(10) Patent No.: US 9309235 B2

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. aliphatic, each said Cls up to 2 additional heteroatoms independently selected cycloaliphatic ring, each said 6 to 10-membered aryl ring, from N, O or S, and wherein each said 4 to 8-membered each said 4 to 8-membered heterocyclic ring and each said heterocyclic ring and each said 5-membered heteroaryl 5 to 10-membered heteroaryl ring is optionally and inde ring is optionally and independently Substituted by up to 3 pendently substituted with up to 3 instances of R: instances of R: each R’ is independently selected from hydrogen, a C when JP is N(R)SORP, the RP group together with the aliphatic, -(C-caliphatic)-R, a Css cycloaliphatic ring, a oxygenatomattached to the RP group, with the sulfur atom 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-mem attached to said oxygenatom in the SORP portion of the bered heteroaryl ring; wherein each said 4 to 8-membered N(R)SORP group, with the nitrogen atom attached to heterocylic ring and each said 5 to 6-membered heteroaryl 25 the R" group, and with the R" group alternatively form a 4 ring contains between 1 and 3 heteroatoms independently to 8-membered heterocyclic ring or a 5-membered het selected from O, N or S; and wherein each said Cali eroaryl ring; wherein each said 4 to 8-membered hetero phatic, each said C.s cycloaliphatic ring, each said 4 to cyclic ring and each said 5-membered heteroaryl ring 8-membered heterocyclic ring, each said phenyl and each optionally contains up to 2 additional heteroatoms inde said 5 to 6-membered heteroaryl ring is optionally and 30 pendently selected from N, O or S, and wherein each said independently substituted with up to 3 instances of R: 4 to 8-membered heterocyclic ring and each said 5-mem each R" is independently selected from hydrogen, a C bered heteroaryl ring is optionally and independently sub aliphatic, —(Caliphatic)-R', a Css cycloaliphatic ring, a stituted by up to 3 instances of R: 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-mem each R is independently selected from halogen, —CN, bered heteroaryl ring; wherein each said heterocylic ring 35 —NO. C. alkyl, a Czaralkyl, Css cycloalkyl ring, and each said heteroaryl ring contains between 1 and 3 C. haloalkyl, C, a cyanoalkyl, -OR. —SR, heteroatoms independently selected from O, N or S; and OCOR, COR, C(O) OR, C(O)N(R), wherein each said C. aliphatic, each said Cls N(R)C(O)R, N(R), SOR, SON(R), cycloaliphatic ring, each said 4 to 8-membered heterocy —N(R)SO.R. phenylor an oxo group; wherein each said clic ring, each said phenyl and each said 5 to 6-membered 40 phenyl group is optionally and independently Substituted heteroaryl ring is optionally and independently substituted with up to 3 instances of halogen, —OH, -NH2, —NH by up to 3 instances of R: (C. alkyl). —N(C. alkyl). —NO. —CN. C. alkyl, each R is independently selected from a Css cycloaliphatic C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to and wherein each said C7-2 aralkyl and each said 6-membered heteroaryl ring; wherein each said heterocylic 45 cycloalkyl group is optionally and independently Substi ring and each said heteroaryl ring contains between 1 and tuted with up to 3 instances of halogen; 3 heteroatoms independently selected from O, N or S; and each R is independently selected from halogen, —CN, wherein each said C. aliphatic, each said Cls —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, cycloaliphatic ring, each said 4 to 8-membered heterocy C. haloalkyl, C, a cyanoalkyl, -OR. —SR. clic ring, each said phenyl and each said 5 to 6-membered 50 OCOR, COR, C(O)OR, C(O)N(R), heteroaryl ring is optionally and independently substituted N(R)C(O)R, N(R), SOR, SON(R), by up to 3 instances of R: —N(R)SOR, phenyl oran oxo group; wherein each said when JP is C(O)N(R) - N(R') or -SON(RP), the phenyl group is optionally and independently Substituted two instances of RP together with the nitrogen atom with up to 3 instances of halogen, OH, -NH. NH attached to the R', alternatively form a 4 to 8-membered 55 (C. alkyl). —N(C. alkyl). —NO. —CN, C- alkyl, heterocyclic ring or a 5-membered heteroaryl ring; C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); wherein each said 4 to 8-membered heterocyclic ring and and wherein each said C7-2 aralkyl and each said each said 5-membered heteroaryl ring optionally contains cycloalkyl group is optionally and independently Substi up to 2 additional heteroatoms independently selected tuted with up to 3 instances of halogen; from N, O or S, and wherein each said 4 to 8-membered 60 each R is independently selected from halogen, —CN, heterocyclic ring and each said 5-membered heteroaryl —NO. C. alkyl, a Czaralkyl, Css cycloalkyl ring, ring is optionally and independently Substituted by up to 3 C. haloalkyl, C, a cyanoalkyl, -OR. —SR, instances of R; or –OCOR, COR, C(O)OR, C(O)N(R), when JP is N(R')C(O)R’, the RP group together with the N(R)C(O)R, N(R), SOR, SON(R), carbon atom attached to the RP group, with the nitrogen 65 —N(R)SO.R. phenylor an oxo group; wherein each said atom attached to the R group and with the R group alter phenyl group is optionally and independently Substituted natively form a 4 to 8-membered heterocyclic ring or a with up to 3 instances of halogen, —OH, -NH2, —NH US 9,309,235 B2 5 6 (C. alkyl). —N(C. alkyl). —NO. —CN, C alkyl, bered heterocycle is optionally and independently substi C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); tuted with up to 3 instances of J: and wherein each said C. aralkyl and each said each J is independently selected from halogen, —CN, cycloalkyl group is optionally and independently Substi —NO, a Caliphatic, —OR', SR', N(R'), a Cas tuted with up to 3 instances of halogen; cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; each R is independently selected from halogen, —CN, wherein said 4 to 8-membered heterocyclic ring contains 1 —NO. C. alkyl, a Czaralkyl, Cs cycloalkyl ring, or 2 heteroatoms independently selected from N, O or S; C. haloalkyl, C, a cyanoalkyl, -OR. -SR, wherein each said C. aliphatic, each said Cls –OCOR, COR, C(O)OR, C(O)N(R), cycloaliphatic ring and each said 4 to 8-membered hetero N(R)C(O)R, N(R), SOR, SON(R), 10 cyclic ring, is optionally and independently substituted - N(R)SO.R, phenyl oran oxo group; wherein each said with up to 3 instances of R"; or alternatively, two J groups phenyl group is optionally and independently substituted attached to two vicinal ring C atoms, taken together with with up to 3 instances of halogen, —OH, -NH2, —NH said two vicinal ring C atoms, form a 5 to 7-membered (C. alkyl). —N(C. alkyl). —NO. —CN. C. alkyl, heterocycle resulting in a fused ring C; wherein said 5 to C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); 15 7-membered heterocycle contains from 1 to 2 heteroatoms and wherein each said C, aralkyl and each said independently selected from N, O or S; cycloalkyl group is optionally and independently Substi each R' is independently selected from hydrogen, a C tuted with up to 3 instances of halogen; aliphatic, a Cs cycloaliphatic ring or a 4 to 8-membered each R is independently selected from hydrogen, a Ca heterocyclic ring; wherein each said 4 to 8-membered het alkyl, a C2 alkenyl, phenyl, a C7-12 aralkyl or a Cas erocylic ring contains between 1 and 3 heteroatoms inde cycloalkyl ring; wherein each said C. alkyl, each said pendently selected from O, N or S; and wherein each said Calkenyl, each said phenyl, each said C-2 aralkyl and Caliphatic, each said Cas cycloaliphatic ring, each said each said C.s cycloalkyl group is optionally and indepen 4 to 8-membered heterocyclic ring, is optionally and inde dently substituted with up to 3 instances of halogen; pendently substituted with up to 3 instances of R'; alternatively, two instances of R linked to the same nitrogen 25 alternatively, two instances of R'linked to the same nitrogen atom of R, together with said nitrogenatom of R, form a atom of J, together with said nitrogen atom of J. form a 5 to 8-membered heterocyclic ring or a 5-membered het 4 to 8-membered heterocyclic ring or a 5-membered het eroaryl ring; wherein each said 5 to 8-membered hetero eroaryl ring; wherein each said 4 to 8-membered hetero cyclic ring and each said 5-membered heteroaryl ring cyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms inde 30 optionally contains up to 2 additional heteroatoms inde pendently selected from N, O or S; or pendently selected from N, O or S, and wherein each said alternatively, one instance of R linked to a nitrogenatom of 4 to 8-membered heterocyclic ring and each said 5-mem Randone instance of R linked to a carbon or sulfur atom bered heteroaryl ring is optionally and independently Sub of the same R, together with said nitrogen and said carbon stituted by up to 3 instances of R'; or or sulfur atom of the same R, form a 5 to 8-membered 35 each R" is independently selected from halogen, —CN, heterocyclic ring or a 5-membered heteroaryl ring; —NO, C alkyl, C. haloalkyl, Cs cycloalkyl ring, wherein each said 5 to 8-membered heterocyclic ring and —OR, SR, N(R), or an oxo group; wherein each each said 5-membered heteroaryl ring optionally contains said cycloalkyl group is optionally and independently Sub up to 2 additional heteroatoms independently selected stituted with up to 3 instances of halogen; from N, O or S: 40 each R' is independently selected from halogen, —CN, or, alternatively, two JP groups attached to two vicinal ring D —NO, C alkyl, C. haloalkyl, Cs cycloalkyl ring, atoms, taken together with said two vicinal ring Datoms, —OR. —SR, N(R), or an oxo group; wherein each form a 5 to 7-membered heterocycle resulting in a fused said cycloalkyl group is optionally and independently Sub ring D wherein said 5 to 7-membered heterocycle contains stituted with up to 3 instances of halogen; from 1 to 3 heteroatoms independently selected from N, O 45 each R' is independently selected from halogen, —CN, or S; and wherein said 5 to 7-membered heterocycle is —NO, C alkyl, C. haloalkyl, Cs cycloalkyl ring, optionally and independently substituted by up to 3 —OR. —SR, N(R), or an oxo group; wherein each instances of halogen, —OH, -NH2, —NH(C. alkyl). said cycloalkyl group is optionally and independently Sub —N(C. alkyl). —CN, C alkyl, C. haloalkyl, stituted with up to 3 instances of halogen; —O(C. alkyl), —O(C- haloalkyl). OXO or phenyl: 50 each R is independently selected from hydrogen, a Ca wherein said phenyl is optionally and independently Sub alkyl, Chaloalkyl or a C-scycloalkyl ring; wherein each stituted by up to three instances of halogen, —OH, -NH2, said cycloalkyl group is optionally and independently Sub —NH(C. alkyl). —N(C. alkyl). —NO. —CN, C stituted with up to 3 instances of halogen; alkyl, Ca haloalkyl, -O(C. alkyl) or —O(C- alternatively, two instances of R linked to the same nitrogen haloalkyl); 55 atom of R", together with said nitrogenatom of R", form a R is a ring C. ring C is a phenyl ring, a monocyclic 5 or 5 to 8-membered heterocyclic ring or a 5-membered het 6-membered heteroaryl ring, a bicyclic 8 to 10-membered eroaryl ring; wherein each said 5 to 8-membered hetero heteroaryl ring, a monocyclic 3 to 10-membered cyclic ring and each said 5-membered heteroaryl ring cycloaliphatic ring, or a monocyclic 4 to 10-membered optionally contains up to 2 additional heteroatoms inde heterocycle; wherein said monocyclic 5 or 6-membered 60 pendently selected from N, O or S; and heteroaryl ring, said bicyclic 8 to 10-membered heteroaryl R" is selected from hydrogen, halogen, C, alkyl or Ca ring, or said monocyclic 4 to 10-membered heterocycle haloalkyl. contain between 1 and 4 heteroatoms selected from N, O or The invention also provides a method of treating or pre S; wherein said monocyclic 5 or 6-membered heteroaryl venting a disease, health condition or disorder in a Subject in ring is not a 1.3.5-triazinyl ring; and wherein said phenyl, 65 need thereof, comprising administering, alone or in combi monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to nation therapy, a therapeutically or prophylactically effective 10-membered heteroaryl ring, or monocyclic 4 to 10-mem amount of a compound of Formula I or a pharmaceutically US 9,309,235 B2 7 8 acceptable salt thereof to the subject; wherein the disease, variable occurs more than one time at any position, its defi health condition or disorder is a peripheral, pulmonary, nition on each occurrence is independent from every other hepatic, liver, cardiac or cerebral vascular/endothelial disor OCCUCC. der or condition, a urogenital-gynecological disorder or con Selection of substituents and combinations envisioned by dition, a thromboembolic disease, a fibrotic disorder, or other this disclosure are only those that result in the formation of pulmonary or respiratory disorder, renal or hepatic disorder, stable or chemically feasible compounds. Such choices and metabolic disorder, atherosclerosis or a lipid related disorder combinations will be apparent to those of ordinary skill in the that benefits from sGC stimulation or from an increase in the art and may be determined without undue experimentation. concentration of NO or cGMP. The term “stable', as used herein, refers to compounds that 10 are not substantially altered when subjected to conditions to DETAILED DESCRIPTION OF THE INVENTION allow for their production, detection, and, in