-bromo-3-fluoro-5-(l-fluorocyclopropyl)-2 -iodo-benzene (6 g) in THF (60 mL) (dried with 4A molecular sieves) was degassed and purged with N2 for three times and cooled to 0 °C. Isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 14.1 mL) was added dropwise to the mixture at 0 °C under N2 and then the mixture was stirred at 0 °C for 1 hour under N2. DMF (1.8 g) (dried with 4A molecular sieves) was added dropwise to the mixture at 0 °C under N2 and then the mixture was stirred at 0 °C for 30 minutes under N2. The mixture was diluted with saturated aqueous NH4CI solution at 0 °C under N2 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 column chromatography (silica gel, eluted with EtOAc in hexane) to give the8463020443.1title compound (3.1 g). 'HNMR^OO MHz, DMSO-d6) 5 1.37-1.40 (2H, m), 1.60-1.65 (2H, m), 7.25 (1H, d, J= 12.0 Hz), 7.45 (1H, s), 10.17 (1H, s).

[0441] E) 2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl) phenyl]-l-methyl-7H-purin-6-one

[0442] A mixture of 5-amino-N-methyl-lH-imidazole-4-carboxamide (1.6 g), 2-bromo-6-fluoro-4-(l-fluorocyclopropyl)benzaldehyde (2.5 g) and iodine(4.9 g) in dry DMSO (25 mL) was stirred at 100 °C under N2 for 16 hours. The mixture was quenched with Na2SO3aqueous solution at 25 °C 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 column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.1 g). 'H NMR (400 MHz, DMSO-d6) 5 1.38-1.42 (2H, m), 1.59-1.64 (2H, m), 3.31 (3H, s), 7.41 (1H, d, J= 10.0 Hz), 7.56 (1H, s), 8.16-8.33 (1H, m), 13.38-13.76 (1H, m).

[0443] F) 8-bromo-2-[2-bromo-6-fluoro-4-(l -fluorocyclopropyl) phenyl] -l-methyl-7H-purin-6-one

[0444] A mixture of 2-[2-bromo-6-fluoro-4-(l -fluorocyclopropyl) phenyl] -l-methyl-7H-purin-6-one (1.1 g) and NBS (1 g) in CH3CN (100 mL) was stirred at 50 °C for 16 hours. The mixture was diluted with saturated aqueous NH4CI solution at 0 °C under N2 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1 g).1HNMR (400 MHz, DMSO-d6) 5 1.38-1.42 (2H, m), 1.57-1.62 (2H, m), 3.30 (3H, s), 7.41 (1H, dd, J= 10.4, 1.2 Hz), 7.56 (1H, s), 14.21-14.61 (1H, m).

[0445] G) 8-bromo-2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) phenyl] - 1 -methyl-7 -(2-trimethylsilylethoxymethyl) purin-6-one

[0446] To a solution of 8-bromo-2-[2-bromo-6-fhioro-4-(l-fluorocyclopropyl)phenyl]-l-methyl-7H-purin-6-one (750 mg) in DMF (10 mL) was degassed and purged with N2 for three times and cooled to 0 °C. Then NaH (130 mg, 60% in mineral oil) was added to the mixture at 0 °C under N2. After stirring for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (544 mg, 3.26 mmol) was added to the mixture at 0 °C and it was stirred at 25 °C for 2 hours under N2. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (711 mg). MS: [M+H]+589.0.8563020443.1

[0447] H) 2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8-methoxy-l-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one

[0448] To a solution of 8-bromo-2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl) phenyl]-l-methyl-7-(2 -trimethylsilylethoxymethyl) purin-6-one (700 mg) in THF (10 mL) was added sodium methoxide (192 mg) at 0 °C. The mixture was stirred at 50 °C for 16 hours. The mixture was quenched with 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 column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (285 mg). MS: [M+H]+540.9.

[0449] I) 2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl )phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0450] To a solution of 2-[2-bromo-6-fhroro-4-(l-fluorocyclopropyl)phenyl]-8-methoxy-l-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one (265 mg) in CH2Cl2(3 mL) was added TFA (2 mL) and the mixture was stirred at 25 °C for 4 hours. The mixture was bubbled by N2 for 5 minutes to remove CH2Cl2and TFA to give the residue. The residue was purified by preparative HPLC (Column: 97-Boston Prime C18200x40 mm, 10 pm; Mobile phase: [H2O (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; Gradient: 23%-43% ACN over 15 minutes) to give the title compound (64.2 mg). 'HNMR (400 MHz, DMSO-de) 5 1.37-1.40 (2H, m), 1.57-1.64 (2H, m), 3.28 (3H, s), 4.04 (3H, s), 7.39 (1H, dd, J= 10.0, 1.6 Hz), 7.54 (1H, s), 12.87 (1H, brs).

[0451] Example 117

[0452] (Raor. S'„)-2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0453] 2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (60.0 mg) was separated by chiral SFC (Column: 101-DAICEL CHIRALPAK IM (250 mm x 30 mm, 10 pm); Mobile phase: CO2 / 0.1% NH3·H2O containing MeOH = 50 / 50 (v / v)). The desired fraction (shorter retention time) was concentrated under vacuum at 20 °C to give a residue. The residue was diluted with CH3CN (5 mL) and pure water (5 mL). The remaining solvents were removed by lyophilization to give the title compound (28.6 mg, shorter retention time). 'HNMR (400 MHz, DMSO-de) 5 1.35-1.41 (2H, m), 1.57-1.65 (2H, m), 3.28 (3H, s), 4.04 (3H, s), 7.39 (1H, dd, J= 10.0, 1.2 Hz), 7.54 (1H, s), 12.97 (1H, brs).

[0454] Example 1188663020443.1

[0455] (Saor / ?„)-2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0456] 2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) phenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (60.0 mg) was separated by chiral SFC (Column: 101-DAICEL CHIRALPAK IM (250 mm x 30 mm, 10 pm); Mobile phase: CO2 / 0.1% NH3·H2O containing MeOH = 50 / 50 (v / v)). The desired fraction (longer retention time) was concentrated under vacuum by oil pump at 20 °C to give a residue. The residue was diluted with CH3CN (5 mL) and pure water (5 mL). The remaining solvents were removed by lyophilization to give 2-(2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl) phenyl)-8-methoxy-l-methyl-l,7-dihydro-6H-purin-6-one (25.8 mg, longer retention time). 'H NMR (400 MHz, DMSO-ofc) 5 1.34-1.44 (2H, m), 1.57-1.65 (2H, m), 3.28 (3H, s), 4.04 (3H, s), 7.39 (1H, dd, J= 10.0, 1.2 Hz), 7.54 (1H, s), 12.95 (1H, brs).

[0457] Example 128

[0458] 2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy- 1 -methyl- 1,7-dihydro- 6H-purin-6-one

[0459] A) 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0460] To a mixture of 2-bromo-5-(l-fluorocyclopropyl)-l,3-dimethylbenzene (6.8 g, 27.9 mmol) and bis(pinacolato)diboron (14.1 g) in dioxane (70 mL) were added potassium acetate (8.2 g) and Pd(dppf)Ch-CH2C12 (2.27 g) in portions at 25 °C under N2. The resulting mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was quenched with water at 0 °C, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by preparative HPLC (Column: XB C18 50 x 250 mm, 10 pm; Mobile Phase A: H2O, Mobile Phase B: CH3CN; Flow rate: 100 mL / min; Gradient: 55 % B to 85 % B over 30 minutes) to give the title compound (2.66 g). 'HNMR (400 MHz, DMSO-de) 5 1.05-1.16 (2H, m), 1.32 (12H, s), 1.36-1.49 (2H, m), 2.32 (6H, s), 6.85 (2H, s).

[0461] B) 6-(benzyloxy)-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

[0462] A mixture of tert-butyl 6-(benzyloxy)-2-chloro-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1.41 g), 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (970 mg), 1, 1 -bis(di-tert-butylphosphino)ferrocene palladium dichloride (218 mg) and K2CO3 (1.39 g) in DME (178763020443.1mL) and H2O (4.3 mL) was degassed with Ar and then stirred at 90 °C for 4 hours under Ar. A second reaction was performed following the same procedure using tert-butyl 6-(benzyloxy)-2-chloro-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1.33 g), 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (920 mg), l,l-bis(di-tert-butylphosphino)ferrocene palladium dichloride (207 mg) and K2CO3 (1.31 g) in DME (17 mL) and H2O ( 4 mL). Both reaction mixtures were combined, diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (2.42 g). MS: [M+H]+549.3.

[0463] C) 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one

[0464] To a mixture of 6-(benzyloxy)-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (2.42 g) in MeOH (34.7 mL) was added Pd / C (10% palladium on carbon) (694 mg) under N2. The mixture was placed under H2 (1 atm). The mixture was stirred at room temperature for 30 minutes, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound (1.57 g). MS: [M+H]+459.1.

[0465] D) 2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy- 1 -methyl-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one

[0466] To a mixture of 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-l,9-dihydro-6H-purin-6-one (1.57 g) and K2CO3 (1.42 g) in DMF (61.1 mL) was added methyl iodide (0.428 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.09 g). MS: [M+H]+473.2.

[0467] E) 2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0468] TFA (18 mL) was added to 2-(4-(l-fhiorocyclopropyl)-2,6-dimethylphenyl)-8-methoxy-l-methyl-9-((2-(trimethylsilyl)ethoxy)methyl)-l,9-dihydro-6H-purin-6-one (1.09 g) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was quenched with saturated aqueous NaHCO3 solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried 8863020443.1over anhydrous NaiSC and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The resulting material was recrystallized from EtOH to give the title compound (640 mg). 'H NMR (400 MHz, DMSO-d6) 5 1.16-1.25 (2H, m), 1.44-1.55 (2H, m), 2.04 (6H, s), 3.16 (3H, s), 4.04 (3H, s), 7.10 (2H, s), 12.81 (1H, br s).

[0469] Example 139

[0470] 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0471] A) l-chloro-3-(difluoromethyl)-2-nitrobenzene

[0472] To amixture of 3-chloro-2 -nitrobenzaldehyde (10.0 g) in toluene (200 mL) was added diethylaminosulfur trifluoride (11 mL) at 0 °C. The mixture was stirred at room temperature under N2 overnight. The mixture was poured into saturated aqueous NaHCCE solution at 0 °C. The organic layer was separated, washed with water and brine, dried over anhydrous NaiSC and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc / hexane) to give the title compound (10.7 g). 'H NMR (400 MHz, DMSO-d6) 5 7.09-7.44 (1H, m), 7.81-7.86 (2H, m), 7.99-8.07 (1H, m)..

[0473] B) 2-chloro-6-(difluoromethyl)aniline

[0474] To a mixture of 1-chloro-3-(difluoromethyl)-2-nitrobenzene (10.7 g), EtOH (160 mL) and water (40 mL) were added NH4CI (29.6 g) and iron (14.4 g) at room temperature. The mixture was stirred at 60 °C for 4 hours. The insoluble material was removed by filtration through a pad of Celite and washed with EtOAc. The filtrate was neutralized with saturated aqueous NaHCOi solution at room temperature. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (6.46 g). MS: [M+H]+177.8.

