(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization II International Bureau (10) International Publication Number (43) International Publication Date WO 2014/125397 Al 21 August 2014 (21.08.2014) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 513/04 (2006.01) A61P 3/10 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/542 (2006.01) A61P 25/28 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/IB2014/058777 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 4 February 2014 (04.02.2014) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/765,283 15 February 2013 (15.02.2013) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, New York, New York 10017 (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventors: BECK, Elizabeth Mary; c/o Pfizer Inc., 700 KM, ML, MR, NE, SN, TD, TG). Main Street, Cambridge, Massachusetts 02139 (US). BRODNEY, Michael Aaron; 100 Upland Avenue, New Declarations under Rule 4.17 : ton, Massachusetts 02461 (US). BUTLER, Christopher — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Ryan; 12 1 Spring Lane, Canton, Massachusetts 02021 (US). O'NEILL, Brian Thomas; 111 Meeting House — as to applicant's entitlement to apply for and be granted a Road, Haddam, Connecticut 06438 (US). patent (Rule 4.1 7(H)) (74) Agent: KLEIMAN, Gabriel L.; Pfizer Inc., 235 East 42nd — as to the applicant's entitlement to claim the priority of the Street, New York, New York 10017 (US). earlier application (Rule 4.1 7(in)) (81) Designated States (unless otherwise indicated, for every Published: kind of national protection available): AE, AG, AL, AM, — with international search report (Art. 21(3)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: SUBSTITUTED PHENYL HEXAHYDROPYRANO[3,4-d][l,3]THIAZIN-2-AMINE COMPOUNDS (I) H2N (57) Abstract: The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variables R 1 and R2 are as defined in the spe cification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also dis closed. SUBSTITUTED PHENYL HEXAHYDROPYRANO[3,4-c/][1,3]THIAZIN-2-AMINE COMPOUNDS Field of the Invention The present invention relates to small molecule compounds and pharmaceutically acceptable salts thereof that are inhibitors of β-site amyloid precursor protein (APP) Cleaving Enzyme 1 (BACE1) and inhibitors of BACE2. This invention relates to inhibiting the production of A-beta peptides that can contribute to the formation of neurological deposits of amyloid protein. The present invention also relates to the treatment of Alzheimer's Disease (AD) and other neurodegenerative and/or neurological disorders, as well as the treatment of diabetes in mammals, including humans. More particularly, this invention relates to thioamidine compounds and pharmaceutically acceptable salts thereof useful for the treatment of neurodegenerative and/or neurological disorders, such as AD and Down's Syndrome, related to A-beta peptide production. Background of the Invention Dementia results from a wide variety of distinctive pathological processes. The most common pathological processes causing dementia are Alzheimer's disease ("AD"), cerebral amyloid angiopathy ("CM") and prion-mediated diseases (see, e.g., Haan et al., Clin. Neurol. Neurosurg., 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci., 1989, 94:1-28). AD is a progressive, neurodegenerative disorder characterized by memory impairment and cognitive dysfunction. AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 million by 2050. The accumulation of amyloid- β (Αβ peptides) is believed to be one of the underlying causes of Alzheimer's Disease (AD), which is the most common cause of cognitive decline in the elderly (Hardy & Allsop, Trends Pharmacol Sci., 1991;12(10):383-8; Selkoe, Behav. Brain Res., 2008; 192(1):106-13). Αβ, the major protein constituent of amyloid plaques, is derived from sequential cleavage of the type I integral membrane protein, amyloid precursor protein (APP) by two proteases, β- and γ- secretase. Proteolytic cleavage of APP by the β-site APP cleaving enzymes (BACE1 and BACE2) generates