some embodi ments, their recovery, purification, and use for one or more of Reference will now be made in detail to certain embodi the purposes disclosed herein. In some embodiments, a stable ments of the invention, examples of which are illustrated in compound is one that is not substantially altered when kept at 15 a temperature of 25°C. or less, in the absence of moisture or the accompanying structures and formulae. While the inven other chemically reactive conditions, for at least a week. A tion will be described in conjunction with the enumerated chemically feasible compound is a compound that can be embodiments, it will be understood that they are not intended prepared by a person skilled in the art based on the disclosures to limit the invention to those embodiments. Rather, the herein Supplemented, if necessary, relevant knowledge of the invention is intended to cover all alternatives, modifications art. and equivalents that may be included within the scope of the A compound, Such as the compounds of Formula I or other present invention as defined by the claims. The present inven compounds herein disclosed, may be present in its free form tion is not limited to the methods and materials described (e.g. an amorphous form, or a crystalline form or a poly herein but include any methods and materials similar or morph). Under certain conditions, compounds may also form equivalent to those described herein that could be used in the 25 co-forms. As used herein, the term co-form is synonymous practice of the present invention. In the event that one or more with the term multi-component crystalline form. When one of of the incorporated literature references, patents or similar the components in the co-form has clearly transferred a pro materials differ from or contradict this application, including ton to the other component, the resulting co-form is referred but not limited to defined terms, term usage, described tech to as a “salt. The formation of a salt is determined by how niques or the like, this application controls. 30 large the difference is in the pKas between the partners that form the mixture. DEFINITIONS AND GENERAL TERMINOLOGY Unless only one of the isomers is drawn or named specifi cally, structures depicted herein are also meant to include all For purposes of this disclosure, the chemical elements are Stereoisomeric (e.g., enantiomeric, diastereomeric, atropoi identified in accordance with the Periodic Table of the Ele 35 Someric and cis-trans isomeric) forms of the structure; for ments, CAS version, and the Handbook of Chemistry and example, the R and S configurations for each asymmetric Physics, 75" Ed. 1994. Additionally, general principles of center, Ra and Sa configurations for each asymmetric axis, organic chemistry are described in “Organic Chemistry’. (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical Thomas Sorrell, University Science Books, Sausalito: 1999, 40 isomers as well as racemates, and mixtures of enantiomers, and “March's Advanced Organic Chemistry”, 5" Ed., Smith, diastereomers, and cis-trans isomers (double bond or confor M. B. and March, J., eds. John Wiley & Sons, New York: mational) of the present compounds are within the scope of 2001, which are herein incorporated by reference in their the present disclosure. Unless otherwise stated, all tautomeric entirety. forms of the compounds of the present disclosure are also As described herein, compounds of Formula I may be 45 within the scope of the invention. optionally Substituted with one or more substituents. Such as The present disclosure also embraces isotopically-labeled illustrated generally below, or as exemplified by particular compounds which are identical to those recited herein, but for classes, Subclasses and species of the invention. The phrase the fact that one or more atoms are replaced by anatom having “optionally substituted” is used interchangeably with the an atomic mass or mass number different from the atomic phrase “substituted or unsubstituted.” In general, the term 50 mass or mass number usually found in nature. All isotopes of “substituted refers to the replacement of one or more hydro any particular atom or element as specified are contemplated gen radicals in a given structure with the radical of a specified within the scope of the compounds of the invention, and their substituent. Unless otherwise indicated, an optionally substi uses. Exemplary isotopes that can be incorporated into com tuted group may have a substituent at each Substitutable posi pounds of the invention include isotopes of hydrogen, carbon, tion of the group. When more than one position in a given 55 nitrogen, oxygen, phosphorus, Sulfur, fluorine, chlorine, and structure can be substituted with more than one substituent iodine, such as PH, H, C, C, C, N, SN, ISO, 7O, O, selected from a specified group, the Substituent may be either P. P, S, F, C1, I, and 'I, respectively. Certain the same or different at each position unless otherwise speci isotopically-labeled compounds of the present invention fied. As will be apparent to one of ordinary skill in the art, (e.g., those labeled with Hand ''C) are useful in compound groups such as —H, halogen, —NO. —CN. —OH, -NH2 60 and/or substrate tissue distribution assays. Tritiated (i.e., H) or —OCF would not be substitutable groups. and carbon-14 (i.e., ''C) isotopes are useful for their ease of The phrase “up to’, as used herein, refers to Zero or any preparation and detectability. Further, substitution with integer number that is equal or less than the number following heavier isotopes such as deuterium (i.e., H) may afford cer the phrase. For example, “up to 3’ means any one of 0, 1, 2, tain therapeutic advantages resulting from greater metabolic or 3. As described herein, a specified number range of atoms 65 stability (e.g., increased in vivo half-life or reduced dosage includes any integer therein. For example, a group having requirements) and hence may be preferred in Some circum from 1-4 atoms could have 1, 2, 3 or 4 atoms. When any stances. Positron emitting isotopes such as "O, N, ''C, and US 9,309,235 B2 10 'Fare useful for positron emission tomography (PET) stud or a bicyclic C7-C2 hydrocarbon. In some embodiments, any ies to examine Substrate receptor occupancy. Isotopically individual ring in a bicyclic or tricyclic ring system has 3-7 labeled compounds of the present invention can generally be members. Suitable cycloaliphatic groups include, but are not prepared by following procedures analogous to those dis limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. closed in the Schemes and/or in the Examples herein below, 5 Examples of aliphatic groups include cyclopropyl, cyclobu by Substituting an isotopically labeled reagent for a non tyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, isotopically labeled reagent. cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, The term “aliphatic' or “aliphatic group', as used herein, cyclononyl, cyclodecyl cycloundecyl cyclododecyl, and the means a straight-chain (i.e., unbranched) or branched, Substi like. tuted or unsubstituted hydrocarbon chain that is completely 10 The term “cycloaliphatic' also includes polycyclic ring saturated or that contains one or more units of unsaturation. systems in which the non-aromatic carbocyclic ring can be Unless otherwise specified, aliphatic groups contain 1-20 “fused to one or more aromatic or non-aromatic carbocyclic aliphatic carbon atoms. In some embodiments, aliphatic or heterocyclic rings or combinations thereof, as long as the groups contain 1-10 aliphatic carbon atoms. In other embodi radical or point of attachment is on the non-aromatic carbocy ments, aliphatic groups contain 1-8 aliphatic carbonatoms. In 15 clic ring. still other embodiments, aliphatic groups contain 1-6 ali “Heterocycle” (or "heterocyclyl or "heterocyclic), as used phatic carbonatoms. In other embodiments, aliphatic groups herein, refers to a ring system in which one or more ring contain 1-4 aliphatic carbon atoms and in yet other embodi members are an independently selected heteroatom, which is ments, aliphatic groups contain 1-3 aliphatic carbon atoms. completely saturated or that contains one or more units of Suitable aliphatic groups include, but are not limited to, linear unsaturation but which is notaromatic, and which has a single or branched, substituted or unsubstituted alkyl, alkenyl, or point of attachment to the rest of the molecule. Unless other alkynyl groups. Specific examples of aliphatic groups wise specified, through this disclosure, heterocycle is used as include, but are not limited to: methyl, ethyl, propyl, butyl, a synonym of “non-aromatic heterocycle'. In some instances isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, pro the term can be used in the phrase “aromatic heterocycle', and pargyl, acetylene and the like. 25 in this case it refers to a "heteroaryl group’ as defined below. The term “alkyl, as used herein, refers to a saturated linear The term heterocycle also includes fused, spiro or bridged or branched-chain monovalent hydrocarbon radical. Unless heterocyclic ring systems. Unless otherwise specified, a het otherwise specified, an alkyl group contains 1-20 carbon erocycle may be monocyclic, bicyclic or tricyclic. In some atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 car embodiments, the heterocycle has 3-18 ring members in bonatoms, 1-6 carbonatoms, 1-4 carbonatoms or 1-3 carbon 30 which one or more ring members is a heteroatom indepen atoms). Examples of alkyl groups include, but are not limited dently selected from oxygen, Sulfur or nitrogen, and each ring to, methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, s-bu in the system contains 3 to 7 ring members. In other embodi tyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like. ments, a heterocycle may be a monocycle having 3-7 ring The term “alkenyl refers to a linear or branched-chain members (2-6 carbonatoms and 1-4 heteroatoms) or a bicycle monovalent hydrocarbon radical with at least one site of 35 having 7-10 ring members (4-9 carbon atoms and 1-6 het unsaturation, i.e., a carbon-carbon, sp' double bond, wherein eroatoms). Examples of bicyclic heterocyclic ring systems the alkenyl radical includes radicals having “cis' and “trans’ include, but are not limited to: adamantanyl, 2-oxa-bicyclo orientations, or alternatively, “E” and “Z” orientations. 2.2.2]octyl, 1-aza-bicyclo2.2.2]octyl. Unless otherwise specified, an alkenyl group contains 2-20 As used herein, the term "heterocycle also includes poly carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 40 cyclic ring systems wherein the heterocyclic ring is fused 2-8 carbon atoms, 2-6 carbonatoms, 2-4 carbonatoms or 2-3 with one or more aromatic or non-aromatic carbocyclic or carbon atoms). Examples include, but are not limited to, heterocyclic rings, or with combinations thereof, as long as vinyl, allyl and the like. the radical or point of attachment is on the heterocyclic ring. The term “alkynyl refers to a linear or branched monova Examples of heterocyclic rings include, but are not limited lent hydrocarbon radical with at least one site of unsaturation, 45 to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahy i.e., a carbon-carbon sp triple bond. Unless otherwise speci drofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, fied, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomor carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 pholino, 3-thiomorpholino, 4-thiomorpholino. 