[0475] C) 2-chloro-6-(difluoromethyl)-4-iodoaniline

[0476] To a mixture of 2-chloro-6-(difluoromethyl)aniline (5.46 g) in EtOH (125 mL) were added silver(I) sulfate (10.0 g) and iodine (8.1 g) at 0 °C. The mixture was stirred at 0 °C for 1 hour. To the mixture was added 10% Na2S2O3aqueous solution at 0 °C. The mixture was stirred at room temperature for 1 hour. The insoluble materials were removed by filtration through a pad of Celite, and washed with EtOAc. The filtrate was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO48963020443.1and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (8.73 g). MS: [M+H]+303.7.

[0477] D) 2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)aniline

[0478] To a mixture of 2-chloro-6-(difluoromethyl)-4-iodoaniline (16.9 g), (1,3-dioxoisoindolin-2-yl) 1-fluorocyclopropanecarboxylate (31.6 g), bis(2,2-bipyridine) Ni2(μ-Cl)2(Cl)2(H2O)2(CAS No: 1012368-96-5) (2.35 g) and Zn (16.9 g) in DMA (205 mL) was added trimethylchlorosilane (13 mL) at -10 °C. The mixture was stirred at -10 °C for 2 hours. The mixture was poured into saturated aqueous NaHCCh solution and extracted with Et2O. The inorganic solid was removed by filtration. The organic layer was separated, washed with water and brine, dried over anhydrous MgSC>4 and concentrated in vacuo. The residue was purified by column chromatography (basic silica gel, eluted with EtOAc in hexane) to give the title compound (4.85 g). MS: [M+H]+235.9.

[0479] E) 1 -chloro-3 -(difluoromethyl)-5 -( 1 -fluorocyclopropyl)-2 -iodo-benzene

[0480] n-Amyl nitrite (3.5 mL) was added to a mixture of 2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)aniline (3.94 g) in CH3CN (125 mL) at 0 °C. The mixture was stirred at 0 °C under N2 for 30 minutes. Cui (4.78 g) and diiodomethane (6.8 mL) were added to the mixture at 0 °C. The mixture was stirred under N2 at 60 °C for 5 hours and at room temperature overnight. The mixture was poured into a mixture of saturated aqueous NH4CI solution and EtOAc at room temperature. The organic layer was separated, washed with saturated aqueous NH4CI solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (4.45 g). 'H NMR (400 MHz, DMSO-de) 5 1.26-1.37 (2H, m), 1.45-1.66 (2H, m), 7.08 (1H, t, J= 54.2 Hz), 7.38 (1H, d, J= 2.0 Hz), 7.60 (1H, d, J= 1.1 Hz).

[0481] F) 1 -chloro-3 -(difluoromethyl)-5-(l-fluorocyclopropyl)-2 -vinyl -benzene

[0482] A mixture of l-chloro-3-(difluoromethyl)-5-(l-fluorocyclopropyl)-2 -iodo-benzene (4.45 g), potassium vinyltrifluoroborate (2.15 g), CS2CO3 (6.28 g), and Pd(dppf)C12-CH2C12 (1.05 g) in DME (120 mL) and water (12 mL) was stirred at 90 °C under Ar overnight. To the mixture was added water at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (2.70 g). 'H NMR (400 MHz, DMSO-de) 5 1.24-1.36 (2H, m), 1.49-1.62 (2H, m), 5.46 (1H, dd, J= 17.8, 1.2 Hz), 5.77 (1H, dd, J= 11.6, 1.3 Hz), 6.73-6.85 (1H, m), 7.06 (1H, t, J= 54.3 Hz), 7.52 (1H, s), 7.53 (1H, s).9063020443.1

[0483] G) 2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)benzaldehyde

[0484] To a mixture of 1-chloro-3-(difluoromethyl)-5-(1-fluorocyclopropyl)-2-vinyl-benzene (2.70 g), 2,6-lutidine (5.1 mL) and sodium periodate (14.0 g) in THF (90 mL) and water (30 mL) was added microencapsulated osmium tetroxide (1.39 g) at room temperature. The mixture was stirred at room temperature overnight. The mixture was passed through a pad of Celite. The filtrate was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (2.44 g).1HNMR(400 MHz, DMSO-d6) 5 1.37-1.50 (2H, m), 1.60-1.73 (2H, m), 7.37 (1H, t, J= 54.4 Hz), 7.61 (2H, s), 10.43 (1H, s).

[0485] H) 5-amino-N-methyl-lH-imidazole-4-carboxamide

[0486] To a mixture of methyl 5-nitro-lH-imidazole-4-carboxylate (5.00 g) in MeOH (50 mL) was added 40% methylamine in MeOH (50 mL) at room temperature. The mixture was stirred at 70 °C overnight. The mixture was concentrated in vacuo. The resulting solid was suspended in EtOAc (250 mL) and stirred at room temperature overnight. The solid was collected, washed with EtOAc, and dried to give crude N-methyl-4-nitro-lH-imidazole-5-carboxamide (5.62 g).

[0487] To a mixture of crude N-methyl-5-nitro-lH-imidazole-4-carboxamid (5.62 g), ethanol (200 mL), and water (40 mL) were added NH4CI (6.30 g) and iron (13.0 g) at room temperature. The mixture was stirred at 80 °C overnight. The insoluble material was removed by filtration through a pad of Celite and washed with EtOH / water. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (basic silica gel, eluted with MeOH in EtOAc) to give the title compound (2.62 g). MS: [M+H]+141.0.

[0488] I) 2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-1-methyl-7H-purin-6-one

[0489] A mixture of 5-amino-N-methyl-lH-imidazole-4-carboxamide (725 mg), 2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)benzaldehyde (1.17 g), and iodine (595 mg) in DMSO (18 mL) was stirred at 120 °C under N2 overnight. To the mixture was added 5-amino-N -methyl- lH-imidazole-4-carboxamide (725 mg) at room temperature. The mixture was stirred at 120 °C under N2 overnight. The mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give crude 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-7H-purin-6-one. The crude product was dissolved in EtOAc, and washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography 9163020443.1(silica gel, eluted with EtOAc in hexane) to give the title compound (667 mg). MS: [M+H]+369.0.

[0490] J) 8-bromo-2- [2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-7H-purin-6-one

[0491] NBS (819 mg) was added to a solution of2-[2-chloro-6-(difluoromethyl)-4-(l-fluorocyclopropyl)phenyl]-l-methyl-7H-purin-6-one (1.13 g) in CH3CN (25 mL) at room temperature. The mixture was stirred at 80 °C for 2 hours. To the mixture was added NBS (273 mg) at room temperature. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (618 mg). MS: [M+H]+446.9.

[0492] K) 8-bromo-2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 8-bromo-2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one

[0493] To a solution of 8-bromo-2-[2-chloro-6-(difluoromethyl)-4-(l-fluorocyclopropyl)phenyl]-l-methyl-7H-purin-6-one (618 mg) in DMF (12 mL) were added 2-(trimethylsilyl)ethoxymethyl chloride (0.5 mL) and NaH (117 mg, 60% purity in mineral oil) at 0 °C. The mixture was stirred at room temperature under N2 for 3 hours. To the mixture were added 2-(trimethylsilyl)ethoxymethyl chloride (0.1 mL) and NaH (22 mg, 60% purity in mineral oil) at 0 °C. The mixture was stirred at room temperature under N2 for 1 hour. To the mixture was added saturated aqueous NH4CI solution at 0 °C, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compounds (563 mg). MS: [M+H]+577.0.

[0494] L) 2- [2-chloro-6-(difluoromethyl)-4-( 1 -fluorocy cl opropyl)phenyl] -8 -methoxy- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocy clopropyl)phenyl] -8-methoxy- 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one

[0495] To a mixture (527 mg) of 8-bromo-2-[2-chloro-6-(difluoromethyl)-4-(l-fluorocyclopropyl)phenyl]- l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 8-bromo-2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-1-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one in THF (8 mL) was added 28% sodium methoxide in MeOH (4.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was poured 9263020443.1into a mixture of EtOAc and saturated aqueous NH4CI solution at 0 °C. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (444 mg). MS: [M+H]+529.1

[0496] M) 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0497] TFA (5.0 mL) was added to a mixture (553 mg) of 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl] -8-methoxy- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-7-(2-trimethylsilylethoxymethyl)purin-6-one at 0 °C. The mixture was stirred at room temperature for 90 minutes. The mixture was concentrated in vacuo. The residue was poured into a mixture of EtOAc and saturated aqueous NaHCOa solution at 0 °C, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was stirred in THF (6 mL) and 9% NH₃ aqueous solution (3 mL) at room temperature for 15 minutes. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (407 mg). 'H NMR (400 MHz, DMSO-de) 5 1.36-1.47 (2H, m), 1.57-1.70 (2H, m), 3.19 (3H, s), 4.05 (3H, s), 6.97 (1H, t, J = 54.0 Hz), 7.65 (1H, s), 7.69 (1H, s), 12.73-13.09 (1H, m).

[0498] Example 140

[0499] (Raor. S'„)-2-| 2-chloro-6-(difluoromcthyl)-4-( I -fluorocyclopropyl)phcnyl |-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0500] 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (407 mg) was separated by chiral SFC (Column:CHIRALPAK IG (AV001), 20 mmID x 250 mmL, 5 pm; Mobile phase: CO₂ / EtOH = 60 / 40 (v / v)) to give the title compound (179 mg, shorter retention time).1H NMR (400 MHz, DMSO-de) 5 1.36-1.46 (2H, m), 1.57-1.69 (2H, m), 3.19 (3H, s), 4.05 (3H, s), 6.97 (lH, t, J = 54.0 Hz), 7.65 (1H, s), 7.69 (1H, s), 12.95 (1H, br s).

[0501] Example 141

[0502] (Saor / ?„)-2-| 2-chloro-6-(difluoromcthyl)-4-( I -fluorocyclopropyl)phcnyl |-8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0503] 2-[2-chloro-6-(difluoromethyl)-4-( 1 -fluorocyclopropyl)phenyl]-8-methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-one (407 mg) was separated by chiral SFC (Column:9363020443.1CHIRALPAK IG (AV001), 20 mmID x 250 mmL, 5 pm; Mobile phase: CO₂ / EtOH = 60 / 40 (v / v)) to give the title compound (180 mg, longer retention time). 'H NMR (400 MHz, DMSO-de) 8 1.37-1.48 (2H, m), 1.55-1.71 (2H, m), 3.19 (3H, s), 4.05 (3H, s), 6.97 (lH, t, J = 54.0 Hz), 7.65 (1H, s), 7.69 (1H, s), 12.94 (1H, br s).

[0504] Example 166

[0505] 2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl]-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0506] A) 2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8-ethoxy-l-methyl-l,7-dihydro-6H-purin-6-one

[0507] To a mixture (750 mg) of 8-bromo-2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl)phenyl]- l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 8-bromo-2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl] - 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one in THF (10 mL) was added 20% sodium ethoxide ethanol solution (5.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was poured into a mixture of EtOAc and saturated aqueous NH4CI solution at 0 °C. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give a mixture (703 mg) of 2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8-ethoxy-l-methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one and 2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl] -8-ethoxy- 1 -methyl-7 -(2-trimethylsilylethoxymethyl)purin-6-one. MS: [M+H]+555.1.

[0508] TFA (14 mL) was added to the residue (703 mg) obtained above at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was stirred in THF (14 mL) and 9% NH3 aqueous solution (6 mL) at room temperature for 15 minutes. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (488 mg). 'H NMR (400 MHz, DMSO-de) 5 1.37 (5H, t, J = 7.1 Hz), 1.55-1.68 (2H, m), 3.25-3.29 (3H, m), 4.39-4.53 (2H, m), 7.39 (1H, dd, J = 10.2, 1.3 Hz), 7.55 (1H, s), 12.77-13.02 (1H, m).