a soluble N-terminal ectodomain of APP (εΑΡΡβ) and the C- terminal fragment C99. Subsequent cleavage of the membrane-bound C99 fragment by the γ-secretase liberates the various Αβ peptide species, of which Αβ40 and Αβ42 are the most predominant forms (Vassar et al., J. Neurosci., 2009; 29(41):12787-94; Marks & Berg, Neurochem. Res., 2010; 35:181-210). Therefore, limiting the generation of Αβ directly through inhibition of BACE1 is one of the most attractive approaches for the treatment of AD, as BACE1 inhibitors could effectively inhibit the formation of all predominant Αβ peptides. In addition, it has been determined that BACE1 knock-out mice had markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions compared with littermate controls. These data suggest BACE1 inhibition as a therapeutic approach to accelerate regeneration and recovery after peripheral nerve damage. (See Farah et al., J. Neurosci., 201 1, 31(15): 5744-5754). Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD. In particular, there is a higher risk of sporadic A D in patients with Type 2 diabetes and A D patients are more prone to Type 2 diabetes (Butler, Diabetes, 53:474-481 , 2004.). Recently, it has also been proposed that A D should be reconsidered as Type 3 diabetes (de la Monte, J. Diabetes Sci. Technol., 2008; 2(6): 1 0 - 3). Of special interest is the fact that AD and Type 2 diabetes share common pathogenic mechanisms and possibly treatments (Park S . A., J. Clin. Neurol., 201 1 ; 7:10-18; Raffa, Br. J. Clin. Pharmacol 201 1 , 7 1(3):365-376). Elevated plasma levels of Αβ, the product of BACE activities, were recently associated with hyperglycemia and obesity in humans (see Meakin et al., Biochem J., 2012, 441(1):285-96.; Martins, Journal of Alzheimer's Disease, 8 (2005) 269-282). Moreover, increased Αβ production prompts the onset of glucose intolerance and insulin resistance in mice (Cozar-Castellano, Am. J. Physiol. Endocrinol. Metab., 302 1373- Ε 1380, 2012; Delibegovic, Diabetologia (201 1) 54:2143-2151). Finally, it is also suggested that circulating Αβ could participate in the development of atherosclerosis in both humans and mice (De Meyer, Atherosclerosis 216 (201 1) 54-58; Catapano, Atherosclerosis 210 (2010) 78-87; Roher, Biochimica et Biophysica Acta 1812 (201 1) 1508-1514). Therefore, it is believed that BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Specifically, BACE1 inhibitors may be potentially useful for increasing insulin sensitivity in skeletal muscle and liver as illustrated by the fact that reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice (see Meakin et al., Biochem. J. 2012, 441(1): 285-96). Of equal interest is the identification of LRP1 as a BACE1 substrate and the potential link to atherosclerosis (Strickland, Physiol. Rev., 88: 887-918, 2008; Hyman, J. Biol. Chem., Vol. 280, No. 18, 17777- 17785, 2005). Likewise, inhibition of BACE2 is proposed as a treatment of Type 2 diabetes with the potential to preserve and restore β-cell mass and stimulate insulin secretion in pre- diabetic and diabetic patients (WO201 1/020806). BACE2 is a β-cell enriched protease that regulates pancreatic β cell function and mass and is a close homologue of BACE1. Pharmacological inhibition of BACE2 increases β-cell mass and function, leading to the stabilization of Tmem27. (See Esterhazy et al., Cell Metabolism 201 1 , 14(3): 365-377). It is suggested that BACE2 inhibitors are useful in the treatment and/or prevention of diseases associated with the inhibition of BACE2 (e.g., Type 2 diabetes, with the potential to preserve and restore β-cell mass and stimulate insulin secretion in pre- diabetic and diabetic patients) (WO201 1/020806). Aminodihydrothiazine or thioamidine compounds are described in US2009/0082560, WO 2009/091016 and WO 2010/038686 as useful inhibitors of the β- secretase enzyme. Co-pending PCT application, PCT/IB2012/054198, filed by Pfizer Inc on August 17, 2012, also describes aminodihydrothiazine compounds that are useful inhibitors of the β-secretase enzyme.