1-pyrrolidi carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). nyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, Examples include, but are not limited to, ethynyl, propynyl, 50 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidi and the like. nyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazoli The term “carbocyclic” refers to a ring system formed only nyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidi by carbon and hydrogen atoms. Unless otherwise specified, nyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, throughout this disclosure, carbocycle is used as a synonym 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazo of “non-aromatic carbocycle' or “cycloaliphatic'. In some 55 lidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following instances the term can be used in the phrase 'aromatic car bicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimida bocycle', and in this case it refers to an “aryl group’ as Zol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroiso defined below. quinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro The term “cycloaliphatic' (or “non-aromatic carbocycle, imidazol-2-one. “non-aromatic carbocyclyl”, “non-aromatic carbocyclic') 60 As used herein, the term “aryl' (as in “aryl ring or “aryl refers to a cyclic hydrocarbon that is completely saturated or group'), used alone or as part of a larger moiety, as in that contains one or more units of unsaturation but which is “aralkyl”, “aralkoxy”, “aryloxyalkyl, refers to a carbocyclic not aromatic, and which has a single point of attachment to ring system wherein at least one ring in the system is aromatic the rest of the molecule. Unless otherwise specified, a and has a single point of attachment to the rest of the mol cycloaliphatic group may be monocyclic, bicyclic, tricyclic, 65 ecule. Unless otherwise specified, an aryl group may be fused, spiro or bridged. In one embodiment, the term monocyclic, bicyclic or tricyclic and contain 6-18 ring mem “cycloaliphatic' refers to a monocyclic C-C2 hydrocarbon bers. The term also includes polycyclic ring systems where US 9,309,235 B2 11 12 the aryl ring is fused with one or more aromatic or non at least two individual atoms or chains of atoms. Examples of aromatic carbocyclic or heterocyclic rings, or with combina bridged bicyclic ring systems include, but are not limited to, tions thereof, as long as the radical or point of attachment is in adamantanyl, norbornanyl, bicyclo3.2.1]octyl, bicyclo the aryl ring. Examples of aryl rings include, but are not 2.2.2]octyl, bicyclo3.3.1nonyl, bicyclo[3.2.3nonyl, limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluo 2-oxa-bicyclo2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza renyl, and anthracenyl. bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03.7nonyl. The term “aralkyl refers to a radical having an aryl ring “Spiro' bicyclic ring systems share only one ring atom (usu Substituted with an alkylene group, wherein the open end of ally a quaternary carbon atom) between the two rings. The term “ring atom” refers to an atom such as C, N, O or the alkylene group allows the aralkyl radical to bond to S that is part of the ring of an aromatic ring, a cycloaliphatic another part of the compound of Formula I. The alkylene 10 ring, a heterocyclic or a heteroaryl ring. A “substitutable ring group is a bivalent, straight-chain or branched, Saturated atom' is a ring carbon or nitrogenatom bonded to at least one hydrocarbon group. As used herein, the term "C. aralkyl hydrogen atom. The hydrogen can be optionally replaced means an aralkyl radical wherein the total number of carbon with a suitable substituent group. Thus, the term “substitut atoms in the aryl ring and the alkylene group combined is 7 to able ring atom' does not include ring nitrogen or carbon 12. Examples of “aralkyl include, but not limited to, a phenyl 15 atoms which are shared when two rings arefused. In addition, ring substituted by a C- alkylene group, e.g., benzyl and “substitutable ring atom' does not include ring carbon or phenylethyl, and a naphthyl group Substituted by a C- alky nitrogen atoms when the structure depicts that they are lene group. already attached to one or more moiety other than hydrogen The term "heteroaryl’ (or "heteroaromatic' or "heteroaryl and no hydrogens are available for Substitution. group' or 'aromatic heterocycle') used alone or as part of a “Heteroatom” refers to one or more of oxygen, sulfur, larger moiety as in "heteroaralkyl or "heteroarylalkoxy” nitrogen, phosphorus, or silicon, including any oxidized form refers to a ring system wherein at least one ring in the system of nitrogen, Sulfur, phosphorus, or silicon, the quaternized is aromatic and contains one or more heteroatoms, wherein form of any basic nitrogen, or a substitutable nitrogen of a each ring in the system contains 3 to 7 ring members and heterocyclic or heteroaryl ring, for example N (as in 3,4- which has a single point of attachment to the rest of the 25 dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR" (as in molecule. Unless otherwise specified, a heteroaryl ring sys N-substituted pyrrolidinyl). tem may be monocyclic, bicyclic or tricyclic and have a total In some embodiments, two independent occurrences of a variable may be taken together with the atom(s) to which each offive to fourteen ring members. In one embodiment, all rings variable is bound to form a 5-8-membered, heterocyclyl, aryl, in a heteroaryl System are aromatic. Also included in this or heteroaryl ring or a 3-8-membered cycloaliphatic ring. definition are heteroaryl radicals where the heteroaryl ring is 30 Exemplary rings that are formed when two independent fused with one or more aromatic or non-aromatic carbocyclic occurrences of a substituent are taken together with the or heterocyclic rings, or combinations thereof, as long as the atom(s) to which each variable is bound include, but are not radical or point of attachment is in the heteroaryl ring. Bicy limited to the following: a) two independent occurrences of a clic 6, 5 heteroaromatic system, as used herein, for example, Substituent that are bound to the same atom and are taken is a six membered heteroaromatic ring fused to a second five 35 together with that atom to form a ring, where both occur membered ring wherein the radical or point of attachment is rences of the substituent are taken together with the atom to on the six-membered ring. which they are bound to form a heterocyclyl, heteroaryl, Heteroaryl rings include, but are not limited to the follow cycloaliphatic or aryl ring, wherein the group is attached to ing monocycles: 2-furanyl, 3-furanyl. N-imidazolyl, 2-limi the rest of the molecule by a single point of attachment; and b) dazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isox 40 two independent occurrences of a Substituent that are bound azolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, to different atoms and are taken together with both of those N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl 2-pyridyl, 3-pyridyl, 4-py atoms to form a heterocyclyl, heteroaryl, cycloaliphatic or ridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazi aryl ring, wherein the ring that is formed has two points of nyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, attachment with the rest of the molecule. For example, where tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 45 a phenyl group is substituted with two occurrences of OR 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyra as in Formula D1: Zolyl), isothiazolyl, 1.2.3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1.3,4- thiadiazolyl, 1,2,5-thiadiazolyl pyrazinyl, 1,3,5-triazinyl, ORO and the following bicycles: benzimidazolyl, benzofuryl, ben 50 Zothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinoli nyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, OR, 3-isoquinolinyl, or 4-isoquinolinyl). As used herein, "cyclo” (or “cyclic”, or “cyclic moiety') 55 encompasses mono-, bi- and tri-cyclic ring systems including these two occurrences of OR are taken together with the cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which carbonatoms to which they are bound to form a fused 6-mem has been previously defined. bered oxygen containing ring as in Formula D2: "Fused bicyclic ring systems comprise two rings which share two adjoining ring atoms. 60 "Bridged' bicyclic ring systems comprise two rings which share three or four adjacent ring atoms. As used herein, the term "bridge” refers to an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two 65 tertiary carbon atoms) are referred to as “bridgeheads'. In vCO addition to the bridge, the two bridgeheads are connected by US 9,309,235 B2 13 14 It will be appreciated that a variety of other rings can be -continued formed when two independent occurrences of a substituent D4 X are taken together with the atom(s) to which each substituent X is bound and that the examples detailed above are not X intended to be limiting. 5 In some embodiments, an alkyl or aliphatic chain can be Y-x optionally interrupted with another atom or group. This X means that a methylene unit of the alkyl oraliphatic chain can X X optionally be replaced with said other atom or group. Unless 10 otherwise specified, the optional replacements form a chemi cally stable compound. Optional interruptions can occur both This also applies to multiple ring systems fused to optional within the chain and/or at either end of the chain; i.e. both at ring systems (which would be represented by dotted lines). the point of attachment(s) to the rest of the molecule and/or at For example, in Formula D5, X is an optional substituent both the terminal end. Two optional replacements can also be 15 for ring A and ring B. adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal N----, end. For example, if —CH2CHCH were optionally inter A B E. rupted with —O—, the resulting compound could be 21 - - - —OCHCH. —CHOCH, or —CH2CH2OH. In another example, if the divalent linker —CH2CH2CH2— were optionally interrupted with —O—, the resulting compound If, however, two rings in a multiple ring system each have could be —OCHCH , —CHOCH , or 25 different substituents drawn from the center of each ring, —CH2CH2O—. The optional replacements can also com then, unless otherwise specified, each Substituent only repre pletely replace all of the carbon atoms in a chain. For sents substitution on the ring to which it is attached. For example, a C aliphatic can be optionally replaced by example, in Formula D6, Y is an optional substituent for ring N(R') , —C(O) , and N(R') to form N(R')C(O) A only, and X is an optional Substituent for ring B only. N(R')— (a urea). In general, the term “vicinal” refers to the placement of D6 Substituents on a group that includes two or more carbon Y atoms, wherein the Substituents are attached to adjacent car -- bon atoms. 35 A B In general, the term “geminal refers to the placement of 2'---- Substituents on a group that includes two or more carbon atoms, wherein the Substituents are attached to the same As used herein, the terms “alkoxy” or “alkylthio’ refer to carbon atom. 40 an alkyl group, as previously defined, attached to the mol The terms “terminally' and “internally” refer to the loca ecule, or to another chain or ring, through an oxygen tion of a group within a Substituent. A group is terminal when (“alkoxy” i.e., —O-alkyl) or a sulfur (“alkylthio’ i.e., —S- the group is present at the end of the substituent not further alkyl) atom. bonded to the rest of the chemical structure. Carboxyalkyl, The terms C., “alkoxyalkyl', C., “alkoxyalkenyl', C. i.e., RO(O)C-alkyl is an example of a carboxy group used 45 “alkoxyaliphatic', and C., “alkoxyalkoxy' mean alkyl, alk terminally. A group is internal when the group is present in the enyl, aliphatic oralkoxy, as the case may be, Substituted with middle of a substituent at the end of the substituent bound to one or more alkoxy groups, wherein the combined total num the rest of the chemical structure. Alkylcarboxy (e.g., alkyl ber of carbons of the alkyl and alkoxy groups, alkenyl and C(O)O— or alkyl-O(CO)—) and alkylcarboxyaryl (e.g., alkoxy groups, aliphatic and alkoxy groups or alkoxy and 50 alkoxy groups, combined, as the case may be, is between the alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of values of n and m. For example, a C alkoxyalkyl has a total carboxy groups used internally. of 4-6 carbons divided between the alkyl and alkoxy portion; As described herein, a bond drawn from a substituent to the e.g. it can be —CHOCH2CHCH. —CH2CH2OCHCH or center of one ring within a multiple-ring system (as shown —CHCHCHOCH. below), represents substitution of the substituent at any sub 55 When the moieties described in the preceding paragraph stitutable position in any of the rings within the multiple ring are optionally substituted, they can be substituted in either or system. For example, formula D3 represents possible substi both of the portions on either side of the oxygen or sulfur. For tution in any of the positions shown in formula D4: example, an optionally Substituted C alkoxyalkyl could be, for instance, —CHCHOCH(Me)CH or -CH(OH)O 60 CHCHCH; a Cs alkoxyalkenyl could be, for instance, -CH=CHO CHCHCH, or -CH=CHCHOCHCH, The terms aryloxy, arylthio, benzyloxy or benzylthio, refer N N to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen ('aryloxy’, benzy yx 65 loxy e.g., —O-Ph, —OCHPh) or sulfur (“arylthio’ e.g., H —S-Ph. —S CHPh) atom. Further, the terms “aryloxy alkyl”, “benzyloxyalkyl” “aryloxyalkenyl' and “aryloxy US 9,309,235 B2 15 16 aliphatic' mean alkyl, alkenyl oraliphatic, as the case may be, a linker can be a Caliphatic chain in which up to two Substituted with one or more aryloxy or benzyloxy groups, as methylene units are substituted by —C(O)—or NH (as the case may be. In this case, the number of atoms for each in —CH NH-CH C(O)—CH2—, or —CH NH C aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated (O)—CH2—). An alternative way to define the same separately. Thus, a 5-6-membered aryloxy(Calkyl) is a 5-6 CH NH-CH C(O)—CH2— and —CH NH C membered aryl ring, attached via an oxygen atom to a Ca (O)—CH2— groups is as a C alkyl chain optionally inter alkyl chain which, in turn, is attached to the rest of the mol rupted by up to two —C(O)— or NH moieties. Cyclic ecule via the terminal carbon of the C alkyl chain. groups can also form linkers: e.g. a 1.6-cyclohexanediyl can As used herein, the terms “halogen' or “halo' mean F, Cl, be a linker between two R groups, as in Br, or I. 10 The terms “haloalkyl, "haloalkenyl', “haloaliphatic’, and "haloalkoxy' mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, Substituted with one or more halogenatoms. For example a C- haloalkyl could be —CFHCHCHF, and a C. haloalkoxy could be —OC(Br)HCHF. This term 15 includes perfluorinated alkyl groups, such as —CF and —CFCF. A linker can additionally be optionally substituted in any As used herein, the term “cyano” refers to —CN or portion or position. - C=N. Divalent groups of the type R CH= or RC—, wherein The terms “cyanoalkyl, “cyanoalkenyl', both free valences are in the same atomandare attached to the “cyanoaliphatic', and “cyanoalkoxy' mean alkyl, alkenyl, same