[0509] Example 167

[0510] (Raor. S'„)-2-|2-bromo-6-fluoro-4-( I -fluorocyclopropyl)phcnyl |-8-cthoxy- 1-methyl- 1,7-dihydro-6H-purin-6-one9463020443.1

[0511] 2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl]-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (462 mg) was separated by chiral SFC (Column: CHIRALPAK IA (AU001), 20 mmID x 250 mmL, 5 pm; Mobile phase: hexane / EtOH = 20 / 80 (v / v)) to give the title compound (210.6 mg, shorter retention time). 'H NMR (400 MHz, DMSO-dr,) 5 1.32-1.45 (5H, m), 1.54-1.69 (2H, m), 3.28 (3H, s), 4.47 (2H, q, J= 7.0 Hz), 7.39 (1H, dd, J = 10.1, 1.5 Hz), 7.54 (1H, s), 12.90 (1H, br s).

[0512] Example 168

[0513] (Saor / ?„)-2-|2-bromo-6-fliioro-4-(l-fliiorocyclopropyl)phcnyl|-8-cthoxy-l-methyl- 1,7-dihydro-6H-purin-6-one

[0514] 2-[2-bromo-6-fluoro-4-( 1 -fluorocyclopropyl)phenyl]-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one (462 mg) was separated by chiral SFC (Column: CHIRALPAK IA (AU001), 20 mmID x 250 mmL, 5 pm; Mobile phase: hexane / EtOH = 20 / 80 (v / v)) to give the title compound (215 mg, longer retention time).1H NMR (400 MHz, DMSO-de) 5 1.33-1.44 (5H, m), 1.54-1.68 (2H, m), 3.28 (3H, s), 4.47 (2H, q, J= 7.0 Hz), 7.39 (1H, dd, J = 10.1, 1.5 Hz), 7.54 (1H, s), 12.90 (1H, br s). 1.33-1.44 (5H, m), 1.54-1.68 (2H, m), 3.28 (3H, s), 4.47 (2H, q, J= 7.0 Hz), 7.39 (1H, dd, J= 10.1, 1.5 Hz), 7.54 (1H, s), 12.90 (1H, br s).

[0515] Example 182

[0516] 8-ethoxy-2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0517] A) 6-(benzyloxy)-8-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

[0518] A mixture of 6-(benzyloxy)-2-chloro-8-ethoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (400 mg), 2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (400 mg), 1, 1 -bis(di-tert-butylphosphino)ferrocene palladium dichloride (59.9 mg) and K2CO3 (381 mg) in DME (4.93 mL) and H₂O (1.17 mL) was degassed with Ar and then stirred at 90 °C for 5 hours under Ar. To the mixture was added H2O at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (428 mg). MS: [M+H]+563.2.

[0519] B) 8-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one9563020443.1

[0520] To a mixture of 6-(benzyloxy)-8-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (425 mg) in MeOH (4.69 mL) was added Pd / C (10% palladium on carbon) (93.8 mg) under N2. The mixture was placed under H₂ (1 atm). The mixture was stirred at room temperature for 1 hour and then filtered through a pad of Celite. After the filter cake was washed with THF, the filtrate was concentrated under reduced pressure to give the title compound (281 mg). MS: [M+H]+473.1.

[0521] C) 8-ethoxy-2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)- 1 -methyl-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one

[0522] To a mixture of 8-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-l,9-dihydro-6H-purin-6-one (279 mg) and K2CO3 (166 mg) in DMF (7.17 mL) was added methyl iodide (50 pL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (128 mg). MS: [M+H]+487.2.

[0523] D) 8-ethoxy-2-(4-( 1 -fluorocyclopropyl)-2,6-dimethylphenyl)- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0524] TFA (2.0 mL) was added to 8-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6-dimethylphenyl)- 1 -methyl-9-((2-(trimethylsilyl)ethoxy)methyl)- 1,9-dihydro-6H-purin-6-one (125 mg) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was quenched with saturated aqueous NaHCOa solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The resulting material was crystallized from EtOAc / hexane to give the title compound (37 mg). 'H NMR (400 MHz, DMSO-dr,) 5 1.16-1.27 (2H, m), 1.37 (3H, t, J= 7.1 Hz), 1.44-1.57 (2H, m), 2.04 (6H, s), 3.15 (3H, s), 4.47 (2H, q, J= 6.9 Hz), 7.10 (2H, s), 12.61-12.79 (1H, m).

[0525] Example 183

[0526] 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-l-methyl- 1,7-dihydro-6H-purin-6-one

[0527] A) 2-[[6-benzyloxy-2-[2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methyl-phenyl]-8-ethoxy-purin-9-yl]methoxy]ethyl-trimethyl-silane9663020443.1

[0528] A mixture of 6-(benzyloxy)-2-chloro-8-ethoxy-9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purine (1.54 g), 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.73 g), 1,1-bis(di-tert-butylphosphino)ferrocene palladium di chloride (231 mg) and K2CO3 ( 1.47 g) in DME (19.0 mL) and H₂O (4.5 mL) was degassed with Ar and then stirred at 90 °C for 4 hours under Ar. To the mixture was added H2O at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (413 mg). MS: [M+H]+599.2.

[0529] B) 2-[2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methyl-phenyl]-8-ethoxy-9-(2-trimethylsilylethoxymethyl)-lH-purin-6-one

[0530] To a mixture of 2-[[6-benzyloxy-2-[2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methyl-phenyl]-8-ethoxy-purin-9-yl]methoxy]ethyl-trimethyl-silane (413 mg) in EtOH (5.4 mL) was added Pd / C (10% palladium on carbon) (102 mg) under N2. The mixture was placed under H2 (1 atm). The mixture was stirred at room temperature for 30 minutes, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound (290 mg). MS: [M+H]+509.2.

[0531] C) 2-[2-(difluoromethyl)-4-( 1 -fluorocyclopropyl)-6-methyl-phenyl]-8-ethoxy- 1 -methyl-9-(2-trimethylsilylethoxymethyl)purin-6-one

[0532] To a mixture of 2- [2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methyl -phenyl] -8-ethoxy-9-(2 -trimethylsilylethoxymethyl)- lH-purin-6-one (350 mg) and K2CO3 (285 mg) in DMF (12.3 mL) was added methyl iodide (86 pL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (208 mg). MS: [M+H]+523.2.

[0533] D) 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-l-methyl- 1,7-dihydro-6H-purin-6-one

[0534] TFA (1 mL) was added to 2-[2-(difhroromethyl)-4-(l-fhiorocyclopropyl)-6-methyl -phenyl] -8-ethoxy-l-methyl-9-(2 -trimethylsilyl ethoxymethyl)purin-6-one (288 mg) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The resulting material was crystallized from EtOAc and hexane to give the title 9763020443.1compound (150 mg). ’HNMR^OO MHZ, DMSO-d6) 5 1.31 (2H, dd, J= 8.9, 2.1 Hz), 1.37 (3H, t, J= 7.1 Hz), 1.58 (2H, dd, J= 19.5, 1.7 Hz), 2.07-2.13 (3H, m), 3.08-3.17 (3H, m), 4.47 (2H, q, J= 7.1 Hz), 6.86 (1H, t, J= 54.4 Hz), 7.44 (1H, s), 7.48 (1H, s), 12.52-13.09 (1H, m).

[0535] Example 184

[0536] (Raor. S'„)-2-(2-(difluoromcthyl)-4-( I -fliiorocyclopropyl)-6-mcthylphcnyl)-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0537] 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-l-methyl- l,7-dihydro-6H-purin-6-one (150 mg) was separated by chiral SFC (Column:CHIRALPAK IJ (FP001) 20mmID x 250mmL, 5pm; Mobile phase: Carbon dioxide / 2-Propanol = 90 / 10 (v / v)) to give the title compound (40 mg, shorter retention time). 'H NMR (400 MHz, DMSO-de) 5 1.26-1.34 (2H, m), 1.37 (3H, t, J= 7.0 Hz), 1.52-1.64 (2H, m), 2.08 (3H, s), 3.12 (3H, s), 4.46 (2H, q, J= 7.1 Hz), 6.86 (1H, t, J= 54.3 Hz), 7.44 (1H, s), 7.48 (1H, s), 12.80 (1H, br s).

[0538] Example 185

[0539] (Saor / ?„)-2-(2-(difluoromcthyl)-4-( I -fluorocyclopropyl)-6-mcthylphcnyl)-8-ethoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one

[0540] 2-(2-(difluoromethyl)-4-(l-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-l-methyl- l,7-dihydro-6H-purin-6-one (150 mg) was separated by chiral SFC (Column:CHIRALPAK IJ (FP001) 20mmID x 250mmL, 5pm; Mobile phase: Carbon dioxide / 2-Propanol = 90 / 10 (v / v)) to give the title compound (48 mg, longer retention time).1H NMR (400 MHz, DMSO-dr,) 5 1.26-1.34 (2H, m), 1.37 (3H, t, J= 7.0 Hz), 1.53-1.64 (2H, m), 2.08 (3H, s), 3.12 (3H, s), 4.46 (2H, q, J= 7.1 Hz), 6.86 (1H, t, J= 54.3 Hz), 7.44 (1H, s), 7.48 (1H, s), 12.80 (1H, br s).

[0541] The compounds of Examples are shown in Table 1-1 to Table 1-24. MS in the tables means actual measured value. The compounds of Examples 1-189 in the following tables were produced according to the methods described in the above mentioned Examples, or methods analogous thereto.

