WO 2016/203347 Al 22 December 2016 (22.12.2016) P O PCT
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(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 2016/203347 Al 22 December 2016 (22.12.2016) P O PCT (51) International Patent Classification: (US). PATEL, Nandini Chaturbhai; 34 Mary Ellen Road, C07D 487/14 (2006.01) C07D 498/22 (2006.01) Waban, Massachusetts 02468 (US). SCIABOLA, Simone; C07D 471/14 (2006.01) C07D 513/14 (2006.01) 109 River Street, Cambridge, Massachusetts 02139 (US). C07D 471/22 (2006.01) A61K 31/4985 (2006.01) VERHOEST, Patrick Robert; 23 Calvin Road, Newton, C07D 487/04 (2006.01) A61K 31/506 (2006.01) Massachusetts 02460 (US). WAGER, Travis T.; 465 C07D 491/147 (2006. \) A61P 25/28 (2006.01) Washington Street, Apt. 6, Brookline, Massachusetts 02446 (US). (21) International Application Number: PCT/IB2016/053398 (74) Agent: WALDRON, Roy F.; Pfizer Inc., 235 East 42nd Street, MS 235/9/S20, New York, NY 10017 (US). (22) International Filing Date: June 2016 (09.06.2016) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 62/180,815 17 June 2015 (17.06.2015) US KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, New York, New York 10017 (US). PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (72) Inventors: CHAPPIE, Thomas Allen; 59 Hemlock Hill TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Road, Carlisle, Massachusetts 01741 (US). CHANDRASEKARAN, Ramalakshmi Yegna; 47 Pat- (84) Designated States (unless otherwise indicated, for every ridge Hollow Road, Gales Ferry, Connecticut 06335 (US). kind of regional protection available): ARIPO (BW, GH, HELAL, Christopher John; 18 Elm Street, Mystic, Con GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, necticut 06355 (US). LACHAPELLE, Erik Alphie; 69 TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Richard Brown Drive, Uncasville, Connecticut 06382 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [Continued on nextpage] (54) Title: TRICYCLIC COMPOUNDS AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS (57) Abstract: The present invention is directed to com pounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein the substituents A, R 1, R2, R , R , R , R and n are as defined herein. The inventions also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds and methods of preparing the compounds. R4 Formula I o v o o w o 2016/203347 A i III II II 11 I Illlll 111 III III 11 II lllll 111 lllll llll llll 11llll LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, — as to the applicant's entitlement to claim the priority of SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, the earlier application (Rule 4.1 ?'(in)) GW, KM, ML, MR, NE, SN, TD, TG). Published: Declarations under Rule 4.17: — with international search report (Art. 21(3)) — as to the identity of the inventor (Rule 4.1 7(i)) — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) TRICYCLIC COMPOUNDS AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS Field of the Invention The present invention relates to tricyclic compounds of Formula I, which are inhibitors of PDE4 isozymes, especially with a binding affinity for the PDE4A, PDE4B and PDE4C isoforms, 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 cleave the phosphodiester bond in second messenger molecules adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP serve as secondary messengers in various cellular pathways. 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 mediated 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 Forest Pharmaceuticals, Inc., is 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 - /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 PDE4A, PDE4B, and PDE4C isoforms. In particular, compounds with enhanced binding affinity for the PDE4A, and PDE4B isoforms 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 PDE4 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 a2-Adrenoreceptor-Mediated Anesthesia, A Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, 110, 1045-1 052). Summary of the Invention The present invention is directed to com ounds of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: Ring A is a fused (4- to 8-membered)oxygen-containing heterocycloalkyl ring, a fused phenyl ring, or a fused (5- to 8-membered)nitrogen-containing heteroaryl ring, and, where chemically permissible, the fused (4- to 8-membered)oxygen-containing heterocycloalkyl ring, the fused phenyl ring and the fused (5- to 8-membered)nitrogen- containing heteroaryl ring are optionally substituted with one to six R8; R is selected from the group consisting of (C3-C8)cycloalkyl, (4- to 10- membered)- heterocycloalkyl, (C6 -C-io)aryl and (5- to 14-membered)heteroaryl, and,