Substituent, are also possible. In this case, they will be aliphatic oralkoxy, as the case may be, Substituted with one or referred to by their IUPAC accepted names. For instance an more cyano groups. For example a C. cyanoalkyl could be alkylidene (such as, for example, a methylidene (=CH-) or —C(CN)2CHCH and a C. cyanoalkenyl could be —CHC an ethylidene (=CH-CH)) would not be encompassed by (CN)H. 25 the definition of a linker in this disclosure. As used herein, an "amino' group refers to —NH. The term “protecting group', as used herein, refers to an The terms “aminoalkyl, "aminoalkenyl', “ami agent used to temporarily block one or more desired reactive noaliphatic', and "aminoalkoxy' mean alkyl, alkenyl, ali sites in a multifunctional compound. In certain embodiments, phatic or alkoxy, as the case may be, Substituted with one or a protecting group has one or more, or preferably all, of the more amino groups. For example a Caminoalkyl could be 30 following characteristics: a) reacts selectively in good yield to —CH(NH2)CHCH-NH and a Caminoalkoxy could be give a protected Substrate that is stable to the reactions occur OCHCH-NH. ring at one or more of the other reactive sites; and b) is The term “hydroxyl or “hydroxy” refers to OH. selectively removable in good yield by reagents that do not The terms “hydroxyalkyl”, “hydroxyalkenyl', “hydroxy attack the regenerated functional group. Exemplary protect aliphatic', and “hydroxyalkoxy' mean alkyl, alkenyl, ali 35 ing groups are detailed in Greene, T. W. et al., “Protective phatic or alkoxy, as the case may be, Substituted with one or Groups in Organic Synthesis'. Third Edition, John Wiley & more —OH groups. For example a C- hydroxyalkyl could Sons, New York: 1999, the entire contents of which is hereby be —CH2(CHOH)CH and a Ca hydroxyalkoxy could be incorporated by reference. The term "nitrogen protecting –OCHC(CH)(OH)CH. group', as used herein, refers to an agents used to temporarily As used herein, a "carbonyl', used alone or in connection 40 block one or more desired nitrogen reactive sites in a multi with another group refers to —C(O)— or —C(O)H. For functional compound. Preferred nitrogen protecting groups example, as used herein, an “alkoxycarbonyl refers to a also possess the characteristics exemplified above, and cer group Such as —C(O)O(alkyl). tain exemplary nitrogen protecting groups are detailed in As used herein, an “oxo” refers to —O, wherein oxo is Chapter 7 in Greene, T. W., Wuts, P. G in “Protective Groups usually, but not always, attached to a carbon atom (e.g., it can 45 in Organic Synthesis'. Third Edition, John Wiley & Sons, also be attached to a Sulfur atom). An aliphatic chain can be New York: 1999, the entire contents of which are hereby optionally interrupted by a carbonyl group or can optionally incorporated by reference. be substituted by an oxo group, and both expressions refer to As used herein, the term “displaceable moiety' or “leaving the same: e.g. —CH2—C(O)—CH. group' refers to a group that is associated with an aliphatic or As used herein, in the context of resin chemistry (e.g. using 50 aromatic group as defined herein and is subject to being solid resins or soluble resins or beads), the term “linker' displaced by nucleophilic attack by a nucleophile. refers to a bifunctional chemical moiety attaching a com As used herein, "amide coupling agent” or "amide cou pound to a solid Support or soluble Support. pling reagent’ means a compound that reacts with the In all other situations, a “linker', as used herein, refers to a hydroxyl moiety of a carboxy moiety thereby rendering it divalent group in which the two free valences are on different 55 Susceptible to nucleophilic attack. Exemplary amide cou atoms (e.g. carbon or heteroatom) or are on the same atom but pling agents include DIC (diisopropylcarbodiimide), EDCI can be substituted by two different substituents. For example, (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC a methylene group can be C alkyl linker (—CH2—) which (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-tris can be substituted by two different groups, one for each of the (dimethylamino)-phosphonium hexafluorophosphate), free valences (e.g. as in Ph-CH-Ph, wherein methylene acts 60 pyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium as a linker between two phenyl rings). Ethylene can be C. hexafluorophosphate), etc. alkyl linker (—CH2CH2—) wherein the two free valences are The compounds of the invention are defined herein by their on different atoms. The amide group, for example, can act as chemical structures and/or chemical names. Where a com a linker when placed in an internal position of a chain (e.g. pound is referred to by both a chemical structure and a chemi —CONH- ). A linker can be the result of interrupting an 65 cal name, and the chemical structure and chemical name aliphatic chain by certain functional groups or of replacing conflict, the chemical structure is determinative of the com methylene units on said chain by said functional groups. E.g. pound's identity. US 9,309,235 B2 17 18 Compound Embodiments each R" is independently selected from hydrogen, a C The present invention is directed to compounds of Formula aliphatic, —(Caliphatic)-R, a Css cycloaliphatic ring, a I, or pharmaceutically acceptable salts thereof, 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-mem bered heteroaryl ring; wherein each said heterocylic ring and each said heteroaryl ring contains between 1 and 3 Formula I heteroatoms independently selected from O, N or S; and wherein each said C. aliphatic, each said Cls RC cycloaliphatic ring, each said 4 to 8-membered heterocy NY (J):By . clic ring, each said phenyl and each said 5 to 6-membered 10 heteroaryl ring is optionally and independently Substituted A by up to 3 instances of R: R4 each R is independently selected from a Css cycloaliphatic N ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to X Z \ 6-membered heteroaryl ring; wherein each said heterocylic S/Yip ring and each said heteroaryl ring contains between 1 and \ S. 3 heteroatoms independently selected from O, Nor S; and wherein each said C. aliphatic, each said Cls wherein: cycloaliphatic ring, each said 4 to 8-membered heterocy ring B is a 5-membered heteroaryl ring selected from furan or clic ring, each said phenyl and each said 5 to 6-membered thiophene; heteroaryl ring is optionally and independently Substituted n is an integer selected from 0 to 3: by up to 3 instances of R: each J is independently selected from halogen, —CN, a C when Jis–C(O)N(RP), N(RP), or -SON(RP), the two aliphatic, —OR or a Css cycloaliphatic group; wherein instances of RP together with the nitrogenatom attached to each said Caliphatic and each said C.s cycloaliphatic 25 the R', alternatively form a 4 to 8-membered heterocyclic group is optionally and independently Substituted with up ring or a 5-membered heteroaryl ring; wherein each said 4 to 3 instances of R: to 8-membered heterocyclic ring and each said 5-mem each R is independently selected from hydrogen, a C bered heteroaryl ring optionally contains up to 2 additional aliphatic or a Css cycloaliphatic ring; wherein each said heteroatoms independently selected from N, O or S, and Caliphatic and each said C.s cycloaliphatic ring is 30 wherein each said 4 to 8-membered heterocyclic ring and optionally and independently substituted with up to 3 each said 5-membered heteroaryl ring is optionally and instances of R: independently substituted by up to 3 instances of R. or each R is independently selected from halogen, —CN, C when J is N(R)C(O)RP, the RP group together with the alkyl, Ca haloalkyl, -O(C. alkyl) or —O(C- carbon atom attached to the RP group, with the nitrogen haloalkyl); 35 atom attached to the R'group and with the R group alter natively form a 4 to 8-membered heterocyclic ring or a 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: 40 eroatoms independently selected from N, O or S, and o 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 ORP, SRP, C(O)RP, C(O)ORP, C(O)N(RP), independently substituted by up to 3 instances of R: CN, N(R), N(R)C(O)R’, N(R)C(O)OR, when Jis-N(R)C(O)ORP, the RP group together with the —SORP, -SON(R), -N (R')SORP, a C- ali 45 oxygen atom attached to the RP group, with the carbon phatic. —(Caliphatic)-R', a Css cycloaliphatic ring, a 6 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 nitrogenatomattached 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 50 wherein each said 4 to 8-membered heterocyclic ring and heteroatoms independently selected from O, N or S; and each said 5-membered heteroaryl ring optionally contains wherein each said C. aliphatic, each said Cls up to 2 additional heteroatoms independently selected cycloaliphatic ring, each said 6 to 10-membered aryl ring, from N, O or S, and wherein each said 4 to 8-membered each said 4 to 8-membered heterocyclic ring and each said heterocyclic ring and each said 5-membered heteroaryl 5 to 10-membered heteroaryl ring is optionally and inde 55 ring is optionally and independently Substituted by up to 3 pendently substituted with up to 3 instances of R: instances of R: each R’ is independently selected from hydrogen, a C when JP is N(R')SORP, the RP group together with the aliphatic, -(C-caliphatic)-R, a Css cycloaliphatic ring, a oxygenatomattached to the RP group, with the sulfur atom 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-mem attached to said oxygenatom in the SORP portion of the bered heteroaryl ring; wherein each said 4 to 8-membered 60 N(R)SORP group, with the nitrogen atom attached to heterocylic ring and each said 5 to 6-membered heteroaryl the R group, and with the R group alternatively form a 4 ring contains between 1 and 3 heteroatoms independently to 8-membered heterocyclic ring or a 5-membered het selected from O, N or S; and wherein each said Cali eroaryl ring; wherein each said 4 to 8-membered hetero phatic, each said C.s cycloaliphatic ring, each said 4 to cyclic ring and each said 5-membered heteroaryl ring 8-membered heterocyclic ring, each said phenyl and each 65 optionally contains up to 2 additional heteroatoms inde said 5 to 6-membered heteroaryl ring is optionally and pendently selected from N, O or S, and wherein each said independently substituted with up to 3 instances of Rya; 4 to 8-membered heterocyclic ring and each said 5-mem US 9,309,235 B2 19 20 bered heteroaryl ring is optionally and independently Sub alternatively, one instance of R linked to a nitrogenatom of stituted by up to 3 instances of R: Randone instance of R linked to a carbon or sulfur atom each R is independently selected from halogen, —CN, of the same R, together with said nitrogen and said carbon —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, or sulfur atom of the same R, form a 5 to 8-membered C, a haloalkyl, C, a cyanoalkyl, -OR. —SR, heterocyclic ring or a 5-membered heteroaryl ring; OCOR, COR, C(O) OR, C(O)N(R), wherein each said 5 to 8-membered heterocyclic ring and N(R)C(O)R°, N(R), SOR, -SON(R), each said 5-membered heteroaryl ring optionally contains - N(R)SO.R, phenyl oran oxo group; wherein each said up to 2 additional heteroatoms independently selected phenyl group is optionally and independently substituted from N, O or S: with up to 3 instances of halogen, —OH, -NH2, —NH 10 or, alternatively, two JP groups attached to two vicinal ring D (C. alkyl). —N(C. alkyl). —NO. —CN, C alkyl, atoms, taken together with said two vicinal ring Datoms, C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); form a 5 to 7-membered heterocycle resulting in a fused and wherein each said C. aralkyl and each said ring D wherein said 5 to 7-membered heterocycle contains cycloalkyl group is optionally and independently Substi from 1 to 3 heteroatoms independently selected from N.O tuted with up to 3 instances of halogen; 15 or S; and wherein said 5 to 7-membered heterocycle is each R is independently selected from halogen, —CN, optionally and independently substituted by up to 3 —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, instances of halogen, —OH, -NH2, —NH(C. alkyl). C. haloalkyl, C, a cyanoalkyl, -OR. -SR, —N(C. alkyl), —CN. C. alkyl, Ca haloalkyl, OCOR, COR, C(O)OR, C(O)N(R), —O(C. alkyl), —O(C. haloalkyl). OXO or phenyl: N(R)C(O)R, N(R), SOR, SON(R), wherein said phenyl is optionally and independently Sub N(R)SO.R. phenyl oran oxo group; wherein each said stituted by up to three instances of halogen, —OH, -NH2, phenyl group is optionally and independently substituted —NH(C. alkyl). —N(C. alkyl). —NO. —CN, C with up to 3 instances of halogen, —OH, -NH. NH alkyl, C. haloalkyl, —O(C. alkyl) or —O(C- (C. alkyl). —N(C. alkyl). —NO. —CN, C alkyl, haloalkyl); C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); 25 R is a ring C; ring C is a phenyl ring, a monocyclic 5 or and wherein each said C. aralkyl and each said 6-membered heteroaryl ring, a bicyclic 8 to 10-membered cycloalkyl group is optionally and independently Substi heteroaryl ring, a monocyclic 3 to 10-membered tuted with up to 3 instances of halogen; cycloaliphatic ring, or a monocyclic 4 to 10-membered each R is independently selected from halogen, CN, heterocycle; wherein said monocyclic 5 or 6-membered —NO. C. alkyl, a Czaralkyl, Cs cycloalkyl ring, 30 heteroaryl ring, said bicyclic 8 to 10-membered heteroaryl C. haloalkyl, C, a cyanoalkyl, -OR. -SR, ring, or said monocyclic 4 to 