[0542] Table 1-19863020443.1Example MS Number Compound name Structure[M+H]+2-(4-cycl.opropyi-2-fluoro-6-methylphenyl)-l,8- 1 i 313.1 dimethyl- l,7-dihydro-6H- purin-6-oneN NII J / \ \°yz.z0I18-cyclopropyl-2-(4-cyclopropyl-2-fluoro-6- L o 2 x — v J A 1 339.1 methylphenyl>-l-methyl-l,7-d:hydro-6H-pL:rin-6-oneN^NIM08-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-l- 3 lx — v J A 1 335.2 methyl-l,7-dihydi'o-6H-purin-6-oneN^NliM08-cyclopropyl-2-[4-cyclopropyl-2- 4 (trifluoromethyl)pheriyi]-l-methyl-l,7-dihydic-6bl -purin 375.1 6-oneN^NMM108-cyclopropyl-2-[4-cyclopropyl-2-(difiuoromethyl)-6- Lx — \< II A 15 375.1 fluorophenyl]-l-methyi-l,7-ciihydro-6H-purin-6-oneN^NTiMFVO8-cyclopropyl-2-(4-cyclopiopyl-2-methylphenyi)-l- |x> — II A 16 321.2 methyl-i,7-dlhydro-6H-purin-6-oneN^N8-chl.oro-2-;4-cyclopropyl-2,6-difluorophenyi)-i-metr:yl.7 336.9 1.,7-dihydro-6H-purin-6-one0F8-bromo-2-(4-cyclopropyl-2,6-difli:orophenyl)-l-methyi- 8BM J JL 1 380.9 l.z-dihydro-SH-purin-S-one9963020443.1

[0543] Table 1-28-bromo-2-(4-cyclopropyl-2,6-dimethoxyphenyt)-l- 9 405.0 methyl-l,7-dihydro-6H-pijrin-6-one08-cyclopropyl-2-[2-fluoro-4-(l-fiuorocyclopropyl)-6- 10 — v- II J 1 357.2 methylphenyli"l-methyl-l,7-dihydrO"6H-purin-6-oneN N02-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-8- -o> I — ii j i11 (l-methoxycyclopropyi)-l-methyl-l,7-dihydro-6H-purin- 387.1 6-one0CODJNAZF8-bromo-2-(4-cyclopropyl-2-fl:joio-6-methylphenyi)-l-BrJI J 112 377.0 methyl-1,7-dihydro-6H-purin-6-one A zN NII J / y oz- r \ \_oHN^AN / CHF2-(4-cyclopropyi-2-f luoro -6 -methylphenyl) -8 -methoxy- 13 Z°^ 1 zl 1 329.1 l-methyl-l,7-dihydro-6H-purin-6-one02-[2-:luoro-4-(l-fluorocyclopropyl)-6-methylphenyl]-8- P~ Il 5 114z347.0 methoxy-i-methyl-l,7-dihydro-6H-purin-6-one JL II FF -02-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-l- 15x= / 394.1 methyl-8-{pyridin-2-yl)-l,7-dihydro-6H-purin-6-one II 1 F0“A.8-ethoxy-2-[2-fluoro-4-(l-fluofocyclopropyl)-6- o- 4 J J 1 I16 361.0 methylphenyli-l-methyl- l,7-dihydro-6H-purin-6-one L II Fl= / s^x / \10063020443.1

[0544] Table 1-38-(cyclopiopyloxy)-2-[2-fluoro-4-(i-fiuc»rocyclopropyl)- ^0_ / N^ JA AN / 1117 373.2 6-methylphenyl]-l-methyl-l,7-dihydro-6H-purin-6-one k JI F02-[2-:luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-l- L / v 11 J 118 methyl-8-;i-methyi-lH-pyrazol.-3-yl.)-l(7-dihydro-6H- 397.2N Npurin-6-one02-[2-fluoro-4-;i-fluorocyciopropyl}-6-methyiphenyl]-l- i19 395.2 methyl-8-(pyrlmidln-4-yi)-l,7-dlhydro-6H-pur1r:-6-oneN niV02-[2-ftuoro-4-{l-fluorocyciopropyl)-6-methyiphenyl]-l-FF\ 1 20 z — v 11 A 1 385.1 methyl-8-(trifluoromethyi)-l.,7-dihydro-6H-purin-6-oneF N NUFF^^ \7 08-(cyclopropy[methyi)-2-[2-fluoro-4-(l- / — 11 121 fluorocyclopropyl)-6-methylphenyl]-l-methyl-l,7- 371.1<dihydro-6H-punn-6-oneN NJL 1F8-(l,4"dioxan"2-yl}-2-[2-fluoro-4"(l-fluorocyclopropy[)- 22 A 403.1 6-methylphenyl]-l-methyH,7-dshydro-6H-purin-6-one II J FF^X^ / \08-(l-ftuorocyclopropyi)-2-[2-fiuoro-4-(l- 23 11 J 1 nuorocyclopropyl)-6-methylphenyl]-l-methyl-l,7- 375.1 dihydro-GH-puPri-o-oneN NJL 1F02-[2-: Luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-8- 24 -0 A v JI J. 1F361.1 (methoxymethyl}-l-methyi-l,7-dihydro-6H-purin-6-oneFX> X^ \710163020443.1

[0545] Table 1-408-cyclopropyl-2-[4-(difiuoromethoxy)-2-fluoro-6- 25 P — II J IN F365.1 methylphenyn-l-methyl-l,7-dihydi'o-6H-purin-6-oneF^^^O^FO8-cyclopropyt-l-methyl-2-[2-methyi-4- 26 p* - II 1 I 349.0 (trifluoromethyr}phenyi]-l,7-dihydro-6H-punn-6-oneN^NII J> F F2-[2-fluoro-4-;i-fluorocyciopropyl}-6-methyiphenyl]-l- 27 387.1 methyl-8-(oxolcn-2-yi)-l,7-dihydro-6H-pu:1n-6 one JI J F2-[2-ftuoro-4-{l-fluorocyciopropyl)-6-methyiphenyl]-l- 28 401.1 methyl-8-(oxan-2-yl)-l,7-d:hydro-6H-pi:rin-6-one II J F0212-fluoro4-;i-fluorocyciopropyl;-6-methyipher:yl]- 129 N,1.-dimethyl-6-oxo-6,7-dihydro-lH-purine-8- 7 — JI J 1— NH 374.1 carboxamide Il 1 F02-[2-fluoro-4-;i-fluorocyciopropyl}-6-methyiphenyl]- 30 N, N,ltrimethyl-6-oxo-6,7-dihydro-lH-purine-8- 388.1 carboxamideXNAATS F8-(2,2-di: Luorocyclopropyj)-2-[2-fiuoro-4-(l- 31 nuorocyclopropyl)-6-methylphenyl]-l-methyl-l,7- I 393.1 dihydro-6H-purir: -6-one JI J F0° HN_AN / 2-[2-: Luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-l- 32 \ / - V JI J. 1-2-yl}-l,7-dihydro-6H-purin-6-oneN NZJI:JJ373.1 methyl-8-;oxetan ^ TI 1 FFX^^ / \10263020443.1

[0546] Table 1-58-(1.,l-dilluoroethyl)-2-[2-fluoro-4-(i-fluorocyclopropyi)- 33 F F 381.0 6-methylphenyl]-l-methyl-l,7-dihydro-6H-purin-6-one II I F08-(di:iuoromethyl>-2-[2-:luoro-4-(l-fluorocyclopropyl)-6 \H,NA',34 / — v II A 1F 367.0 methylphenyli-l-methyl- l,7-dihydro-6H-purin-6-one II \ F2-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-8- 35 (l-hydroxycyclobutyl)-l-methyH,7-dihydro-6H-purin-6- 387.1 one212-fluoro-4-;l-fluorocycl0propyl;-6-methyipher:yl]-l- 36 methyl-8-[l-(tiifluoromethyl)cyclopiopyi]-1.,7-dihydio- 425.2 6H-purin-6-one2-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyiphenyl]-i- I37 methyl-8-(2,2,2-triil.uoroethyl)-l,7-dlhyd: O-6M-purin-6- 399.1 one "'SAO. F2-[2-fiuoro-4-(l-fluorocyciopropyl)-6-rr!ethylphenyl]-l- 38 methyl-8-(3-methyioxetan-3-yi)-l,7-dihydro-6H-purin-6- O-If387.2 one08-[cyclopropyl(dilluoro)methyl]-2-[2-fluoio-4-(l.- 39 fluoiocyclopropyl>-6-methylphenyl]-l-methyl-l,7- 407.3 dihydro-6H-purin-6-one iFY i.08-(2,2-difluoroethoxy)-2-[2-fli:oro-4-(l- HN-^AN^,40 \ 1 fluorocyclop:opyl>-6-methylphenylj-l-methyl-l,7- 397.0F II J Fdi hyd ro-6 H -purin -6-one10363020443.1

[0547] Table 1-602-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-l- 41 0 ) — j J 1 373.2 methyl-8-(oxetan-3-yl)-l,7-d:hydro-6H-purin-6-oneNJL 1F02-[2-:luoro-4-(l-fluorocyclopropyl)-6-methyiphenyl]-l- o-(\ J 4 1 I42 methyl-8-[(propan-2-yl)oxy]-l,7-dihydro-6H-pu:1n-6- 375.11 II F oneF^^ \7O~~ 02-[2-ftuoro-4-{l-fluorocycLopropyl)-6-rr!ethyiphenyl]-l- \ o-(\ J JL 1 I43 389.0 methyl-8-[(oxetan-3-yl)oxy]-l,7-dihydro-6H-purin-6-one L II FF^^x / \8-(di:! Uoromethoxy>-2-[2-fluoro-4-( 1-fiuorocyclopropyl)- 44 383.1 6-methylphenyL]-l-methyH,7-ciihydro-6H-purin-6-one8-(dimethy!.amino;-2-[2-fluoro-4-(l-fiuorocyclopropyi)- 45 360.2 6-methylphenyl]-l-methyl-l,7-dihydro-6H-purin-6-oneN" To02-[2-: Luoro-4-(l-fluorocycLopropyl)-6-methyiphenyl]-l- 46 395.1 methyl-8-;pyrazin-2-yl>-l,7-dihydro-6H-purin-6-one N= / Il J FF^^ \702-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-l- f i47 \=N 395.2 methyl-8-(pyrimidin-2-yl)-lJ-dihydro-6H-purin-6-one II 1 F0HN^AN / 2-[2,6-difluoro-4-(l-fluorocyclopropyl)phenyi]-8- 48 o-<\ JI J 1 351.1 methoxy- l-methyl-l,7-dihydro-6H-purln-6-oneN N F10463020443.1

[0548] Table 1-708-i3,6-dihydro-2H -pyran -4-yl}-2-[2-il.uorG-4-(l- 49 flijoiocyclopropyl>-6-methyiphenyl]-l-methyi-l,7- 399.1 dihydro-6H-purin-6-oneF^^ \70C|2-[2-chioro-6-fluoro-4-(l-fluorocyclopropyl>phenyl]-8- 50 II 1 1 367.1 methoxy- 1 -methyl- l,7-dihydro-6H-purin-6-oneN NO F2-[2-id:fiuoi'omethoxy)-6-fluoro-4-(1.- 51 fluorocyclopropyl)phenyl]-8-methoxy-l-methyl-i,7- 399.1 dihydro-6H -purin -6-oneNA<0212-fluoro-4-;l-fluorocyclopropyl;-6-methyipher:yl]-l- 52 methyl-8-(2-rnethyipy:':midiii-4-yl}-1,7-d:hydro-6H-purin-i i 409.2 6-oneN N02-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyipheoyl]-l- i53 methyl-8-(6-methylpyrim!din-4-yl) -1,7 -dihydro-61-1 -purin- 409.2 6-one / N NrlFo' 02-[2-fluoro-4-(l-fluorocyclopropyl)-6-methyiphenyl]-8- 54 (2-methoxypyrimidln-4-yl)-l-methyl-l,7-dlhydro-6H- 425.2 puriri-6-one F^^^ yy2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methyiphenyl]-l -—C° 055 methyl-8-[2-(2-rnethyip:'opoxy)pyrimidin-4-yl]-l, 7- 467.2 dihydro-6H-purin-6-one02-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyiphenyl]-l- 56 393.1 methyl-8-phenyl”l(7-dihydro-6H-purir: -6-oneX= / FF^^ 'TZ10563020443.1

