US0093 09235B2 (12) United States Patent (10) Patent No.: US 9,309,235 B2 m et al. (45) Date of Patent: Apr. 12, 2016 (54) SGC STIMULATORS 9,061,030 B2 * 6/2015 Kim ..................... CO7D 401/04 9,139,564 B2 * 9/2015 Kim ..................... CO7D 413/14 (71) Applicant: IRONWOOD PHARMACEUTICALS, 2010/0.144864 A1* 6, 2010 Currie .................... A61K 31/04 514,470 INC., Cambridge, MA (US) 2013/O123354 A1* 5, 2013 Currie .................... A61K 31/04 514,470 (72) Inventors: G-Yoon Jamie Im, Cambridge, MA 2013,01784.75 A1* 7, 2013 Moore ................. CO7D 401/04 (US); Rajesh Iyengar, West Newton, 514,245 MA (US); Joel Moore, Lexington, MA 2014/0088071 A1 3/2014 Nakai .................. CO7D 401/04 ...i. s 514,2102 (US); Angelika Fretzen, Somerville, 2014/0323448 A1* 10/2014 Kim ................... A61K 31/4155 MA (US) 514,171 2015,0018353 A1 1/2015 Kim ..................... CO7D 413/14 (73) Assignee: IRONWOOD PHARMACEUTICALS, 514,236.5 INC., Cambridge, MA (US) 2015,0250795 A1* 9, 2015 Kim ..................... CO7D 401/04 424,613 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. WO WO 2011 126903 A2 * 10, 2011 ......... A61K 31,4427 WO 2012OO3405 A1 1, 2012 (21) Appl. No.: 14/428,844 WO 2012O64559 A1 5, 2012 WO 2012O75678 A1 6, 2012 (22) PCT Filed: Sep. 18, 2013 (86). PCT No.: PCT/US2O13/06O295 OTHER PUBLICATIONS S371 (c)(1), International Search Report for PCT/US2013/060295 dated Oct. 25, (2) Date: Mar. 17, 2015 2013. (87) PCT Pub. No.: WO2014/047111 * cited by examiner PCT Pub. Date: Mar. 27, 2014 (65) Prior Publication Data Pririmary Examiner — Al CXaCder RPagano (74) Attorney, Agent, or Firm — Heslin, Rothenberg, Farley US 2015/O274712 A1 Oct. 1, 2015 & Mesiti, P.C. Related U.S. Application Data (60) Provisional application No. 61/702,303, filed on Sep. (57) ABSTRACT 18, 2012. s Compounds of Formula I are described. They are useful as (51) Int. Cl. stimulators of sGC, particularly NO-independent, heme-de A6 IK3I/506 (2006.01) pendent stimulators. These compounds may be useful for CO7D 413/4 (2006.01) treating, preventing or managing various disorders that are A6 IK3I/53 (2006.01) herein disclosed. CO7D 407/14 (2006.01) CO7D 409/14 (2006.01) (52) U.S. Cl. Formula I CPC ............ C07D 413/14 (2013.01); A61 K3I/506 (2013.01); A61 K3I/513 (2013.01); C07D C 407/14 (2013.01); C07D 409/14 (2013.01) R N (JP), (58) Field of Classification Search N CPC. C07D407/14: CO7D 409/14: A61K 31/506; A. / A61K 3.1 F513 R See application file for complete search history. 7 N X (56) References Cited D y S. X D U.S. PATENT DOCUMENTS (J')o 7,300,950 B2 * 1 1/2007 Schindler ............. CO7D405/04 514,405 8,748.442 B2 * 6/2014 Kim ................... A61K 31/4155 514,269 25 Claims, No Drawings US 9,309,235 B2 1. 2 SGC STIMULATORS Treatment with NO-independent sGC stimulators also pro moted Smooth muscle relaxation in the corpus cavernosum of CROSS REFERENCE TO RELATED healthy rabbits, rats and humans, causing penile erection, APPLICATIONS indicating that SGC stimulators are useful for treating erectile dysfunction. This patent application is a 371 filing of PCT/US2013/ NO-independent, heme-dependent, sGC stimulators, such 060295, filed 18 Sep. 2013, which claims the benefit of U.S. as those disclosed herein, have several important differenti Provisional Application No. 61/702.303 filed 18 Sep. 2012, ating characteristics, including crucial dependency on the the disclosures of which are herein incorporated by reference presence of the reduced prosthetic heme moiety for their in their entirety. 10 activity, strong Synergistic enzyme activation when combined with NO and stimulation of the synthesis of c(GMP by direct FIELD OF THE INVENTION stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. The present disclosure relates to stimulators of soluble 15 Additional sGC stimulators with improved potency and guanylate cyclase (sGC), pharmaceutical formulations com specificity for sGC have since been developed. These com prising thereof and their uses, alone or in combination with pounds have been shown to produce anti-aggregatory, anti one or more additional agents, for treating and/or preventing proliferative and vasodilatory effects. various diseases, wherein an increase in the concentration of Since compounds that stimulate sGC in an NO-indepen nitric oxide (NO) or an increase in the concentration of cyclic dent manner offer considerable advantages over other current Guanosine Monophosphate (cGMP) might be desirable. alternative therapies, there is a need to develop novel stimu lators of sGC. They are potentially useful in the prevention, BACKGROUND OF THE INVENTION management and treatment of disorders such as pulmonary hypertension, arterial hypertension, heart failure, atheroscle Soluble guanylate cyclase (sGC) is the primary receptor for 25 