10-membered heterocycle OCOR, COR, C(O)OR, C(O)N(R), contain between 1 and 4 heteroatoms selected from N, O or N(R)C(O)R°, N(R), SOR, -SON(R), S; wherein said monocyclic 5 or 6-membered heteroaryl - N(R)SO.R, phenyl oran oxo group; wherein each said ring is not a 1.3.5-triazinyl ring; and wherein said phenyl, phenyl group is optionally and independently substituted 35 monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to with up to 3 instances of halogen, —OH, -NH2, —NH 10-membered heteroaryl ring, or monocyclic 4 to 10-mem (C. alkyl). —N(C. alkyl). —NO. —CN, C alkyl, bered heterocycle is optionally and independently substi C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); tuted with up to 3 instances of J: and wherein each said C. aralkyl and each said each J is independently selected from halogen, —CN, cycloalkyl group is optionally and independently Substi 40 —NO, a Caliphatic, —OR', SR', N(R'), a Cs tuted with up to 3 instances of halogen; cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; each R is independently selected from halogen, —CN, wherein said 4 to 8-membered heterocyclic ring contains 1 —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, or 2 heteroatoms independently selected from N, O or S; C. haloalkyl, C, a cyanoalkyl, -OR. -SR, wherein each said C. aliphatic, each said Cls OCOR, COR, C(O)OR, C(O)N(R), 45 cycloaliphatic ring and each said 4 to 8-membered hetero N(R)C(O)R, N(R), SOR, SON(R), cyclic ring, is optionally and independently substituted N(R)SO.R. phenyl oran oxo group; wherein each said with up to 3 instances of R"; or alternatively, two J groups phenyl group is optionally and independently substituted attached to two vicinal ring C atoms, taken together with with up to 3 instances of halogen, —OH, -NH. NH said two vicinal ring C atoms, form a 5 to 7-membered (C. alkyl). —N(C. alkyl). —NO. —CN, C alkyl, 50 heterocycle resulting in a fused ring C; wherein said 5 to C. haloalkyl, —O(C. alkyl) or —O(C. haloalkyl); 7-membered heterocycle contains from 1 to 2 heteroatoms and wherein each said C. aralkyl and each said independently selected from N, O or S; cycloalkyl group is optionally and independently Substi each R' is independently selected from hydrogen, a C tuted with up to 3 instances of halogen; aliphatic, a Cs cycloaliphatic ring or a 4 to 8-membered each R is independently selected from hydrogen, a Ca 55 heterocyclic ring; wherein each said 4 to 8-membered het alkyl, a C- alkenyl, phenyl, a C7 aralkyl or a Cs erocylic ring contains between 1 and 3 heteroatoms inde cycloalkyl ring; wherein each said C. alkyl, each said pendently selected from O, N or S; and wherein each said Calkenyl, each said phenyl, each said C-2 aralkyl and Caliphatic, each said Cas cycloaliphatic ring, each said each said C.s cycloalkyl group is optionally and indepen 4 to 8-membered heterocyclic ring, is optionally and inde dently substituted with up to 3 instances of halogen; 60 pendently substituted with up to 3 instances of R'; alternatively, two instances of R linked to the same nitrogen alternatively, two instances of R'linked to the same nitrogen atom of R, together with said nitrogenatom of R, form a atom of J, together with said nitrogen atom of J, form a 5 to 8-membered heterocyclic ring or a 5-membered het 4 to 8-membered heterocyclic ring or a 5-membered het eroaryl ring; wherein each said 5 to 8-membered hetero eroaryl ring; wherein each said 4 to 8-membered hetero cyclic ring and each said 5-membered heteroaryl ring 65 cyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms inde optionally contains up to 2 additional heteroatoms inde pendently selected from N, O or S; or pendently selected from N, O or S, and wherein each said US 9,309,235 B2 21 22 4 to 8-membered heterocyclic ring and each said 5-mem In other embodiments of Formula I, ring B is a furan ring. bered heteroaryl ring is optionally and independently Sub In some embodiments, n=0 and the furan ring in unsubsti stituted by up to 3 instances of R'; or tuted. In other embodiments, ring B is a Substituted furan ring each R" is independently selected from halogen, —CN, and n is an integer selected from 1 and 2. In some of the above —NO, C alkyl, Chaloalkyl, Cs cycloalkyl ring, embodiments, wherein ring B is substituted furan, n is 1 or 2 —OR, SR, N(R), or an oxo group; wherein each and each J is independently selected from fluoro, chloro, said cycloalkyl group is optionally and independently Sub methyl or methoxy. In other embodiments, ring B is a mono stituted with up to 3 instances of halogen; substituted furan and J is fluoro. each R" is independently selected from halogen, —CN, In some of the embodiments of Formula I, wherein ring B 10 is furan, unsubstituted or substituted, X is C-J or C H., so —NO, C alkyl, C. haloalkyl, Cs cycloalkyl ring, that ring D is pyridine unsubstituted or substituted. Ring B —OR, SR, N(R), or an oxo group; wherein each can be 2-furanyl or 3-furanyl. said cycloalkyl group is optionally and independently Sub In some of the embodiments of Formula I, wherein ring B stituted with up to 3 instances of halogen; is furan, unsubstituted or substituted, X is C-J or C H., so each R' is independently selected from halogen, —CN, 15 that ring D is pyridine unsubstituted or substituted, and R is —NO, C alkyl, C. haloalkyl, Cs cycloalkyl ring, 1,3-oxazole or 1,2-oxazole, unsubstituted or substituted. —OR, SR, N(R), or an oxo group; wherein each In some embodiments of Formula I, X in ring D is C-J or said cycloalkyl group is optionally and independently Sub C. H. In other embodiments X in ring D is N. stituted with up to 3 instances of halogen; In some embodiments of Formula I, ring D is unsubstituted each R is independently selected from hydrogen, a Ca and o is 0. In other embodiments of Formula I, o is an integer alkyl, Chaloalkyl ora Css cycloalkyl ring; wherein each selected from 1 to 3. said cycloalkyl group is optionally and independently Sub In those embodiments of Formula I wherein ring D is stituted with up to 3 instances of halogen; substituted, each.JP is independently selected from halogen, a alternatively, two instances of R linked to the same nitrogen Caliphatic, N(R), N(R')C(O)R’, N(R')C(O) atom of R", together with said nitrogenatom of R", form a 25 ORP, N(R)C(O)N(RP), SORP, SON(RP), 5 to 8-membered heterocyclic ring or a 5-membered het - N(R)SORP. —SR, OR, or an optionally substituted eroaryl ring; wherein each said 5 to 8-membered hetero Cs cycloaliphatic ring. In some of the above embodiments, cyclic ring and each said 5-membered heteroaryl ring wherein ring D is substituted, o is 1. In other embodiments, o optionally contains up to 2 additional heteroatoms inde is 2. In other embodiments o is 3. pendently selected from N, O or S; and 30 In some embodiments of Formula I, wherein ring D is R" is selected from hydrogen, halogen, C. alkyl or Ca substituted, o is 1, 2 or 3 and each.JP is independently selected haloalkyl. from methyl, chloro, fluoro, N(R), or -OR': wherein In some embodiments of Formula I, ring B is thiophene. In each RP is independently selected from hydrogen or methyl. Some embodiments, said thiophene ring is a 3-thiophenyl In other embodiments, o is 1 or 2 and each.JP is independently ring. In other embodiments it is a 2-thiophenyl ring. In some 35 selected from fluoro, hydroxyl or amino. embodiments, said thiophene ring is unsubstituted and n=0. In some embodiments of Formula I, R is a phenyl ring, a In other embodiments, said thiophene is substituted and n is monocyclic 5 to or 6-membered heteroaryl ring, a monocy an integer selected from 1, 2 or 3. clic 3 to 10-membered cycloaliphatic ring or a monocyclic 4 In some embodiments of Formula I wherein ring B is to 10-membered heterocycle; each of them optionally and substituted thiophene, each J is independently selected from 40 independently substituted by up to 6 instances of J. In other halogen, a C- aliphatic or —OR. In other embodiments, embodiments of Formula I, ring C is a phenyl ring, a mono each J is independently selected from a halogen atom. In cyclic 5 to 6-membered heteroaryl ring, a monocyclic 3 to some embodiments, when Jis independently selected from a 6-membered cycloaliphatic ring or a monocyclic 4 to 6-mem halogen atom, each J can be independently selected from bered heterocycle; each of them optionally and independently fluoro or chloro, or each Ji is fluoro. In other embodiments, 45 substituted with up to 3 instances of J. each J is independently selected from a Caliphatic. In In some embodiments of Formula I, R is a monocyclic 3 some embodiments, each J’ is methyl or ethyl. In other to 6-membered cycloaliphatic ring, optionally and indepen embodiments, each Jis methyl. Instill other embodiments of dently substituted with up to 2 instances of J. In other Formula I, whereinring B is substituted thiophene, each J is embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl independently selected from —OR'; wherein each R is 50 or cyclohexyl. In other embodiments of Formula I, R is a hydrogen or a C- alkyl. In some embodiments, each R is ring C which is a 4-membered cycloaliphatic ring Substituted methyl, ethyl, propyl or isopropyl. by 1 to 3 instances of J, a 5-membered cycloaliphatic ring In some of the above embodiments, wherein ring B is substituted by 1 to 4 instances of J or a 6-membered substituted thiophene, n is 1 or 2 and each.J. is independently cycloaliphatic ring substituted by 1 to 5 instances of J: selected from fluoro, chloro, methyl or methoxy. In other 55 wherein each J is independently selected from halogen or a embodiments, ring B is a mono substituted thiophene and J’ Caliphatic. is fluoro. In other embodiments of Formula I, R is phenyl, option In some of the embodiments of Formula I, wherein ring B ally and independently substituted by up to 5 instances of J. is thiophene, unsubstituted or substituted, X is N so that ring In some embodiments, ring C is phenyland it is unsubstituted. D is pyrimidine, unsubstituted or substituted. Ring B can be 60 In other embodiments, it is substituted by 1 to 3 instances of 2-thiophenyl or 3-thiophenyl. J; wherein each J is independently selected from halogen, a In some of the embodiments of Formula I, R is 1.2- Caliphatic, —NH2, —CN or —O(Caliphatic). In other oxazole or 13-oxazole, unsubstituted or substituted. embodiments, each J is independently selected from halo In some of the embodiments of Formula I, wherein ring B gen, —NH2, —CN, C- alkyl or —O(C. alkyl). In still is thiophene, unsubstituted or substituted, X is N so that ring 65 other embodiments, ring C is phenyl substituted by 1 to 2 D is pyrimidine, unsubstituted or substituted, and R is 1,3- instances of J and each J is selected from fluoro, chloro, oxazole or 1.2-oxazole, unsubstituted or Substituted. methyl, —CN or —OCH. US 9,309,235 B2 23 24 In still other embodiments of Formula I, R is a 5 to alkyl). In still other embodiments, ring C is phenyl substituted 6-membered heteroaryl ring and is optionally and indepen by 1 to 2 instances of J and each J is selected from fluoro, dently substituted by up to 5 instances of J. In some embodi chloro, methyl, —CN or —OCH. ments, said 5 to 6-membered heteroaryl ring is unsubstituted. In still other embodiments of Formulae HA and IIB. R is In other embodiments, it is substituted with 1 to 3 instances of 5 a 5 to 6-membered heteroaryl ring and is optionally and J. In some of these embodiments, the 5 to 6-membered independently substituted by up to 5 instances of J. In some heteroaryl ring can be selected from thienyl, thiazolyl, oxa diazolyl, oxazolyl, isooxazolyl, tetrazolyl pyrrolyl, triazolyl, embodiments, said 5 to 6-membered heteroaryl ring is unsub furanyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. In stituted. In other embodiments, it is substituted with 1 to 3 10 instances of J. In some of these embodiments, the 5 to yet other embodiments, ring C is an isoxazole ring and it is 6-membered heteroaryl ring can be selected from thienyl, unsubstituted. thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl, tetrazolyl pyr In some embodiments of Formula I, ring C is a 5 to 6-mem rolyl, triazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl or bered heteroaryl ring and it is substituted by 1 to 5 instances pyridazinyl. In other embodiments, the heteroaryl ring C is of J: wherein each J is independently selected from halo 15 selected from isoxazolyl, furanyl, thienyl, thiazolyl, 1,3,4- gen, a Caliphatic, —CN, -NH2 or —O(Caliphatic). oxadiazolyl pyridinyl, pyrimidinyl or pyrazin-3-yl. In still In some embodiments, the compounds of the invention are other embodiments, the heteroaryl ring C is selected from represented by structural Formula IIA or IIB: isoxazolyl, thienyl, thiazolyl, 1,3,4-oxadiazolyl or pyridinyl. In other embodiments, ring C is a 5-6 membered heteroaryl Formula IIA and it is substituted by 1 or 2 instances of J: wherein each J. is selected from fluoro, chloro, bromo, methyl, CN, —NH or —OCH. In yet other embodiments of Formula IIA and IIB, ring C is an isoxazole and it is unsubstituted. 25 The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a com pound is referred to by both a chemical structure and a chemi cal name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the com 30 pound's identity. In some embodiments, compounds of Formula I are Formula IIB selected from those listed in Table 1. JE TABLE 1 A & 35 s2 I-1 AN Yy 40 \S.