[0549] Table 1-802-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-l- 57 394.1 methyl-8-(pyridin-3-yr}-l,7-dihydro-6H-purin-6-one N=ZII I FF^^ \7F02-[2-fLuoro-4-;i-fluorocycLopropyl)-6-methyiphenyl]-8- 58(2WN^NAA i.F411.2 -fluorophenyl>-l-methyl ■l,7-dihydro-6H -pu: ln-6-one0HN^AN / '2-[2-ethyl-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8- 59 p-<\ JL A 1 361.1 methoxy-l-methyL-l,7-dihydro-6H -purin -6- oneN NF0212-f[uoro-4-;l-fluorocyc[opropyl;-6-methyipher:yl]-8-NX_ / N'TAN / I60 (3-fluoro-l-methyl-lH-pyrazol-4-yl)-l-methyi-l,7- 415.2Jl 1 F dihydro-6H-purin-6-one02-[2-iluoro-4-(l-fluorocyclopro|>yl)-6-methyiphenyl]-l- 61 394.1 methyl-8-;pyridin-4-yl)-l,7-dihydro-6H-purin-6-oneN NUF02-[2-:iuoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-l- r° i62 L / / — N^ J JL mN<!'JX^ 1 384.1 ethyl-8-;i,3-oxazoi-2-yi)-l,7-dihydro-6H-pur:n -6-one02-[2-fiuoro-4-(i-fluorocyclopropyl)-6-methyiphenyl]-l - 63 methyi-8-(l-methyi-1. H-pyrazol-4-yO-l,7-dihydro-6H- 397.3 purin-6-one02-[2-:luoro-4-(l-fluorocyclopropyl)-6-methyiphenyl]-l- \N-N HN^AN / 64 methyl-8-;2-methyi-2H-l,2(3-triazoi-4-yi)-l,7-dihydro- 398.1 6H-puhn-6-one10663020443.1

[0550] Table 1-902-[2--iluoro-4-(l-fluorocyclopropyl}-6-methyiphenyl]-l- 65 methyl-8-;5-methyipynmidin-4-yl)-l,7-dihydro-6H-purin- N / — \\ 11 J 1 409.46-one \N N1 1FF 02-[2-:luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-8- 66 (4-fluoro-l-methy!.-lH-pyrazol-3-yl;-i-methyi-l,7- / N'N 415.3 dihydro-6H-punn-6-one2-[2-: Luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-8- F067 (5-nuoro-l-methyl-lH-pyrazol-4-yl}-l-methyi-l,7- I 415.2 dihydro-SH-purtn -6-one Il 1 F02-[2-:luoro-4-;l-fluorocyc!opropyr)-6-methyiphenyl]-8- / ^N HN^AW / 68 (6-methoxypyrimidin-4-yO-l-methyl-17-dihydro-6H- ( HI I i 425.5 purin-6-one ° 1 JL,F2-]2-fluoro4-;i-fluorocyciopropyl;-6-methyipher:yl]-l- / ?N'n\ i69 methyl-8-(l-methyi-lH-pyrazol-5-yl>-l,7-dihydro-6H- L JI A 1 397.0 purin-6-oneN N1 1F0rs2-[2--iluoro-4-(l-fluorocyclopropyl}-6-methyiphenyl]-l- 70 H / / — JI J 1 400.1 methyl-8-;l,3-th:azol-2-yl)-1.,7-dihydro-6H-purin-6-one0N-F MMV |2-[2-:luoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-l- 71 395.2 methyl-8-;pyridazin-3-yi)-l,7-dihydro-6H -pu:1n-6-one II 1 F0 F8-cyclopropyL-2-(4-cyclopropyL-2-fluoro-6- 72 methylphenyL)-l-(di: Luoromethyl)-l,7-d!hydro-6H-purin- II J 1 375.16-oneN^N11 110763020443.1

[0551] Table 1-1002-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-l- 73 383.2 methyl-8-(lH-pyrazo!-l-yl)-l.,7-c!ihydTO-6H-p:jrin-6-one8-cyclopropyH-(difluoromethyl)-2-[2-fluoro-4-(l- 74 fluorocyclop:opyl>-6-methylphenylj-l,7-dihydro-6H- 393.2 purin-6-one0\l-(difiuoromethyl>-2-[2-fluoro-4-(l-fluorocyclopropyl)-6F75 methylphenyl]-8-(l-methyHH-pyrazol-3-yl)-l,7- L / — v JI A 1 433.2 dihydro-6H -purin -6-one UF2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methyiphenyl]-l- 76OXNY¥ I 409.1 methyl-8-phenoxy-l,7-dihydro-6H-purin-6-one X2-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyiphenyl]-8- 77 i(5-methoxypyridin--2-yl}-l-methyl-l,7-dihydro-6H-purin- / \ - f 424.2 6-oneFJU^2-[2-fLuoro-4-{l-fluorocycLopropyl)-6-rr!ethyiphenyl]-l- 78 methyl-8-{5-methyipyridin-2-yi)-l,7-dihydro-6H-pi:r:n-6- 408.2 oneN-{2-[2-fluoio-4-(1.-:liJOTOcyclopiopyi)-6-methylphenyl]-0H79 l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl}-N- / N^I X X 388.2 methylacetamideN NJL 1F2-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyiphenyl]-i- 80 345.7 methyl-8-(methylamino)-l,7-dlhydro-6H-purin--6-one10863020443.1

[0552] Table 1-112-[2-iluoro-4-(l-fluorocyclopro|>yl)-6-methyiphenyl]-l- 81 methyl-8-;5-methyi-1.,3-thiazol-2-yl)-l,7-d:hydro-6H- 414.3 purin-6-one / \ \w ° 0 "2-[2-:luoro-4-(l-fluorocyclopropyl)-6-methyiphenyl]-l- 82 methyl-8 ■■4-methyi-l,3-thiazol-2-yl)-l,7-d^ydro-6H ■ 414.2 purin-6-one02-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methyiphenyl]-8- / %F HN_AN / 83 (3-fluorooxetan-3-yj)-l-methyl-l,7-dihydro-6H-purin-6- °. y— <\ j J i 391.0 one iAT1F212-fluoro-4-;l-fluorocyclopropyl;-6- 84 (trifliJOTOmethyr)phenyi]-8-methoxy-l-methyi-l,7- 401.2 dihydro-6H-purin-6-oneY Oz- 0|8-cycloPutyl-2-[2-fluoro-4-(l-fiuorocyclopropyi)-6- < / — II J 185 371.1 methylphenylj-l-methyl-l,7-d^ydto-6H -purin-S-oneN N1 1FF^^ \7 0 Fl-(difiuoromethyL)-2-[2-fLuoro-4-{l-fluorocycLopropyl)-686o-<\ J A 1 383.1 methylphenyl]-8-methoxy-l,7-dihydro-6H-purin-6-oneN NJL 1 F02-[2-chiora-4-;l-fiuorocycjopropyl)-6-methyiphenyl]-8- 87 Z0-^ Jl A X 363.1 methoxy-l-methyL-l,7-d!hydro-6H -purin -6-oneN N\XXL2-[2,6-dichioro-4-(l-fluorocyciopropyL)phenyi]-8- 88 383.0 methoxy-l-methyL-l,7-dihydro-6H-purin-6-one10963020443.1

[0553] Table 1-1208-i2,3-dihydrofurG[3,2-b]pyridiP-5-yl)-2J2-fliioro-^-il- Q-N 189 flijoiocyclopropyl>-6-methyiphenyl]-l-methyi-l,7- 436.3 dihydro-6H-pui'in-6-oneNI I F02-[2-:luoro-4-(l-fluorocyclopropyl)-6-methylphenyl]-8- i90 (furo[3,2-b]py!ldin-5-yl) -l-methyl-l,7-dihydro-6H-purin- 434.2 6-onef Nnf\ 0 ifmethyl {2-[2-fluoro-4-( l-fluorocyclopropyl)-6- 91 I methylphenyl]-l-methyl-6-oxo-6,7-dihydro-iH-purin-8- 404.2 yljmethyicarbamate0HN_AN / 8-ethyl-2-[2-fluoro-4-(l-fluorocyclopropyl)-6- 92 / — xs JJ JL 1 345.2 methylphenyl]-l-methyl-1,7-dihydro-6H-purin-6-oneN No2-[2-fluoro-4-(1-fluorocyclopropyl)-6-methyiphenyl]-l - 93 KJLY 359.3 methyl-8-(propan-2-yl)-i,7-dlhydro-6H-purin-6-one IN'VI 1 '=o <kF2-[2-fluoro-4-;i-fluorocyclopropyl)-6-(2,2,2- HN^AN / O>94 triTluoroethoxy)phenylJ-8-methoxy-l-methyl-l(7" o-(\ JI 1 1 431.2 di hyd ro-6 H -p u ri n -6-o n eN N FF'X^5^T72-[2-:luoro-4-(l-fluorocyclopropyl)-6-methylphenyl]- 95 331.1 l. S-dimethyl-lJ-dihydro-SH-pijriri-S-Gnen nrlF0O-A _HN^AN / 2-[2-fluoro-4-(l-f!uorocyclopropy!)-6-methylphenyl]-l- 96 L / - N' 11 1 1 387.1 methyl-8-{oxolan-3-yl)-l,7-dihydro-6H-punn-6-one II J F11063020443.1

[0554] Table 1-1308-(3,3-difluorocyclobuty!.j-2 -[2-fluoro 4-(l- 97 fluoiocyclopropyl>-6-methyiphenyl]-l-methyi-l,7- 407.1 dihydro-6H-purin-6-oneFAA8-cyclopentyl-2-[2-fluoro-4-(l-fluorocyclopropyl)-6- 98 385.2 methylphenyli-l-methyl- l,7-ciihydro-6H-purin-6-oneNA P08-tei't-butyl-2-[2-fLioro-4-(T-: Euorocyclopropyi)-6- 99 4-4NVx 373.2 methylphenyl]-l-methyl-l,7-dihydro-6H-purin-6-one ANAT1-ethyi-2-[2-fiuoro-4-(l-fluorocyciopropyl)-6- A J100 o4NXX 361.1 methylphenyL]-8-methoxy-l,7-dihydro-6H-purin-6-one IN NJMJ08-(azetidin-l-yl)-2-[2"fluoro-4-(l"iluorocyclopropy0-6- 101 372.1 methylpheny[j-l-methyl-l,7-diPydro-6H-purin-6-or:eN NAAL02-[2-: Luoro-4-(l-fluorocycLopropyl)-6-methyiphenyl]-l- 102 OAYX 386.1 methyl-8-;pyrrolidin-l-yl)-i,7-dihydro-6H-purin-6-one IN NAAr8-i3,3-difliJoraazetidin-l-yl)-2-[2-fluoro-4-(1.- 103 fluoiocyclopropyl>-6-methyiphenyl]-l-methyi-l,7- 408.2 dihydro-6H-purin-6-one AA08-(3,3-difiuoropyrfolidifi-l-yl)-2-[2-fluoro-4-(l- 104 fluorocyclop:opyl>-6-methylphenylj-l-methyl-l,7- AAA / A 422.3 di hyd ro-6 H -purin -6-oneF11163020443.1

