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WO 2016/044447 Al 24 March 2016 (24.03.2016) P O P C T

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WO 2016/044447 Al 24 March 2016 (24.03.2016) 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 2016/044447 Al 24 March 2016 (24.03.2016) P O P C T (51) International Patent Classification: ue, Belmont, Massachusetts 02478 (US). IYER, Karthik; C07D 401/14 (2006.01) A61K 31/505 (2006.01) 30 Cambridge Park Drive, Apt. #6121, Cambridge, Mas C07D 413/14 (2006.01) A61K 31/519 (2006.01) sachusetts 02140 (US). IYENGAR, Rajesh R.; 23 Strat C07D 403/04 (2006.01) A61K 31/53 (2006.01) ford Road, West Newton, Massachusetts 02465 (US). IM, C07D 403/14 (2006.01) A61P 9/00 (2006.01) G-Yoon Jamie; 93 1 Massachusetts Avenue, Apt. 604, C07D 417/14 (2006.01) A61P 25/00 (2006.01) Cambridge, Massachusetts 02139 (US). C07D 487/04 (2006.01) A61P 15/00 (2006.01) (74) Agent: FREDERICKS, Kellie S.; Heslin Rothenberg Far C07D 491/10 (2006.01) A61P 3/00 (2006.01) ley & Mesiti P.C., 5 Columbia Circle, Albany, New York C07D 495/04 (2006.01) 12203 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 15/050468 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 116 September 2015 (16.09.201 5) 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, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/05 1,557 17 September 2014 (17.09.2014) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/204,710 13 August 2015 (13.08.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: IRONWOOD PHARMACEUTICALS, INC. (84) Designated States (unless otherwise indicated, for every [US/US]; 301 Binney Street, Cambridge, Massachusetts kind of regional protection available): ARIPO (BW, GH, 02142 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors: BARDEN, Timothy Claude; 19 Intervale TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Road, Salem, Massachusetts 01970 (US). SHEPPECK, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, James Edward; 356 Crittenden Drive, Newtown, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Pennsylvania 19940 (US). RENNIE, Glen Robert; 46 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Elmwood Street #2, Somerville, Massachusetts 02144 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (US). RENHOWE, Paul Allan; 19 Sky View Road, Sud bury, Massachusetts 01776 (US). PERL, Nicholas; 7 Gib- Published: bens Street, Somerville, Massachusetts 02143 (US). NA- KAI, Takashi; 7 Gardner Street, Newton, Massachusetts — with international search report (Art. 21(3)) 02458 (US). MERMERIAN, Ara; 50 Milton Street, — before the expiration of the time limit for amending the Waltham, Massachusetts 02453 (US). LEE, Thomas Wai- claims and to be republished in the event of receipt of Ho; 665 Lowell Street, Unit 60, Lexington, Massachusetts amendments (Rule 48.2(h)) 02420 (US). JUNG, Joon; 111 Wendell Road, Newton, Massachusetts 02459 (US). JIA, James; 4 Jeanette Aven © v o (54) Title: PYRAZOLE DERIVATIVES AS SGC STIMULATORS (57) Abstract: There are described imidazole and pyrazole derivatives which are useful as stimulators of sGC, particularly NO-inde - pendent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed. PYRAZOLE DERIVATIVES AS SGC STIMULATORS CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims priority from US provisional application numbers 62/051,557, filed September 17, 2014, and 62/204,710, filed August 13, 2015. The entire contents of each of these applications are hereby incorporated herein by reference. FIELD OF THE INVENTION [002] The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations comprising them and their uses thereof, alone or in combination with one or more additional agents, for treating and/or preventing various diseases, wherein an increase in the concentration of nitric oxide (NO) or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP) might be desirable. BACKGROUND OF THE INVENTION [003] Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in vivo. sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts GTP into the secondary messenger cyclic GMP (cGMP). The increased level of cGMP, in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels. [004] In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle relaxation and blood pressure. [005] Experimental and clinical evidence indicates that reduced bioavailability and/or responsiveness to endogenously produced NO contributes to the development of cardiovascular, endothelial, renal and hepatic disease, as well as erectile dysfunction and other sexual disorders (e.g. female sexual disorder or vaginal atrophy). In particular, the NO signaling pathway is altered in cardiovascular diseases, including, for instance, systemic and pulmonary hypertension, heart failure, angina, stroke, thrombosis and other thromboembolic diseases, peripheral arterial disease, fibrosis of the liver, lung or kidney and atherosclerosis. [O j s sumulators+ are also useful m the+ treatment+ 01 lipid related+ disorders sucn as e.g., dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis. [007] Pulmonary hypertension (PH) is a disease characterized by sustained elevation of blood pressure in the pulmonary vasculature (pulmonary artery, pulmonary vein and pulmonary capillaries), which results in right heart hypertrophy, eventually leading to right heart failure and death. In PH, the bioactivity of NO and other vasodilators such as prostacyclin is reduced, whereas the production of endogenous vasoconstrictors such as endothelin is increased, resulting in excessive pulmonary vasoconstriction. sGC stimulators have been used to treat PH because they promote smooth muscle relaxation, which leads to vasodilation. [008] Treatment with NO-independent sGC stimulators also promoted smooth muscle relaxation in the corpus cavernosum of healthy rabbits, rats and humans, causing penile erection, indicating that sGC stimulators are useful for treating erectile dysfunction. [009] NO-independent, heme-dependent, sGC stimulators, such as those disclosed herein, have several important differentiating characteristics, including crucial dependency on the presence of the reduced prosthetic heme moiety for their activity, strong synergistic enzyme activation when combined with NO and stimulation of the synthesis of cGMP by direct stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity for sGC have since been developed. These compounds have been shown to produce anti-aggregatory, anti-proliferative and vasodilatory effects. [0010] Since compounds that stimulate sGC in an NO-independent manner offer considerable advantages over other current alternative therapies, there is a need to develop novel stimulators of sGC. They are potentially useful in the prevention, management and treatment of disorders such as pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis, lung fibrosis, erectile dysfunction, female sexual arousal disorder and vaginal atrophy and other cardiovascular disorders; they are also potentially useful for the prevention, management and treatment of lipid related disorders. SUMMARY OF THE INVENTION [0011] The present invention is directed to compounds, or their pharmaceutically acceptable salts, useful as sGC stimulators. Compounds of the invention are depicted in Table IA or Table IB. Table IA Table IB 10 11 [0012] The invention is also directed to a pharmaceutical composition comprising a compound from Table IA or Table IB, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier. The invention is also directed to a pharmaceutical formulation or dosage form comprising the pharmaceutical composition. [0013] The invention also provides a method of treating or preventing a disease, health condition or disorder in a subject in need thereof, comprising administering, alone or in combination therapy, a therapeutically effective amount of a compound from Table IA or Table IB or a pharmaceutically acceptable salt thereof to the subject; wherein the disease, health condition or disorder is a peripheral, pulmonary, hepatic, kidney, cardiac or cerebral
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