wherein.J is selected from hydrogen or a halogen. In some 45 embodiments the halogen is fluro. In some embodiments of Formulae IIA and IIB, X in ring D is C. H. In other embodiments X in ring D is N. In some embodiments of Formulae IIA and IIB, ring D is unsubstituted and o is 0. In other embodiments of Formulae 50 IIA and IIB, o is an integer from 1 to 3. In those embodiments of Formula IIA and IIB whereinring D is substituted, each.JP is independently selected from halo I-2 gen, a Caliphatic, —N(R') —ORP or an optionally Sub stituted Cls cycloaliphatic ring. In other embodiments, n is 2 55 and each.JP is independently selected from a halogenatom or —NH or —OH. In still other embodiments, n is 2 and one instance of JP is fluoro and the other one is OH. In other embodiments, n is 1 and JP is NH2. In other embodiments of Formulae IIA and IIB, R is 60 phenyl, optionally and independently substituted by up to 5 instances of J. In some embodiments, ring C is phenyland it is unsubstituted. In other embodiments, it is substituted by 1 to 3 instances of J: wherein each J is independently selected from halogen, a Caliphatic. —NH2, —CN or —O(C- 65 aliphatic). In other embodiments, each J is independently selected from halogen, —NH-CN, C-alkyl or —O(C- US 9,309,235 B2 25 TABLE 1-continued -continued

O OLi Step 2 I-3 1N i 21 OE H2NHN R R HCI EtOH O 700 C. B ? R ? R 10 R N Step 3 R N Y AIMe, NHCI Y. A toluene M 110° C. OEt NH2 15 O HN I-4 C D

Step 1: Dione Enolate Formation: To a solution of ketone A in THF cooled to -78° C., LiHMDS (e.g., 0.9 eq, 1.0 M in toluene) is added dropwise via syringe. The reaction is then allowed to warm to 0°C., then charged with diethyl oxalate (1.2 eq). At this time, the reaction is warmed to room temperature and stirred at that 25 temperature until judged complete (e.g., using either TLC or LC/MS analysis). Once the reaction is complete (reaction time was typically 45 minutes), the product dione enolate B is F used as-is in Step 2, i.e., the cyclization step, without any further purification. F I-5 30 Step 2: Pyrazole Formation: Dione enolate B is diluted with ethanol and consecutively charged with HCl (e.g., 3 eq, 1.25M solution in ethanol) and arylhydrazine hydrate (e.g., 1.15 eq). The reaction mixture is 35 heated to 70° C. and stirred until cyclization is deemed com plete (e.g., by LC/MS analysis, typically 30 minutes). Once complete, the reaction mixture is treated carefully with solid Sodium bicarbonate (e.g., 4 eq) and diluted with dichlo romethane and water. Layers are separated, and aqueous layer 40 is further diluted with water before extraction with dichlo romethane (3x). The combined organics are washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting pyrazole C is then purified by SiO, chromatog Methods of Preparing the Compounds raphy using an appropriate gradient of EtOAC in hexanes. The compounds of Formula I may be prepared according to 45 Step 3: Amidine Formation: the schemes and examples depicted and described below. To a suspension of NHCl (e.g., 5 eq) in toluene cooled to Unless otherwise specified, the starting materials and various 0° C. is added AlMe (e.g., 5 eq, 2.0M solution in toluene) intermediates may be obtained from commercial sources, dropwise via Syringe. Reaction is allowed to warm to room prepared from commercially available compounds or pre temperature, and stirred until no more bubbling is observed. pared using well-known synthetic methods. Another aspect of 50 Pyrazole C is added in 1 portion to the reaction, heated to 110° the present invention is a process for preparing the com C., and stirred at this temperature until judged complete (e.g., pounds of Formula I as disclosed herein. General synthetic procedures for the compounds of this using either TLC or LC/MS analysis). Once complete, reac invention are described below. The synthetic schemes are tion is cooled, treated with excess methanol, and stirred Vig presented as examples and do not limit the scope of the 55 orously for 1 hour at room temperature. The thick slurry is invention in any way. filtered, and the resulting solid cake is washed with methanol. General Procedure A The filtrate is concentrated in vacuo, and the resulting Solids are re-suspended in an ethyl acetate:isopropyl alcohol 5:1 solvent mixture. The reaction is further treated with saturated O Step 1 60 sodium carbonate solution, and stirred for 10 minutes before LHMDS -e- the layers are separated. The aqueous layer is extracted with THF/toluene the ethyl acetate:isopropyl alcohol=5:1 solvent mixture (3x), R Me O and the combined organics are washed with brine. The organ A OEt ics are further dried over MgSO4, filtered, and the solvent is 65 removed in vacuo. The product amidine D is used as-is in EtO subsequent steps without further purification. See more details in the Example section. US 9,309,235 B2 27 28 Pharmaceutically Acceptable Salts of the Invention. The preparation of the pharmaceutically acceptable salts The phrase “pharmaceutically acceptable salt, as used described above and other typical pharmaceutically accept herein, refers to pharmaceutically acceptable organic or inor able salts is more fully described by Berget al., “Pharmaceu ganic salts of a compound of Formula I. The pharmaceutically tical Salts.” J. Pharm. Sci., 1977:66:1-19, incorporated here acceptable salts of a compound of Formula I are used in 5 by reference in its entirety. medicine. Salts that are not pharmaceutically acceptable may, In addition to the compounds described herein, their phar however, be useful in the preparation of a compound of For maceutically acceptable salts may also be employed in com mula I or of their pharmaceutically acceptable salts. A phar positions to treat or prevent the herein identified disorders. maceutically acceptable salt may involve the inclusion of Pharmaceutical Compositions and Methods of Administra another molecule Such as an acetate ion, a Succinate ion or 10 tion. other counter ion. The counter ion may be any organic or The compounds herein disclosed, and their pharmaceuti inorganic moiety that stabilizes the charge on the parent com cally acceptable salts thereof may be formulated as pharma pound. Furthermore, a pharmaceutically acceptable salt may ceutical compositions or “formulations'. have more than one charged atom in its structure. Instances A typical formulation is prepared by mixing a compound where multiple charged atoms are part of the pharmaceuti 15 of Formula I, or a pharmaceutically acceptable salt thereof, cally acceptable salt can have multiple counter ions. Hence, a and a carrier, diluent or excipient. Suitable carriers, diluents pharmaceutically acceptable salt can have one or more and excipients are well known to those skilled in the art and charged atoms and/or one or more counterion. include materials such as carbohydrates, waxes, water soluble Pharmaceutically acceptable salts of the compounds and/or swellable polymers, hydrophilic or hydrophobic mate described herein include those derived from the compounds rials, gelatin, oils, solvents, water, and the like. The particular with inorganic acids, organic acids or bases. In some embodi carrier, diluent or excipient used will depend upon the means ments, the salts can be prepared in situ during the final isola and purpose for which a compound of Formula I is being tion and purification of the compounds. In other embodiments formulated. Solvents are generally selected based on solvents the salts can be prepared from the free form of the compound recognized by persons skilled in the art as safe (GRAS-Gen in a separate synthetic step. 25 erally Regarded as Safe) to be administered to a mammal. In When a compound of Formula I is acidic or contains a general, safe solvents are non-toxic aqueous solvents such as sufficiently acidic bioisostere, suitable “pharmaceutically water and other non-toxic solvents that are soluble or miscible acceptable salts' refers to salts prepared form pharmaceuti in water. Suitable aqueous solvents include water, ethanol, cally acceptable non-toxic bases including inorganic bases propylene glycol, polyethylene glycols (e.g., PEG400, and organic bases. Salts derived frominorganic bases include 30 PEG300), etc. and mixtures thereof. The formulations may aluminum, ammonium, calcium, copper, ferric, ferrous, also include other types of excipients such as one or more lithium, magnesium, manganic salts, manganous, potassium, buffers, stabilizing agents, antiadherents, surfactants, wetting sodium, zinc and the like. Particular embodiments include agents, lubricating agents, emulsifiers, binders, Suspending ammonium, calcium, magnesium, potassium and sodium agents, disintegrants, fillers, Sorbents, coatings (e.g. enteric or salts. Salts derived from pharmaceutically acceptable organic 35 slow release) preservatives, antioxidants, opaquing agents, non-toxic bases include salts of primary, secondary and ter glidants, processing aids, colorants, Sweeteners, perfuming tiary amines, Substituted amines including naturally occur agents, flavoring agents and other known additives to provide ring Substituted amines, cyclic amines and basic ion exchange an elegant presentation of the drug (i.e., a compound of For resins, such as arginine, betaine, caffeine, choline, N. mula I or pharmaceutical composition thereof) or aid in the N.sup. 1-dibenzylethylenediamine, diethylamine, 2-diethy 40 manufacturing of the pharmaceutical product (i.e., medica laminoethanol, 2-dimethylaminoethanol, ethanolamine, eth ment). ylenediamine, N-ethylmorpholine, N-ethylpiperidine, glu The formulations may be prepared using conventional dis camine, glucosamine, histidine, hydrabamine, Solution and mixing procedures. For example, the bulk drug isopropylamine, lysine, methylglucamine, morpholine, pip Substance (i.e., a compound of Formula I, a pharmaceutically erazine, piperidine, polyamine resins, procaine, purines, 45 acceptable salt thereof, or a stabilized form of the compound, theobromine, triethylamine, trimethylamine tripropylamine, such as a complex with a cyclodextrin derivative or other tromethamine and the like. known complexation agent) is dissolved in a suitable solvent When a compound of Formula I is basic or contains a in the presence of one or more of the excipients described sufficiently basic bioisostere, salts may be prepared from above. A compound having the desired degree of purity is pharmaceutically acceptable non-toxic acids, including inor 50 optionally mixed with pharmaceutically acceptable diluents, ganic and organic acids. Such acids include acetic, benzene carriers, excipients or stabilizers, in the form of a lyophilized Sulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formulation, milled powder, or an aqueous solution. Formu fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lation may be conducted by mixing at ambient temperature at isethionic, lactic, maleic, malic, mandelic, methanesulfonic, the appropriate pH, and at the desired degree of purity, with mucic, nitric, pamoic, pantothenic, phosphoric, succinic, Sul 55 physiologically acceptable carriers. The pH of the formula furic, tartaric, p-toluenesulfonic acid and the like. Particular tion depends mainly on the particular use and the concentra embodiments include citric, hydrobromic, hydrochloric, tion of compound, but may range from about 3 to about 8. maleic, phosphoric, Sulfuric and tartaric acids. Other exem When the agent described herein is a solidamorphous disper plary salts include, but are not limited, to Sulfate, citrate, sion formed by a solvent process, additives may be added acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, 60 directly to the spray-drying Solution when forming the mix phosphate, acid phosphate, isonicotinate, lactate, Salicylate, ture such as the additive is dissolved or suspended in the acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, Solution as a slurry which can then be spray dried. Alterna ascorbate. Succinate, maleate, gentisinate, fumarate, glucon tively, the additives may be added following spray-drying ate, glucuronate, Saccharate, formate, benzoate, glutamate, process to aid in the forming of the final formulated product. methanesulfonate, ethanesulfonate, benzenesulfonate, 65 The compound of Formula I or a pharmaceutically accept p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2- able salt thereof is typically formulated into pharmaceutical hydroxy-3-naphthoate)) salts. dosage forms to provide an easily controllable dosage of the US 9,309,235 B2 29 30 drug and to enable patient compliance with the prescribed anol: 3-pentanol; and m-cresol); proteins. Such as serum albu regimen. Pharmaceutical formulations of a compound of For min, gelatin, or immunoglobulins; hydrophilic polymers such mula I, or a pharmaceutically acceptable salt thereof, may be as polyvinylpyrrolidone; amino acids such as glycine, prepared for various routes and types of administration. Vari glutamine, asparagine, histidine, arginine, or lysine; ous dosage forms may exist for the same compound, since monosaccharides, disaccharides, and other carbohydrates different medical conditions may warrant different routes of including glucose, mannose, or dextrins; chelating agents administration. Such as EDTA; Sugars such as Sucrose, mannitol, tretralose or The amount of active ingredient that may be combined Sorbitol; salt-forming counter-ions such as sodium; metal with the carrier material to produce a single dosage form will complexes (e.g. Zn-protein complexes); and/or non-ionic Sur vary depending upon the Subject treated and the particular 10 factants such as TWEENTM, PLURONICSTM or polyethylene mode of administration. For example, a time-release formu glycol (PEG). The active pharmaceutical ingredients may lation intended for oral administration to humans may contain also be entrapped in microcapsules prepared, for example, by approximately 1 to 1000 mg of active material compounded coacervation techniques or by interfacial polymerization, with an appropriate and convenient amount of carrier material e.g., hydroxymethylcellulose or gelatin-microcapsules and which may vary from about 5 to about 95% of the total 15 poly-(methylmethacylate) microcapsules, respectively; in compositions (weight: weight). The pharmaceutical compo colloidal drug delivery systems (for example, liposomes, sition can be prepared to provide easily measurable amounts albumin microspheres, microemulsions, nanoparticles and for administration. For example, an aqueous solution nanocapsules) or in macroemulsions. Such techniques are intended for intravenous infusion may contain from about 3 to disclosed in Remingtons: The Science and Practice of Phar 500 ug of the active ingredient per milliliter of solution in macy, 21 'Edition, University of the Sciences in Philadelphia, order that infusion of a suitable volume at a rate of about 30 Eds., 2005 (hereafter “Remington's'). mL/hr can occur. As