[0555] Table 1-1402-[2-(difluoromethyl)-6-fluoro-4-(l- \ F105 flijorocyclopropyl>phenyl]-8-methoxy-l-methyi-1.,7- J J 1 383.1 dihydro-6H-purin-6-oneFV0(RsorSa)-2-[2-;difluoromethyl)-6-fiuoro-4-(l- \ Fo-<\ J A 1106 fluorocyclopropyl>phenyl]-8-methoxy-l-methyi-l,7- 383.1 dihydro-6H - purin -6-one FVtR1O\ HN^AN / F(S3orRa)-2-[2-{difluoromethyl)-6-fiuoro-4-(l- ° II Ji i107 fluorocyciopropyl)phenyl]-8-methoxy-1.-methyi-l,7- 383.1 dihydro-6H-purin-6-one I ' Y y,FV1tR2O2-[2-(d:fiuoromethyi)-4-(1.-fiuorocyclopTOpyi)-6- 108 methylphenyL]-8-methoxy-l-methyi-l,7-dihydro-6H- 379.2 purin-6-one vX0iRaor Sa)-2-[2-(difluoromethyl)-4-;l- \ I109 fli:orocyclopropyl)-6-methylphenyl]-8-methoxy-l- 379.1 methyl-i,7-dihydro-6H-purio-6-one Y XtR10(Saor Ra )-2-[2-(di fluoromethyl)-4-; 1- 110 fl:jorocyclopropy[)-6-methylphenyi]-8-methoxy-1.- 379.1 methyl-l,7-dihydro-6H-purin-6-onetR2O F2-[2-chloro-4-(l-fli:orocyciopropyl)-6-methylphenyl]-l- 111 (di:luoromethyl>-8-methoxy-l,7-dihydro-6H-purin-6- °-<\ H j I 399.1 oneN NJL 1FC|X^: J\72-[2-(2,2-difiuoroethoxy)-6-fluoro-4-(l- HN_A °N / OFY>F112 fl:jorocyclopropyi)phenyl]-8-methoxy-l-methyi-1.,7- oY JI J 1 413.2 dihydro-6H-pijriri -6-one 11 J,F11263020443.1

[0556] Table 1-152-[2-(difluoromethoxy)-4-(l-fluorocyclopropyi)-6- 113 methylphenyij-8-methoxy-1.-methyl-l.7-dihydro-6H- 395.4 purin-6-one A? u.°Fyl-(2,2-difLuoroethyl)-2-[2-fluoro-4-(i-fLuorocyclopropyi)-FMNA?F114 6-metbylpheny[]-8-metboxy- 1,7-dihydro -6H- purin-6- zK p-<\ JL A X 397.1 oneN NAALl-(difiuoromethy[)-8-(ciimethylamino)-2-[2-fluoro-4-(l- 115 fluorocyclopropyL>-6-methylphenyL]-l,7-dihydro-6H- 396.2 purin-6-one02-[2-bromo-6-fLuoro-4-(l-fiuorocyctopropyl)pheny[]-8- 116 QAVX A 411.0 methoxy-l-methyL-l,7-dihydro-6H -purin -6-oneN NA 1F0iRgor Sa)-2-[2-bromo-6-fiuoro-4-; 1-Bro^\ JI J I117 nuorocyclopropyl)phenyl]-8-methoxy-l-methyi-l,7-N N411.0 di hyd r o -6 H -p u r i n -•S o n etR10rSaor / ?j-2-[2-bromo-6-fiuoro-4-(i- / NJ'1AI JN / BiR118 fluorocyclopropy[)phenyl]-8-methoxy-l-methyi-l,7- 411.0 dihydfo-6H-piiriri -6-oneN N11FtR2F2-[2-fiuoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]-8- 119 methoxy-l-(2,2,2-trifluoroethyl)-l,7-dihydro-6H-purin-6- p-<\ ji i i 415.2 oneN NJUJ O F1.-idifiuoramethyl)-8-ethyl-2-[2-fiuoro-4-(l- \jAA120 fluorocyclopropy[)-6-methylpheny[]-l,7-dihydro-6H- - v 11 A 1N381.2 puriri-6-one k JI F11363020443.1

[0557] Table 1-1602-[4-(i-chiorocyclopropyl)-2-fiuoro-6-methyiphenyl]-8- JNA l121 o-<\ II J 1metho7AAA 363.1 xy-l-methyi-l,7-dihydro-6H-puri n -6-one II J Cl F / X' \72-[2-:luoro-4-(l-fluorocyclopropyl)-6- / AAf A122 (trifluoromethoxyjphenylj-S-methoxy-l-methyl-l,?"7NAAA 417.1 di hyd ro-6 H -purin -6-oneF2-[2-(difluoromethyi)-6-fiuoro-4-(l- A J123 fluorocyclopropyl>phenyl]-l-ethyl-8-methoxy-l,7- 1 I 397.2 dihydro-SH -purin -6-oneFVA J( / ?aorSa)-2-[2-(difluoromethyl)-6-fiuoro-4-(l- O-<\NY JL I124 fluorocyclopropyl.)phenyl]-l-ethyl-8-methoxy-l,7- 397.1 di hyd ro-6 H -p u ri n -6-o n eNOUJFVtR1A J(SsorRa)-2-[2-(difluoromethyl)-6-fluoro-4-(l- 125 fluorocyclopropyl)phenyl]-l-ethyl-8-methoxy-l,7- 397.1 di hyd r o -6 H -p u ri n -•S o n eFVtR2o2-[2-(l,l-difiiioroethyl)-6-fli'Ofo-4-(l- r. FP JI A 1126 fluorocyclopropyt)phenyl]-8-methoxy-l-methyi-l,7- 397.2 di hyd ro-6 H -p u ri n -6-o n e AJUULFJ \702-[2-chioro-4-(l-fluorocyciopropyl)phenyi]-8-methoxy- 127 °A J J 349.1 l-methyl-l,7-dihydro-6H-purin-6-oneN N2-[4-(l-fiuorocyclopropyl)-2,6-dimethylphenyi]-8- 128 1 343.1 methoxy-l-methyi-l,7-dihydro-6H -purin -6-oneNAXL11463020443.1

[0558] Table 1-178-cyclop: opyl-2--[2-(difiMoror:'tethoxy}-6-fl-Joro--4-(i- 129 flijoiocyclopropyl>phenyl]-l.-(d:fluoromethyi)-l,7- 445.1 dihydro-6H-pui'in-6-oneO r ZZ-- / Coz= £O F ^ HN^AN>- (ff3orSa)-8-cyclopropyi-2-[2-{drfluoromethoxy)-6-FFII J 1130 fluoro-4-( l-fluorocyclopropyi)pheriyl]" T k II F 445.4 (difiiioromethyb-lJ-dihydro-SH-piirin-e-oneF^FtR1O F(S3orRa)-8-cyclopropyi-2-[2-(difluoromethoxy)-6- 131 fluoro-4-(i-flu0rocyclopropyi)phenyl]-l- KXX L II F 445.1 (diftuoromethyL)-l,7-dihydro-6H-purin-6-one °^^ / \F^FtR2O F2-[2-chioro-6-(difluoromethoxy)-4-(l- \' CA0o F— II I I132 fluorocyclopropyl)phenyl]-8-methoxy-l-methyi-i,7- 415.1Xdi hyd ro-6H -purin -6-o r i e JL II F )O Z -n=vb—L Fr.niff3or Ss)-2-[2-chloro-6-(dif[uoromethoxy)-4-(l-- 133 fluorocyclopropyl)phenyl]-8-methoxy-l-methyi-l,7- 415.0 di hyd r o -6 H -p u r i r> ■•S o n eO F ISsorffa)-2-[2-chloro-6-(difiuoromethoxy)-4-(l- \ CAF0-('' J J. 1134 fl:jorocyclopropyi)phenyl]-8-methoxy-l-methyi-l,7- 415.0L II Fdihydro-6H-puriri -6-oneCIX^X / \tR22-[2-:[uoro-4-(l-fluorocyciopropyl)-6-methyiphenyl]- 135 363.1 l. S-dimethoxy-V-dihydro-GH -purin-6-oneiffaorSa)-8-ethoxy-2-[2-f!uoro-4-(i-fluorocyclopropyi)- 136 361.2 S-methylphenyl.j-l methyl-lJ-dihydro-SH-purin-S-one L II FtR111563020443.1

[0559] Table 1-180(SgorRa)-8-ethoxy-2-[2-f!uoro-4-(l-fluorocyclopropyi)- 0-(\ 1 J. 1137 361.2 S-methylphenylJ-l-methyl-lJ-dihydro-SH-purin-e-one L II F ^7 — / \ \tR2o A J2-[2-chloro4-(l-fluorocyciopropyl}phenyl]-l--ethyl-8- 138 oI o-<\ JL A 363.2 methoxy-l,7-dihydro-6H-pur:n-6-oneN No2-[2-chioi'o-6-fdifluoromethyl)-4-(i- r c. Hx l| I C Il139 fluorocyclopropyl)phenyl]-8-rnethoxy-l-methyi-l,7- / N^NAA 399.1 dihydro -6H -purin -6-oneFV0iRaor-Sa)-2-[2-chloro-6-(di:luoromethyl)-4-(1- 140 fluorocyclopropyt)phenyl]-8-methoxy-l-methyi-l,7-- 399.1 di hyd ro-6 H -p u ri n -6-p n e FTXXLFVtR10(S3or ) -2-[2-chloro-6-(difLuoromethyl.)-4-( 1- „_ / N^||X^n / ClO-<\ JI J I141 nuorocyclopropyl)phenyl]-8-methoxy-l-methyi-l,7- 399.1 di hyd r o -6 H -p u ri r> -•S o n e FJUUFVtR22-[2-fluoro-4-;i-fluorocyclopropyl)-6-methyiphenyl]-8- 142 (2-metnoxyethoxy;-l-rnethyl.-l,7-dihydio-6l-l-purin-6- 391.2 oneHN^A NN, O I8-cyclopropyl-2-[2-ftuoro-4-(l-fiuorocycLopropyl)-6- 143 1 / — v J JL 1 373.1 methylpheny[j-l-methoxy-l,7-dihydro-6H-purin-6-oneF Vo2-[2-bromo-4-(i-fluorocyclopropyi)phenyl]-8-rnethoxy- Br144 / °^ A A 1 393.1 l-methyl-l,7-dihydro-6H-purin-6-oneF11663020443.1

[0560] Table 1-190 F2-[2-chloro-4-(l-fluorocyclopropyl)phenyi]-8- 145 cyciopropyl-l-(difluoromethyl)-l,7-dshydro-6H-purin-6- 1 / — V 11 395.1 oneN N02-]2,6-dibron'iO”4-(l-fluorocyclopropyl)phenyli-8- 146 pXYV T 471.0 methoxy- l-methyl-l,7-dihydro-6H-puri n -6-oneN NrX02-[2-bromo-6-chioro-4-;i-fluorocyclopropyl)phenyl]-8- 147 / O4NVA A 427.0 methoxy- 1 -methyl- l,7-dihydro-6H -purin -6-oneNF02-[2-bromo-4-(l-:luorocyclopropyl)-6-methylphenyi]-8- 148 407.0 methoxy-l-methyl-l,7-dihydro-6H-purin-6-one0iff3orSa)"2"[2-fluoro-4-(l-fluorocyclopropyl)-6- 10-< X II J 1149 methylphenyl]-8-methoxy-l-methyl-l,7-dihydro-6H-7JL II F 347.0 purin-6-oneF—tR10(Saor Ra)-2-[2-fluoro-4-(l-flL:orocyclopropyl)-6- 150 methylphenyl]-8-methoxy-l-methyl-l,7-dihydro-6H- L II F 347.0 purin-6-onetR2O F2-[2-chloro-6-{2,2-difluoroethyl)-4-(l- HN^AN^ AF151 nuorocyclopropyl)phenyl]-8-methoxy-l-methyl-l,7- 7° A JI J 1 413.0 di hyd r o -6 H -p u ri ■ ■ -6-o n e II JFCl"^^ \7o 1K Cl2-[2-chioro-4-- l-f!uorocyciopropyl)phenyi]-8- 152 1 / - V J J 1 375.0 cyclopropyl-l-methoxy-l,7-dihydro-6H-purin-6-onev' v11763020443.1

