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WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T

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WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 498/04 (2006.01) A61K 31/5365 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 519/00 (2006.01) A61P 25/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB20 17/050844 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (22) International Filing Date: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, 15 February 2017 (15.02.2017) MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (25) Filing Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (26) Publication Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/298,657 23 February 2016 (23.02.2016) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, New York, New York 10017 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: CHAPPIE, Thomas Allen; 59 Hemlock Hill DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Road, Carlisle, Massachusetts 0 1741 (US). PATEL, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Nandini Chaturbhai; 34 Mary Ellen Road, Waban, Mas SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, sachusetts 02468 (US). VERHOEST, Patrick Robert; 23 GW, KM, ML, MR, NE, SN, TD, TG). Calvin Road, Newton, Massachusetts 02460 (US). HELAL, Christopher John; 18 Elm Street, Mystic, Con Declarations under Rule 4.17 : necticut 06355 (US). SCIABOLA, Simone; 109 River — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Street, Cambridge, Massachusetts 021 39 (US). LACHAPELLE, Erik Alphie; 69 Richard Brown Drive, — as to applicant's entitlement to apply for and be granted a Uncasville, Connecticut 06382 (US). WAGER, Travis T.; patent (Rule 4.1 7(H)) 465 Washington Street, Apt. 6, Brookline, Massachusetts — as to the applicant's entitlement to claim the priority of the 02446 (US). HAYWARD, Matthew Merrill; 3 Pyrus earlier application (Rule 4.1 7(in)) Court, Old Lyme, Connecticut 06371 (US). Published: (74) Agent: WALDRON, Roy F.; Pfizer Inc., 235 East 42nd Street, MS 235/9/S20, New York, NY 10017 (US). — with international search report (Art. 21(3)) (54) Title: 6,7-DIHYDRO-5H-PYRAZOLO[5,l-B][l,3]OXAZINE-2-CARBOXAMIDE COMPOUNDS R - (57) Abstract: The present invention is directed to PDE4B inhibitors of Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein the substituents R1, R2, R 3, and R are as defined herein. The invention is also directed to pharmaceutical compositions com- o prising the compounds, methods of treatment using the compounds, and methods of preparing the compounds. 6 -Dihydro-5H-pyrazolor5,1 -b\\ 1,31oxazine-2-carboxamide Compounds Field of the Invention The present invention relates to 6,7-dihydro-5/-/-pyrazolo[5,1-0][1 ,3]oxazine compounds of Formula I , which are inhibitors of PDE4 isozymes, especially with a binding affinity for the PDE4B isoform, and to the use of such compounds in methods for treating central nervous system (CNS), metabolic, autoimmune and inflammatory diseases or disorders. Background of the Invention Phosphodiesterases (PDEs) are a class of intracellular enzymes that hydrolyze the second messenger signaling molecules 3',5'-cyclic adenosine monophosphate (cAMP) and guanosine 3',5'-cyclic guanosine monophosphate (cGMP) into the nonsignaling 5' - adenosine monophosphate and 5' - guanosine monophosphate, respectively. cAMP functions as a second messenger regulating many intracellular processes within the body. One example is in the neurons of the central nervous system, where the activation of cAMP-dependent kinases and the subsequent phosphorylation of proteins are involved in acute regulation of synaptic transmission as well as neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP. There are at least ten families of adenylyl cyclases, and eleven families of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron. A principal mechanism for regulating cyclic nucleotide signaling is via phosphodiesterase-catalyzed cyclic nucleotide catabolism. The eleven known families of PDEs are encoded by 2 1 different genes; each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE isozymes may offer particular therapeutic effects, fewer side effects, or both (Deninno, M., Future Directions in Phosphodiesterase Drug Discovery. Bioorganic and Medicinal Chemistry Letters 2012, 22, 6794-6800). The present invention relates to compounds having a binding affinity for the fourth family of PDEs (i.e., PDE4A, PDE4B, PDE4C, and PDE4D), and, in particular, a binding affinity for the PDE4A, PDE4B, and PDE4C isoforms. The PDE4 isozymes carry out selective, high-affinity hydrolytic degradation of the second messenger adenosine 3',5'-cyclic monophosphate (cAMP), and are characterized by sensitivity to inhibition by Rolipram™ (Schering AG); beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models. A number of other PDE4 inhibitors have been discovered in recent years. For example, Roflumilast (Daliresp®), marketed by AstraZenecais approved for severe chronic obstructive pulmonary disease (COPD) to decrease the number of flare- ups or prevent exacerbations of COPD symptoms. Apremilast (Otezla®) has been approved by the U.S. Food and Drug Administration for the treatment of adults with active psoriatic arthritis. While beneficial pharmacological activity of PDE4 inhibitors has been shown, a common side effect of these treatments has been the induction of gastrointestinal symptoms such as nausea, emesis, and diarrhea, which are hypothesized to be associated with inhibition of the PDE4D isoform. Attempts have been made to develop compounds with an affinity for the PDE4B isoform over the PDE4D isoform (See: Donnell, A . F. et al., Identification of pyridazino[4,5-0/indolizines as selective PDE4B inhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20, 2163-7; and Naganuma, K . et al., Discovery of selective PDE4B inhibitors. Bioorganic and Medicinal Chemistry Letters 2009, 19, 3 174-6). However, there remains a need to develop selective PDE4 inhibitors, especially those having an affinity for the PDE4B isoform. In particular, compounds with enhanced binding affinity for the PDE4B isoform over the PDE4D isoform are anticipated to be useful in the treatment of various diseases and disorders of the central nervous system (CNS). The discovery of selected compounds of the present invention addresses this continued need, and provides additional therapies for the treatment of various diseases and disorders of the central nervous system (CNS), as well as metabolic, autoimmune and inflammatory diseases or disorders. Treatment with the PDE4B inhibitors of the present invention may also lead to a decrease in gastrointestinal side effects (e.g., nausea, emesis and diarrhea) believed to be associated with inhibition of the PDE4D isoform (Robichaud, A . et al., Deletion of Phosphodiesterase 4D in Mice Shortens D2-Adrenoreceptor-Mediated Anesthesia, A Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, 110, 1045-1052). Summary of the Invention The present invention is directed to compounds of Formula I : or a pharmaceutically acceptable salt thereof, wherein: R is a substituent selected from the group consisting of (C3 -Cs)cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C6 -Cio)aryl , and (5- to 10-membered)heteroaryl, wherein the (C3 -Cs)cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C6 -Cio)aryl and (5- to 10-membered)heteroaryl are optionally substituted with one to five R5; R2 and R3 are each independently selected from the group consisting of hydrogen, optionally substituted (Ci-Ce )alkyl , (C3 -Cs)cycloalkyl, (4- to 10- membered)heterocycloalkyl, (C6 -Cio)aryl , and (5- to 10-membered)heteroaryl, wherein the (C3-C8 )cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C6 -Cio)aryl , and (5- to 10- membered)heteroaryl are optionally substituted with one to five R6; or R2 and R3 taken together with the nitrogen to which they
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