rosis, inflammation, thrombosis, renal fibrosis and failure, nitric oxide (NO) in vivo. sGC can be activated via both liver cirrhosis, lung fibrosis, erectile dysfunction, female NO-dependent and NO-independent mechanisms. In sexual arousal disorder and vaginal atrophy and other cardio response to this activation, sGC converts GTP into the sec vascular disorders; they are also potentially useful for the ondary messenger cyclic GMP (cGMP). The increased level prevention, management and treatment of lipid related disor ofcCMP in turn, modulates the activity of downstream effec 30 ders. tors including protein kinases, phosphodiesterases (PDES) and ion channels. SUMMARY OF THE INVENTION In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by The present invention is directed to compounds according sequential reduction of inorganic nitrate. Three distinct iso 35 to Formula I, or pharmaceutically acceptable salts thereof, forms 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 neurotransmis Formula I sion and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle 40 RC relaxation and blood pressure. N Experimental and clinical evidence indicates that reduced Y (JP), bioavailability and/or responsiveness to endogenously pro A duced NO contributes to the development of cardiovascular, R4 endothelial, renal and hepatic disease, as well as erectile 45 dysfunction and other sexual disorders (e.g. female sexual % N disorder or vaginal atrophy). In particular, the NO signaling pathway is altered in cardiovascular diseases, including, for \:S. instance, systemic and pulmonary hypertension, heart failure, X.)o angina, stroke, thrombosis and other thromboembolic dis 50 eases, peripheral arterial disease, fibrosis of the liver, lung or wherein: kidney and atherosclerosis. ring B is a 5-membered heteroaryl ring selected from furan or sGC stimulators are also useful in the treatment of lipid thiophene; related disorders such as e.g., dyslipidemia, hypercholester n is an integer selected from 0 to 3: olemia, hypertriglyceridemia, sitosterolemia, fatty liver dis 55 each J is independently selected from halogen, —CN, a C ease, and hepatitis. aliphatic, —OR or a Css cycloaliphatic group; wherein Pulmonary hypertension (PH) is a disease characterized by each said Caliphatic and each said C.s cycloaliphatic Sustained elevation of blood pressure in the pulmonary vas group is optionally and independently Substituted with up culature (pulmonary artery, pulmonary vein and pulmonary to 3 instances of R: capillaries), which results in right heart hypertrophy, eventu 60 each R is independently selected from hydrogen, a C ally leading to right heart failure and death. In PH, the bioac aliphatic or a C-s cycloaliphatic ring; wherein each said tivity of NO and other vasodilators such as prostacyclin is Caliphatic and each said C.s cycloaliphatic ring is reduced, whereas the production of endogenous vasocon optionally and independently substituted with up to 3 strictors such as endothelin is increased, resulting in exces instances of R". sive pulmonary vasoconstriction. SGC stimulators have been 65 each R is independently selected from halogen, —CN, C used to treat PH because they promote smooth muscle relax alkyl, Ca haloalkyl, —O(C. alkyl) or —O(C- ation, which leads to vasodilation. haloalkyl); US 9,309,235 B2 3 4 each R" is independently selected from halogen, —CN, C 5-membered heteroaryl ring; wherein each said 4 to alkyl, Ca haloalkyl, -O(C. alkyl) or —O(C- 8-membered heterocyclic ring and each said 5-membered haloalkyl); heteroaryl ring optionally contains up to 2 additional het X is selected from N, C-JP or C H: eroatoms independently selected from N, O or S, and is an integer selected from 0 to 3: wherein each said 4 to 8-membered heterocyclic ring and each JP is independently selected from halogen, NO, each said 5-membered heteroaryl ring is optionally and OR', SR, C(O)R’, C(O)OR, C(O)N(R), independently substituted by up to 3 instances of R: CN, N(RP), N(R)C(O)RP, N(R)C(O)ORP, when Jis-N(R)C(O)ORP, the RP group together with the - SORP, -SON(RP), -N (R)SORP, a C- ali oxygen atom attached to the RP group, with the carbon phatic. —(Caliphatic)-R', a Css cycloaliphatic ring, a 6 10 atom of the -C(O)— portion of the N(R')C(O)ORP to 10-membered aryl ring, a 4 to 8-membered heterocyclic group, with the nitrogenatom attached to the R group, and ring or a 5 to 10-membered heteroaryl ring; wherein each with the R group alternatively form a 4 to 8-membered said 4 to 8-membered heterocylic ring and each said 5 to heterocyclic ring or a 5-membered heteroaryl ring; 10-membered heteroaryl ring contains between 1 and 3 wherein each said 4 to 8-membered heterocyclic ring and heteroatoms independently selected from O, N or S; and 15 each said 5-membered heteroaryl ring optionally contains wherein each said C.