[0561] Table 1-20HNA AN> J2-[2-(d:fiuoromethyl)-4-(l.-fiuorocyclopTOpyi)phenyl]-l- 153 pA A A 379.1 ethyi-8-methoxy-l,7-dihydro-6H-purin-6-one FAJAF >< o —=V0z2-[2-(d:fluoromethyi)-4-(i-fluorocyclopropyl)phenyl]-8- 154 0 A JI Jmethoxy- - e h l l7I AAA 365.0 1 m t y -,7-dihydro-6H-purin-6-oneFAJAA FVA J2-[2-bromo-4-(l-:luorocyclopropyl)phenyl]-l-ethyl-8- 155 pA JI Jmethoxy-17-dihydro7NA’AA 407.0-6H-purin-6-one L JI F0 18-cyclopropyl.-2-[2-(difiuoromethyl)-4-(l■ f.H,NAN'O156 fluorocyciopropyl)phenyl]-l-methoxy-l,7-dihydro-6H- lx*- AT v JI JL 391.1Xz\purin-6-one FUUULo= 7)' F ™z-VO I8-cyclopropyl-2-[2-(difluoromethyl)-6-fluoro-4-(l- KJNVV FIx> — II 1 1157 fluorocyclopropyl.)phenyl]-l-methoxy-l,7-dlhyd: C-6H- A 409.1 purin-6-oneFV2-[2-(dlfluoromethoxy)-4-(l-fluorocyclopropyl)phenyl]- 158 395.1 l-ethyl-8-methoxy-l,7-dihydro-6H-purin-6-one2-[2-bromo-4-(i-flu0rocyclopropyl)phenyl]-8- 159 419.0 cyclopropyl-l-methoxy-l,7-dihydro-6H-punn-6-one2-[2-bromo-6-fluoro-4-(l-fluorocyclopropyl)phenyl]-8- 160 437.0 cyclopropyl-l-methoxy-lJ-dihydro-SH-purln -6-one11863020443.1

[0562] Table 1-21° IBr(RsorSa}-2-[2-bromo-6--iluoro-4-(l- p5- V II J 1161 fluorocyclopropyl)phenyl]-8-cyclopropyi--l--methoxy- II 1 F 437.1 1.7-dihydro--6H-purin-6-onetR1n IBr(Saor.% )-2-[2-bromo-6-:iuoro-4-(l- II J 1162 437.1 fluorocyclopropyl)phenyl]-8-cyclopropyi-l-methoxy- II 1 Fl,7-dihydro-6H-purin-6-onetR202-[2,6-bis(di: Luoromethyl)-4-(l- „ JN^XN / VF163 P~<\ Jl A 1 fluorocyclopropyl)phenyl]-8-rnethoxy-l-methyi-l,7- 415.1FJCU dihydro -6H -purin -6-oneFV0HN^AN / 2-[2-bromo-3-fiuoro-4-(l-fiuorocycLopropyl)phenyi]-8- O-<\ J 1164 425.1 ethoxy-l-methyl-l,7-dihydro-6H-purin-6-one II JFBr" T^ \7FvoHN^AN / 2-[2-bromo-3-fluoro-4-(l-fiuorocyclopropyl)phenyl]-8- p-(\ JI 1165 411.0 methoxy-l-methyi-l,7-dihydro-6H-piirin-6-one II \ FBr|X" \7FV02-[2-brorno-6-fluoro-4-(l-fiuorocyclopropyl)phenyl]-8- 166 425.1 J! JL 1 ethoxy-1.-methyl-l,7-dihydro-6H-purin-6-one0Hf< AN / F(Raor Sa)-2-[2-bromo-6-fiuoro-4-{ 1- J A 1167 425.1 fluorocyclopropyl)pheny!]-8-ethoxy-l-methyi-l,7- II J F dihydro-6H-purin-6-onetR10(Saor / ?a)-2-[2-bromo-6-fiuoro-4-(l- P~^ J A 1168 425.1 fluorocyclopropyl)phenyl]-8-ethoxy-l-methyl-l,7-NTVdi hyd ro-6 H -purin -6-onetR211963020443.1

[0563] Table 1-22o8-bromo-2-[2-f liJOTO-4-(l-f! Uorocyclopropyl)-6- Br-<x J I / 169 395.0 methylphenyl]-l-methyl-l.,7-dihydro-6H-p:jrin-6-oneN^NTS08-bromo-2-(4-cyclopropyl-2,6-dimethylphenyl)-l- Br- J I I170 373.0 methyl-l,7-dihydro-6H-purin-6-oneN^N11 1U Nl|l3-chtoro-2-(8-ethoxy-l-methyl-6-oxo-6,7-dihydro-lH- O-(\ J J 1171 - 388.1 pLirirr2-yl)-5-(l“fli'Ofocyclopropyl)benzofiitfiie1L II F02-[2-bromo-6-ch!oro-4-(l-fiuorocyclopropyl)phenyl]-8-B172 p-(\ J JL 1r441.0 ethoxy-l-methyH,7-dihydro-6H-purin-6-one L II F02-(8"ethoxy-l-methy[-6" Oxo-6,7-dihydro-lH"punn-2-yl)- 173 °~C\ J,1 1 I 368.1 5-(l"iluorocyclopropy0"3-methylbenzonitrileN NJCXL Vo5-(l-: Luorocyclopropyi)-2-(8-methoxy-l-methyi-6-oxo- 174 °4NVV i 354.1 6,7-dihydro-lH-purin-2-yl)-3-methylbenzonitrileN N\7 02-(5-cyclopropyi-3-methylthiophen-2-yl)-8-methoxy-1.- „ / 175 317.1 methyl-17-dihydro-6H-purin-6-oneS\U N3-chloro-5-(l-fluorocyclopropyl)-2-(8-methoxy-l- _JN^N^ l|l176 p— Jl j* T 374.1 methyl-6-Gxo-6,7-dihydro-lH-pudn-2-yl.)benzonitril.ek 1. F12063020443.1

[0564] Table 1-23O F2-[6-cyclopropyl-2-(difluoromethoxy)pyridin-3-yl]-8-177 °-<\ II 7 Y 364.1 methoxy-l-methyl-l,7-dihydro-6H-puri n -6-oneo2-(2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl)-8- (6-hydroxyspiro[3.3]heptan-2-yl)-1-methyl-1,7-dihydro-HO—x / xz-^ Il 1 1178 427.2 6H-purin-6-one F0 F8-cyclopropyl-1-(difluoromethyl)-2-(2-(difluoromethyl)- HN^N>FF179 6-fluoro-4-(1-fluorocyclopropyl)phenyl)-1,7-dihydro-6H- 429.1 purin-6-one UUUFV0 F2-(2-(2,2-difluoroethyl)-6-fluoro-4-(1-180 fluorocyclopropyl)phenyl)-8-methoxy-1-methyl-1,7- 397.1 dihydro-6H-purin-6-oneN N0HN^AN / 2-[2,6-dimethyl-4-(trifluoromethyl)phenyl]-8-methoxy-l,o— (\ JI 1 1181 353.0 methyl-1,7-dihydro-6H-purin-6-oneF F08-ethoxy-2-(4-(l-fluorocyclopropyl)-2,6- 182 p— JI 1 1 357.0 dimethylphenyl)-1-methyl-1,7-dihydro-6H-purin-6-oneN 1jOkL02-(2-(difluoromethyi)-4-(l-fluorocyclopropyl)-6- 183 methylphenyl)-8-ethoxy-l-methyl-l,7-dihydro-6H-purin- 393.0 6-one0(Raor Sa)-2-(2-(difluoromethyl)-4-(1- 184 fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl- 393.1 1,7-dihydro-6H-purin-6-onetR112163020443.1

[0565] Table 1-240(Saor Ra)-2-(2-(difluoromethyl)-4-(1-185 fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl- 393.0 1,7-dihydro-6H-purin-6-oneFVtR2O2-(2-chloro-6-(difluoromethyl)-4-(1- CIo-<\ J A 1186 fluorocyclopropyl)phenyl)-8-ethoxy-l-methyl-l,7- 413.0 di hyd ro-6 H -purin -6-oneFV02-(2,6-dimethyl-4-(trifluoromethyl)phenyi)-8-ethoxy-l- HN. A,N / 1187,o-(\ A 1 367.0 methyl-1,7-dihydro-6H-purin-6-oneF F0\ O'"2-[2-fluoro-4-(l-fluorocyclopropyl)-6-methoxyphenyl]-8- 188 363.1 methoxy-l-methyl-l,7-dihydro-6H-purin-6-oneN^N11 1F'^^ y-XFO2-[4-(l-fluorocyclopropyl)-2-methoxyphenyl]-8-methoxy-l- / A J J 0- 189 ' AAA 345.1 methyl-l,7-dihydro-6H-purin-6-oneA

[0566] BIOLOGICAL ACTIVITY

[0567] The biological activity of the compound of Formula 1 with respect to NLRP3 was determined using the following in vitro method.

[0568] IL- 1 P TR-FRET Assay (reported as percentage of inhibition at 6 pM)

[0569] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in accordance with the provider’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-y (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 #12263020443.1781091) 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 pL 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.

[0570] TNF-a Assay (reported as IC50)

[0571] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in accordance with the provider’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-y 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 (Coming, 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-KB 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 pL) was removed, and TNF-alpha were monitored using an ELISA (Human TNF-a ELISA, R& D systems, Cat # DY210) according to the manufacturer’s instructions. 100% inhibition is determined with positive control, TPCA- 1.

[0572] Data Interpretation

[0573] The percentage of inhibition at 6 pM in the IL- 1 [3 TR-FRET assay was calculated by the following formula: Percentage of inhibition = [1 - (HTRF signaltest - HTRF signal LOW) / (HTRF signalHigh- HTRF signalLow) ] * 100, where HTRF signaltest is the HTRF signal in the well to which test compound is added, HTRF signalLowis the HTRF signal in the well to which 3 pM MCC-950 is added, and the HTRF signalHighis the HTRF signal in the well to which DMSO is added.12363020443.1

[0574] The IC50 values in the TNF-a 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 + 10A[(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.

[0575] Table 2 lists in vitro biological assay data (IL- 1 (3 and TNF-a assay) for the compounds shown in the examples. These assays are described in the section entitled Biological Activity, above.