a general proposition, the initial phar “Controlled drug delivery systems' supply the drug to the maceutically effective amount of the inhibitor administered body in a manner precisely controlled to Suit the drug and the will be in the range of about 0.01-100 mg/kg perdose, namely conditions being treated. The primary aim is to achieve a about 0.1 to 20 mg/kg of patient body weight per day, with the 25 therapeutic drug concentration at the site of action for the typical initial range of compound used being 0.3 to 15 mg/kg/ desired duration of time. The term “controlled release' is day. often used to refer to a variety of methods that modify release The term “therapeutically effective amount’ as used herein of drug from a dosage form. This term includes preparations means that amount of active compound or pharmaceutical labeled as “extended release”, “delayed release”, “modified agent that elicits the biological or medicinal response in a 30 release' or “Sustained release'. In general, one can provide tissue, system, animal or human that is being sought by a for controlled release of the agents described herein through researcher, veterinarian, medical doctor or other clinician. the use of a wide variety of polymeric carriers and controlled The therapeutically or pharmaceutically effective amount of release systems including erodible and non-erodible matri the compound to be administered will be governed by such ces, osmotic control devices, various reservoir devices, considerations, and is the minimum amount necessary to 35 enteric coatings and multiparticulate control devices. ameliorate, cure or treat the disease or disorder or one or more “Sustained-release preparations' are the most common of its symptoms. applications of controlled release. Suitable examples of Sus The pharmaceutical compositions of Formula I will be tained-release preparations include semipermeable matrices formulated, dosed, and administered in a fashion, i.e., of Solid hydrophobic polymers containing the compound, amounts, concentrations, Schedules, course, vehicles, and 40 which matrices are in the form of shaped articles, e.g. films, or route of administration, consistent with good medical prac microcapsules. Examples of Sustained-release matrices tice. Factors for consideration in this context include the include polyesters, hydrogels (for example, poly(2-hydroxy particular disorder being treated, the particular mammal ethyl-methacrylate), or poly(vinylalcohol)), polylactides being treated, the clinical condition of the individual patient, (U.S. Pat. No. 3,773.919), copolymers of L-glutamic acid and the cause of the disorder, the site of delivery of the agent, the 45 gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl method of administration, the scheduling of administration, acetate, degradable lactic acid-glycolic acid copolymers, and and other factors known to medical practitioners, such as the poly-D-(-)-3-hydroxybutyric acid. age, weight, and response of the individual patient. “Immediate-release preparations' may also be prepared. The term “prophylactically effective amount” refers to an The objective of these formulations is to get the drug into the amount effective in preventing or Substantially lessening the 50 bloodstream and to the site of action as rapidly as possible. chances of acquiring a disease or disorder or in reducing the For instance, for rapid dissolution, most tablets are designed severity of the disease or disorder before it is acquired or to undergo rapid disintegration to granules and Subsequent reducing the severity of one or more of its symptoms before deaggregation to fine particles. This provides a larger Surface the symptoms develop. Roughly, prophylactic measures are area exposed to the dissolution medium, resulting in a faster divided between primary prophylaxis (to prevent the devel 55 dissolution rate. opment of a disease) and secondary prophylaxis (whereby the Agents described herein can be incorporated into an erod disease has already developed and the patient is protected ible or non-erodible polymeric matrix controlled release against worsening of this process). device. By an erodible matrix is meant aqueous-erodible or Acceptable diluents, carriers, excipients, and Stabilizers water-swellable or aqueous-Soluble in the sense of being are those that are nontoxic to recipients at the dosages and 60 either erodible or swellable or dissolvable in pure water or concentrations employed, and include buffers such as phos requiring the presence of an acid or base to ionize the poly phate, citrate, and other organic acids; antioxidants including meric matrix Sufficiently to cause erosion or dissolution. ascorbic acid and methionine; preservatives (such as octade When contacted with the aqueous environment of use, the cyldimethylbenzyl ammonium chloride; hexamethonium erodible polymeric matrix imbibes water and forms an aque chloride; benzalkonium chloride, benzethonium chloride; 65 ous-swollen gel or matrix that entraps the agent described phenol, butyl or benzyl alcohol; alkyl parabens Such as herein. The aqueous-swollen matrix gradually erodes, Swells, methyl or propyl paraben; catechol; resorcinol, cyclohex disintegrates or dissolves in the environment of use, thereby US 9,309,235 B2 31 32 controlling the release of a compound described herein to the generally include a core containing one or more agents as environment of use. One ingredient of this water-swollen described herein and a water permeable, non-dissolving and matrix is the water-swellable, erodible, or soluble polymer, non-eroding coating Surrounding the core which controls the which may generally be described as an osmopolymer, influx of water into the core from an aqueous environment of hydrogel or water-swellable polymer. Such polymers may be use so as to cause drug release by extrusion of some or all of linear, branched, or cross linked. The polymers may be the core to the environment of use. In certain embodiments, homopolymers or copolymers. In certain embodiments, they the coating is polymeric, aqueous-permeable, and has at least may be synthetic polymers derived from vinyl, acrylate, one delivery port. The core of the osmotic device optionally methacrylate, urethane, ester and oxide monomers. In other includes an osmotic agent which acts to imbibe water from embodiments, they can be derivatives of naturally occurring 10 the Surrounding environment via Such a semipermeable mem polymers such as polysaccharides (e.g. chitin, chitosan, dex brane. The osmotic agent contained in the core of this device tran and pullulan, gum agar, gum arabic, gum karaya, locust may be an aqueous-Swellable hydrophilic polymer or it may bean gum, gum tragacanth, carrageenans, gum ghatti, guar be an osmogen, also known as an osmagent. Pressure is gum, Xanthan gum and Scleroglucan), starches (e.g. dextrin generated within the device which forces the agent(s) out of and maltodextrin), hydrophilic colloids (e.g. pectin), phos 15 the device via an orifice (of a size designed to minimize solute phatides (e.g. lecithin), alginates (e.g. ammonium alginate, diffusion while preventing the build-up of a hydrostatic pres Sodium, potassium or calcium alginate, propylene glycol Sure head). Nonlimiting examples of osmotic control devices alginate), gelatin, collagen, and cellulosics. Cellulosics are are disclosed in U.S. patent application Ser. No. 09/495,061. cellulose polymer that has been modified by reaction of at The amount of water-swellable hydrophilic polymers least a portion of the hydroxyl groups on the saccharide repeat present in the core may range from about 5 to about 80 wt % units with a compound to form an ester-linked or an ether (including for example, 10 to 50 wt %). Non limiting linked substituent. For example, the cellulosic ethyl cellulose examples of core materials include hydrophilic vinyl and has an ether linked ethyl substituent attached to the saccharide acrylic polymers, polysaccharides such as calcium alginate, repeat unit, while the cellulosic cellulose acetate has an ester polyethylene oxide (PEO), polyethylene glycol (PEG), linked acetate substituent. In certain embodiments, the cellu 25 polypropylene glycol (PPG), poly(2-hydroxyethyl methacry losics for the erodible matrix comprises aqueous-soluble and late), poly(acrylic) acid, poly(methacrylic) acid, polyvi aqueous-erodible cellulosics can include, for example, ethyl nylpyrrolidone (PVP) and cross linked PVP polyvinyl alco cellulose (EC), methylethyl cellulose (MEC), carboxymethyl hol (PVA). PVA/PVP copolymers and PVA/PVP copolymers cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), with hydrophobic monomers such as methyl methacrylate, hydroxypropyl cellulose (HPC), cellulose acetate (CA), cel 30 vinyl acetate, and the like, hydrophilic polyurethanes con lulose propionate (CP), cellulose butyrate (CB), cellulose taining large PEO blocks, sodium croScarmellose, carrag acetate butyrate (CAB), CAP CAT, hydroxypropyl methyl eenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellu cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl lose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose acetate trimellitate (HPMCAT), and ethyl carboxymethyl cellulose (CMC) and carboxyethyl cellulose hydroxyethylcellulose (EHEC). In certain embodiments, the 35 (CEC), sodium alginate, polycarbophil, gelatin, Xanthan cellulosics comprises various grades of low viscosity (MW gum, and sodium starch glycolat. Other materials include less than or equal to 50,000 daltons, for example, the Dow hydrogels comprising interpenetrating networks of polymers MethocelTM series E5, E15LV, E50LV and K10OLY) and high that may be formed by addition or by condensation polymer viscosity (MW greater than 50,000 daltons, for example, ization, the components of which may comprise hydrophilic E4MCR, E1OMCR, K4M, K15M and K10OM and the 40 and hydrophobic monomers such as those just mentioned. MethocelTM K series) HPMC. Other commercially available Water-swellable hydrophilic polymers include but are not types of HPMC include the Shin Etsu Metolose 90SH series. limited to PEO, PEG, PVP, sodium croscarmellose, HPMC, Other materials useful as the erodible matrix material Sodium starch glycolate, polyacrylic acid and cross linked include, but are not limited to, pullulan, polyvinyl pyrroli versions or mixtures thereof. done, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid 45 The core may also include an osmogen (or osmagent). The esters, polyacrylamide, polyacrylic acid, copolymers of amount of osmogen present in the core may range from about ethacrylic acid or methacrylic acid (EUDRAGITR), Rohm 2 to about 70 wt % (including, for example, from 10 to 50 wt America, Inc., Piscataway, N.J.) and other acrylic acid deriva %). Typical classes of Suitable osmogens are water-soluble tives such as homopolymers and copolymers of butyl organic acids, salts and Sugars that are capable of imbibing methacrylate, methylmethacrylate, ethylmethacrylate, ethy 50 water to thereby effect an osmotic pressure gradient across lacrylate, (2-dimethylaminoethyl) methacrylate, and the barrier of the Surrounding coating. Typical useful (trimethylaminoethyl) methacrylate chloride. osmogens include but are not limited to magnesium sulfate, Alternatively, the agents of the present invention may be magnesium chloride, calcium chloride, Sodium chloride, administered by or incorporated into a non-erodible matrix lithium chloride, potassium sulfate, Sodium carbonate, device. In Such devices, an agent described herein is distrib 55 Sodium Sulfite, lithium sulfate, potassium chloride, sodium uted in an inert matrix. The agent is released by diffusion Sulfate, mannitol. Xylitol, urea, Sorbitol, inositol, raffinose, through the inert matrix. Examples of materials suitable for Sucrose, glucose, fructose, lactose, citric acid, Succinic acid, the inert matrix include insoluble plastics (e.g. methyl acry tartaric acid, and mixtures thereof. In certain embodiments, late-methyl methacrylate copolymers, polyvinyl chloride, the osmogen is glucose, lactose, Sucrose, mannitol. Xylitol, polyethylene), hydrophilic polymers (e.g. ethyl cellulose, 60 Sodium chloride, including combinations thereof. cellulose acetate, cross linked polyvinylpyrrolidone (also The rate of drug delivery is controlled by such factors as the known as crospovidone)), and fatty compounds (e.g. car permeability and thickness of the coating, the osmotic pres nauba wax, microcrystalline wax, and triglycerides). Such Sure of the drug-containing layer, the degree of hydrophilicity devices are described further in Remington: The Science and of the hydrogel layer, and the surface area of the device. Those Practice of Pharmacy, 20th edition (2000). 