[0576] Table 2: Biological Assay DataIL-ipExample inhibitory TNF-a IC50No rate (pM)at 6 pM (%)1 102 >302 103 >303 100 >304 105 >305 99 >306 95 >307 34 >308 83 >309 52 >3010 105 >3011 99 >3012 79 >3013 99 >3014 103 >3015 100 >3016 99 >3017 99 >3018 101 >3019 97 >3020 39 >3021 99 >3022 101 >3023 98 >3024 100 >3025 99 >3026 99 >3027 101 >3012463020443.128 100 >3029 99 >3030 80 >3031 101 >3032 97 >3033 99 >3034 80 >3035 100 >3036 100 >3037 100 >3038 100 >3039 99 >3040 98 >3041 99 >3042 100 >3043 101 >3044 100 1.145 100 >3046 97 >3047 99 >3048 100 >3049 100 >3050 100 >3051 99 >3052 97 >3053 83 >3054 99 1855 97 1756 97 >3057 101 >3058 99 >3059 98 >3060 100 >3061 100 >3062 99 >3063 98 >3064 101 >3065 98 >3066 100 >3067 100 >3068 68 >3069 98 >3070 86 >3071 100 >307273 96 >30125 63020443.174 104 >3075 98 >3076 82 >3077 93 >3078 101 >3079 92 >3080 103 >3081 92 2182 80 >3083 97 >3084 98 >3085 97 >3086 97 >3087 99 >3088 99 >3089 99 >3090 101 >3091 91 >3092 100 >3093 100 >3094 94 >3095 98 >3096 100 >3097 99 >3098 99 >3099 98 >30100 102 >30101 99 >30102 99 >30103 98 >30104 102 >30105 102 >30106 97 >30107 98 >30108 95 >30109 103 >30110 102 >30111 100 >30112 104 >30113 99 >30114 101115 100 >30116 100 >30117 101 >30118 95 >30119 99 >30126 63020443.1120 101 >30121 101 >30122 102 >30123 96 >30124 96 >30125 100 >30126 104 >30127 100 >30128 96 >30129 107 >30130 60 >30131 101 >30132 99 >30133 100 >30134 101 >30135 104 >30136 97 >30137 106 >30138 99 >30139 97 >30140 99 >30141 99 >30142 101 >30143 101 >30144 100 >30145 98 >30146 98 >30147 101 >30148 100 >30149 100 >30150 98 >30151 105 >30152 100 >30153 102 >30154 105 >30155 96 >30156 101 >30157 98 >30158 96 >30159 102 >30160 99 >30161 95 >30162 97 >30163 91 >30164 95 >30165 97 >30127 63020443.1166 95 >30167 102 >30168 97 >30169 98 >30170 88 >30171 101 >30172 101 >30173 100 >30174 100 >30175 98 >30176 100 >30177 100 >30178 96 >30179 99 >30180 103 >30181 100 >30182 99183 101184 92185 96186 98187 100188189

[0577] The results showed that compounds of the present invention suppress the production of IL-1J3. It was also confirmed that the compounds of the present invention show more selective to IL- 1 p than TNF-a. These indicate that the compounds inhibit the targeted NLRP3 inflammasome activation pathway with little or no interference of the NF-KB 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.

[0578] The following in vitro assays may be used to assess the ability of a compound of Formula 1 to enter the CNS through the blood-brain barrier.

[0579] Multidrug Resistance Protein 1 (MDR1) Substrate Screening Assay

[0580] Method 1

[0581] Human MDR1-expressing Madine-Darby Canine Kidney (MDCK) cells were cultured, 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 12863020443.1with 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 pmol / 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, STD 100 and R, STD10) / Slope of R, STD 100 and R, STD 10where 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, AtoBwhere Papp, AtoB and Papp, BtoA represent the apparent permeability in the apical-to-basal direction and the basal-to-apical direction, respectively.

[0582] Method 2

[0583] 1. Cell Culture

[0584] MDR1-MDCK I cells were seeded onto polyethylene membranes (PET) in 96-well Coming insert systems at 2.5 x 105cells / mL until to 4-7 days for confluent cell monolayer formation.

[0585] 2. Experimental Procedures

[0586] For control compounds, the transport buffer in the study was HBSS with 10.0 mM HEPES 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 pM bi-directionally in duplicate. Digoxin was tested at 10.0 pM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 pM in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1%. The plate was incubated for 1 hour in CO2 incubator at 37±1 °C, with 5% CO2 at 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 pL supernatant solution was diluted with 150 pL ultra-pure water for LC-MS / MS analysis. In addition, the efflux ratio of each compound was 12963020443.1also 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, followed by the addition of 75 pL of 100 pM lucifer yellow in transport buffer and 250 pL transport buffer in apical and basolateral chambers, respectively. The plate was incubated for 30 minutes at 37 °C with 5% CO2 and 95% relative humidity without shaking. After 30 minutes incubation, 20 pL of lucifer yellow samples were taken from the apical sides, followed by the addition of 60 pL of Transport Buffer. And then 80 pL 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.

[0587] 3. Data Analysis

[0588] The apparent permeability coefficient Papp (cm / s) was calculated using the equation:Papp = (dCr / dt) x Vr / (A x CO)Where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (pM / 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; CO is the initial concentration in the donor chamber (pM).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 CO)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:%Lucifer Yellow = [formula image]Where RFU Apical and RFUBasolateral are the relative fluorescence unit values of lucifer 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 1.0.13063020443.1

[0589] Breast Cancer Resistance Protein (BCRP) Substrate Screening Assay

[0590] Human BCRP-expressing MDCKII cells were cultured, 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 (Coming Life 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 pmol / 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, STD 100 and R, STD10) / Slope of R, STD 100 and R, STD 10where 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, AtoBwhere Papp, AtoB and Papp, BtoA represent the apparent permeability in the apical-to-basal direction and the basal-to-apical direction, respectively.

[0591] Formulation Example 1 (production of capsule)1) compound of Example 1 30 mg2) crystalline cellulose 10 mg3) lactose 19 mg4) magnesium stearate 1 mgtotal 60 mg1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

[0592] Formulation Example 2 (production of tablet)1) compound of Example 1 30 g2) lactose 50 g3) cornstarch 15 g4) calcium carboxymethylcellulose 44 g13163020443.15) magnesium stearate 1 g1000 tablets 140 g in totalThe 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 punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

[0593] 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.13263020443.1

Claims

1. WHAT IS CLAIMED IS1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:3.O5. 7.wherein8.R1is (1) a halogen atom, (2) an optionally substituted Ci-6 alkyl group, (3) an optionally substituted C3-8 cycloalkyl group, (4) an optionally substituted C6-10aromatic hydrocarbon ring group, (5) an optionally substituted 4- to 7-membered heterocyclic group or (6) -CONRaRb;9.L is (1) a bond, (2) -O- or (3) -NRC-;10.R2is (1) an optionally substituted C1-6 alkyl group, (2) an optionally substituted C3-8cycloalkyl group or (3) an optionally substituted C1-6alkoxy group;11.R3is (1) a C6-10aromatic hydrocarbon ring group further having at least two substituents or (2) a 5- or 6-membered aromatic heterocyclic ring further having substituent(s);12.Rais (1) a hydrogen atom or (2) a substituent;13.Rbis (1) a hydrogen atom or (2) a substituent; and14.Rcis (1) a hydrogen atom, (2) an optionally substituted C1-6 alkyl group or (3) an optionally substituted C1-6 alkoxy group.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2is (1) an optionally substituted C1-6 alkyl group or (2) an optionally substituted C3-8 cycloalkyl group.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1is17.(1) a halogen atom,18.(2) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of19.(i) a halogen atom,20.(ii) a C3-8 cyclopropyl group,21.(iii) a C1-6 alkoxy group, and22.13363020443.1(iv) an oxo group,24.(3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of25.(i) a halogen atom,26.(ii) an optionally halogenated C1-6 alkyl group,27.(iii) a C1-6 alkoxy group, and28.(iv) a hydroxy group,29.(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group,30.(5) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of31.(i) a halogen atom,32.(ii) a C1-6 alkyl group,33.(iii) a C1-6 alkoxy group, and34.(iv) 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, or35.(6) -C0NRalRbl(wherein Ralis (1) a hydrogen atom or (2) a C1-6 alkyl group, and Rblis a Ci- 6 alkyl group);36.L is37.(1) a bond,38.(2) -O-, or39.(3) -NRcl- (wherein Rclis a C1-6 alkyl group);40.R2is (1) an optionally halogenated C1-6 alkyl group or (2) a C1-6 alkoxy group; and41.R3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of42.(i) a halogen atom,43.(ii) an optionally halogenated C1-6 alkyl group,44.(iii) an optionally halogenated C3-8 cycloalkyl group, and45.(iv) an optionally halogenated C1-6 alkoxy group.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1is47.(1) a halogen atom,48.(2) a C1-6 alkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of49.13463020443.1(i) a halogen atom,51.(ii) a C3-8 cyclopropyl group, and52.(iii) a C1-6 alkoxy group,53.(3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of54.(i) a halogen atom,55.(ii) an optionally halogenated C1-6 alkyl group,56.(iii) a C1-6 alkoxy group, and57.(iv) a hydroxy group,58.(4) an optionally halogenated Ce-io aromatic hydrocarbon ring group,59.(5) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of60.(i) a halogen atom,61.(ii) a C1-6 alkyl group, and62.(iii) a C1-6 alkoxy group, or63.(6) -CONRalRbl(wherein Ralis (1) a hydrogen atom or (2) a C1-6 alkyl group, and Rblis a Ci-6 alkyl group);64.L is65.(1) a bond,66.(2) -O-, or67.(3) -NRcl- (wherein Rclis a C1-6 alkyl group);68.R2is an optionally halogenated C1-6 alkyl group; and69.R3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of70.(i) a halogen atom,71.(ii) an optionally halogenated C1-6 alkyl group,72.(iii) an optionally halogenated C3-8 cycloalkyl group, and73.(iv) an optionally halogenated C1-6 alkoxy group.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1is a C1-6 alkyl group;75.L is -O-;76.R2is a C1-6 alkyl group; and77.13563020443.1R3is a Ce-io aromatic hydrocarbon ring group further having two or three substituents selected from the group consisting of79.(i) a halogen atom,80.(ii) an optionally halogenated Ci-6 alkyl group, and81.(iii) an optionally halogenated C3-8 cycloalkyl group.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:83.2-[2-fluoro-4-( 1 -fluorocyclopropyl)-6-methylphenyl] -8-methoxy- 1 -methyl- 1,7-dihydro-6H-purin-6-one;84.2-[2,6-dichloro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;85.2-[2-(difluoromethyl)-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;86.2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;87.(Ra or Sa)-2-[2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;88.2-[2-bromo-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;89.(Ra or Sa)-2-[2-bromo-6-fluoro-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;90.2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;91.2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;92.(Ra or Sa)-2-[2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl]-8-methoxy-1-methyl-1,7-dihydro-6H-purin-6-one;93.8-ethoxy-2-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)-1-methyl-1,7-dihydro-6H-purin-6-one;94.2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one;95.(Ra or Sa)-2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one;96.13663020443.1(Sa or Ra)-2-(2-(difluoromethyl)-4-(1-fluorocyclopropyl)-6-methylphenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one; and98.2-(2-chloro-6-(difluoromethyl)-4-(1-fluorocyclopropyl)phenyl)-8-ethoxy-1-methyl-1,7-dihydro-6H-purin-6-one.

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 NLRP3.

8. 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.

9. 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.

10. The method according to claim 9, 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).

11. 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.

12. 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 1.105.13763020443.

113. 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.

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

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

16. The medicament according to claim 14, which is an agent for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

17. The medicament according to claim 14, which is an agent for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

18. The medicament according to claim 17, 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).

19. The medicament according to claim 14, which is an agent for the treatment of a neurodegenerative disease.

20. The medicament according to claim 14, which is an agent for the treatment of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease.

21. The medicament according to claim 14, which is an agent for the treatment of obesity.

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 NLRP3.116.13863020443.

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 disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

24. 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).

25. The use according to claim 24 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).

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 a neurodegenerative 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 Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease28. 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.

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

30. 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.

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

32. The compound according to claim 31, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease127.13963020443.1(NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

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

34. 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.

35. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating obesity.132.14063020443.1

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