65 skilled in the art will appreciate that increasing the thickness As noted above, the agents described herein may also be of the coating will reduce the release rate, while any of the incorporated into an osmotic control device. Such devices following will increase the release rate: increasing the per US 9,309,235 B2 33 34 meability of the coating; increasing the hydrophilicity of the semipermeable layer formed over the expandable layer. A hydrogel layer, increasing the osmotic pressure of the drug delivery port connects the liquid formulation with the aque containing layer, or increasing the device's Surface area. ous use environment. Such devices are described, for In certain embodiments, entrainment of particles of agents example, in U.S. Pat. No. 6,419,952, U.S. Pat. No. 6,342.249, described herein in the extruding fluid during operation of 5 U.S. Pat. No. 5,324,280, U.S. Pat. No. 4,672,850, U.S. Pat. such osmotic device is desirable. For the particles to be well No. 4,627,850, U.S. Pat. No. 4,203,440, and U.S. Pat. No. entrained, the agent drug form is dispersed in the fluid before 3,995,631. the particles have an opportunity to settle in the tablet core. As further noted above, the agents described herein may be One means of accomplishing this is by adding a disintegrant provided in the form of microparticulates, generally ranging that serves to break up the compressed core into its particulate 10 in size from about 10 um to about 2 mm (including, for components. Nonlimiting examples of standard disintegrants example, from about 100 um to 1 mm in diameter). Such include materials such as Sodium starch glycolate (e.g., multiparticulates may be packaged, for example, in a capsule ExplotabTMCLV), microcrystalline cellulose (e.g., AviceITM), Such as a gelatin capsule or a capsule formed from an aque microcrystalline silicified cellulose (e.g., ProSolviM) and ous-soluble polymer such as HPMCAS, HPMC or starch; croscarmellose sodium (e.g., Ac-Di-SolTM), and other disin 15 dosed as a Suspension or slurry in a liquid; or they may be tegrants known to those skilled in the art. Depending upon the formed into a tablet, caplet, or pill by compression or other particular formulation, Some disintegrants work better than processes known in the art. Such multiparticulates may be others. Several disintegrants tend to form gels as they swell made by any known process. Such as wet- and dry-granulation with water, thus hindering drug delivery from the device. processes, extrusion/spheronization, roller-compaction, Non-gelling, non-Swelling disintegrants provide a more rapid melt-congealing, or by spray-coating seed cores. For dispersion of the drug particles within the core as water enters example, in wet- and dry-granulation processes, the agent the core. In certain embodiments, non-gelling, non-Swelling described herein and optional excipients may be granulated to disintegrants are resins, for example, ion-exchange resins. In form multiparticulates of the desired size. one embodiment, the resin is AmberliteTM IRP 88 (available The agents can be incorporated into microemulsions, from Rohm and Haas, Philadelphia, Pa.). When used, the 25 which generally are thermodynamically stable, isotropically disintegrant is present in amounts ranging from about 1-25% clear dispersions of two immiscible liquids, such as oil and of the core agent. water, stabilized by an interfacial film of surfactant molecules Another example of an osmotic device is an osmotic cap (Encyclopedia of Pharmaceutical Technology, New York: sule. The capsule shell or portion of the capsule shell can be Marcel Dekker, 1992, volume 9). For the preparation of semipermeable. The capsule can be filled either by a powder 30 microemulsions, Surfactant (emulsifier), co-surfactant (co or liquid consisting of an agent described herein, excipients emulsifier), an oil phase and a water phase are necessary. that imbibe water to provide osmotic potential, and/or a Suitable surfactants include any surfactants that are useful in water-Swellable polymer, or optionally solubilizing excipi the preparation of emulsions, e.g., emulsifiers that are typi ents. The capsule core can also be made such that it has a cally used in the preparation of creams. The co-surfactant (or bilayer or multilayer agent analogous to the bilayer, trilayer or 35 “co-emulsifier) is generally selected from the group of concentric geometries described above. polyglycerol derivatives, glycerol derivatives and fatty alco Another class of osmotic device useful in this invention hols. Preferred emulsifier/co-emulsifier combinations are comprises coated swellable tablets, for example, as described generally although not necessarily selected from the group in EP3784.04. Coated swellable tablets comprise a tablet core consisting of glyceryl monostearate and polyoxyethylene comprising an agent described hereinanda Swelling material, 40 Stearate; polyethylene glycol and ethylene glycol palmito preferably a hydrophilic polymer, coated with a membrane, Stearate; and caprilic and capric triglycerides and oleoyl mac which contains holes, orpores through which, in the aqueous rogolglycerides. The water phase includes not only water but use environment, the hydrophilic polymer can extrude and also, typically, buffers, glucose, propylene glycol, polyethyl carry out the agent. Alternatively, the membrane may contain ene glycols, preferably lower molecular weight polyethylene polymeric or low molecular weight water-soluble porosigens. 45 glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the Porosigens dissolve in the aqueous use environment, provid like, while the oil phase will generally comprise, for example, ing pores through which the hydrophilic polymer and agent fatty acid esters, modified vegetable oils, silicone oils, mix may extrude. Examples of porosigens are water-soluble poly tures of mono- di- and triglycerides, mono- and di-esters of mers such as HPMC, PEG, and low molecular weight com PEG (e.g., oleoyl macrogol glycerides), etc. pounds such as glycerol. Sucrose, glucose, and sodium chlo 50 The compounds described herein can be incorporated into ride. In addition, pores may be formed in the coating by pharmaceutically-acceptable nanoparticle, nanosphere, and drilling holes in the coating using a laser or other mechanical nanocapsule formulations (Delie and Blanco-Prieto, 2005, means. In this class of osmotic devices, the membrane mate Molecule 10:65-80). Nanocapsules can generally entrap rial may comprise any film-forming polymer, including poly compounds in a stable and reproducible way. To avoid side mers which are water permeable or impermeable, providing 55 effects due to intracellular polymeric overloading, ultrafine that the membrane deposited on the tablet core is porous or particles (sized around 0.1 um) can be designed using poly contains water-soluble porosigens or possesses a macro mers able to be degraded in vivo (e.g. biodegradable poly scopic hole for water ingress and drug release. Embodiments alkyl-cyanoacrylate nanoparticles). Such particles are of this class of Sustained release devices may also be multi described in the prior art. layered, as described, for example, in EP3784.04. 60 Implantable devices coated with a compound of this inven When an agent described herein is a liquid or oil. Such as a tion are another embodiment of the present invention. The lipid vehicle formulation, for example as described in WO05/ compounds may also be coated on implantable medical 01 1634, the osmotic controlled-release device may comprise devices, such as beads, or co-formulated with a polymer or a soft-gel or gelatin capsule formed with a composite wall and other molecule, to provide a "drug depot', thus permitting the comprising the liquid formulation where the wall comprises a 65 drug to be released over a longer time period than adminis barrier layer formed over the external surface of the capsule, tration of an aqueous solution of the drug. Suitable coatings an expandable layer formed over the barrier layer, and a and the general preparation of coated implantable devices are US 9,309,235 B2 35 36 described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304, Solid dosage forms for oral administration include cap 121. The coatings are typically biocompatible polymeric Sules, tablets, pills, powders, and granules. In Such solid dos materials such as a hydrogel polymer, polymethyldisiloxane, age forms, the active compound is mixed with at least one polycaprolactone, polyethylene glycol, polylactic acid, eth inert, pharmaceutically acceptable excipient or carrier Such as ylene vinyl acetate, and mixtures thereof. The coatings may Sodium citrate or dicalcium phosphate and/or a) fillers or optionally be further covered by a suitable topcoat of fluoro extenders such as starches, lactose, Sucrose, glucose, manni silicone, polysaccharides, polyethylene glycol, phospholip tol, and silicic acid, b) binders such as, for example, car ids or combinations thereof to impart controlled release char boxymethylcellulose, alginates, gelatin, polyvinylpyrrolidi acteristics in the composition. none. Sucrose, and acacia, c) humectants such as glycerol. d) The formulations include those suitable for the administra 10 disintegrating agents such as agar-agar, calcium carbonate, tion routes detailed herein. The formulations may conve potato or tapioca starch, alginic acid, certain silicates, and niently be presented in unit dosage form and may be prepared Sodium carbonate, e) solution retarding agents such as paraf by any of the methods well known in the art of pharmacy. fin, f) absorption accelerators such as quaternary ammonium Techniques and formulations generally are found in Reming compounds, g) wetting agents such as, for example, cetyl tons. Such methods include the step of bringing into asso 15 alcohol and glycerol monostearate, h) absorbents such as ciation the active ingredient with the carrier which constitutes kaolin and bentonite clay, and i) lubricants such as talc, cal one or more accessory ingredients. In general the formula cium Stearate, magnesium Stearate, Solid polyethylene gly tions are prepared by uniformly and intimately bringing into cols, sodium lauryl Sulfate, and mixtures thereof. Tablets may association the active ingredient with liquid carriers or finely be uncoated or may be coated by known techniques including divided Solid carriers or both, and then, if necessary, shaping microencapsulation to mask an unpleasant taste or to delay the product. disintegration and adsorption in the gastrointestinal tract and The terms “administer”, “administering or “administra thereby provide a Sustained action over a longer period. For tion' in reference to a compound, composition or formulation example, a time delay material Such as glyceryl monostearate of the invention means introducing the compound into the or glyceryl distearate alone or with a wax may be employed. system of the animal in need of treatment. When a compound 25 A water Soluble taste masking material Such as hydroxypro of the invention is provided in combination with one or more pyl-methylcellulose or hydroxypropyl-cellulose may be other active agents, “administration' and its variants are each employed. understood to include concurrent and/or sequential introduc Formulations of a compound of Formula I that are suitable tion of the compound and the other active agents. for oral administration may be prepared as discrete units such The compositions described herein may be administered 30 as tablets, pills, troches, lozenges, aqueous or oil suspensions, systemically or locally, e.g.: orally (e.g. using capsules, pow dispersible powders or granules, emulsions, hard or soft cap ders, solutions, suspensions, tablets, sublingual tablets and Sules, e.g. gelatin capsules, syrups or elixirs. Formulations of the like), by inhalation (e.g. with an aerosol, gas, inhaler, a compound intended for oral use may be prepared according nebulizer or the like), to the ear (e.g. using ear drops), topi to any method known to the art for the manufacture of phar cally (e.g. using creams, gels, liniments, lotions, ointments, 35 maceutical compositions. pastes, transdermal patches, etc), ophthalmically (e.g. with Compressed tablets may be prepared by compressing in a eye drops, ophthalmic gels, ophthalmic ointments), rectally Suitable machine the active ingredient in a free-flowing form (e.g. using enemas or Suppositories), nasally, buccally, vagi Such as a powder or granules, optionally mixed with a binder, nally (e.g. using douches, intrauterine devices, vaginal Sup lubricant, inert diluent, preservative, Surface active or dis positories, vaginal rings or tablets, etc), via an implanted 40 persing agent. Molded tablets may be made by molding in a reservoir or the like, or parenterally depending on the severity Suitable machine a mixture of the powdered active ingredient and type of the disease being treated. The term “parenteral as moistened with an inert liquid diluent. used herein includes, but is not limited to, Subcutaneous, Formulations for oral use may also be presented as hard intravenous, intramuscular, intra-articular, intra-synovial, gelatin capsules wherein the active ingredient is mixed with intrasternal, intrathecal, intrahepatic, intralesional and intrac 45 an inert Solid diluent, for example, calcium carbonate, cal ranial injection or infusion techniques. Preferably, the com cium phosphate or kaolin, or as Soft gelatin capsules wherein positions are administered orally, intraperitoneally or intra the active ingredient is mixed with water soluble carrier such venously. as polyethyleneglycol or an oil medium, for example peanut The pharmaceutical compositions described herein may be oil, liquid paraffin, or olive oil. orally administered in any orally acceptable dosage form 50 The active compounds can also be in microencapsulated including, but not limited to, capsules, tablets, aqueous Sus form with one or more excipients as noted above. pensions or solutions. Liquid dosage forms for oral adminis When aqueous Suspensions are required for oral use, the tration include, but are not limited to, pharmaceutically active ingredient is combined with emulsifying and Suspend acceptable emulsions, microemulsions, Solutions, Suspen ing agents. If desired, certain Sweetening and/or flavoring sions, syrups and elixirs. In addition to the active compounds, 55 agents may be added. Syrups and elixirs may be formulated the liquid dosage forms may contain inert diluents commonly with Sweetening agents, for example glycerol, propylene gly used in the art such as, for example, water or other solvents, col, Sorbitol or Sucrose. Such formulations may also contain a solubilizing agents and emulsifiers such as ethyl alcohol, demulcent, a preservative, flavoring and coloring agents and isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alco antioxidant. hol, benzyl benzoate, propylene glycol. 1,3-butylene glycol, 60 Sterile injectable forms of the compositions described dimethylformamide, oils (in particular, cottonseed, ground herein (e.g. for parenteral administration) may be acqueous or nut, corn, germ, olive, castor, and sesame oils), glycerol, oleaginous Suspension. These suspensions may be formu tetrahydrofurfuryl alcohol, polyethylene glycols and fatty lated according to techniques known in the art using Suitable acid esters of sorbitan, and mixtures thereof. Besides inert dispersing or wetting agents and Suspending agents. The ster diluents, the oral compositions can also include adjuvants 65 ile injectable preparation may also be a sterile injectable Such as Wetting agents, emulsifying and Suspending agents, Solution or Suspension in a non-toxic parenterally-acceptable Sweetening, flavoring, and perfuming agents. diluent or solvent, for example as a solution in 1,3-butanediol. US 9,309,235 B2 37 38 Among the acceptable vehicles and solvents that may be polymer employed, the rate of compound release can be con employed are water, Ringer's Solution and isotonic sodium trolled. Examples of other biodegradable polymers include chloride solution. In addition, sterile, fixed oils are conven poly(orthoesters) and poly(anhydrides). Depot injectable for tionally employed as a solvent or Suspending medium. For mulations are also prepared by entrapping the compound in this purpose, any bland fixed oil may be employed including liposomes or microemulsions that are compatible with body synthetic mono- or di-glycerides. Fatty acids, such as oleic tissues. acid and its glyceride derivatives are useful in the preparation The injectable solutions or microemulsions may be intro of injectables, as are natural pharmaceutically-acceptable duced into a patient’s bloodstream by local bolus injection. oils, such as olive oil or castor oil, especially in their poly Alternatively, it may be advantageous to administer the solu oxyethylated versions. These oil solutions or Suspensions 10 tion or microemulsion in Such away as to maintain a constant may also contain a long-chain alcohol diluent or dispersant, circulating concentration of the instant compound. In order to Such as carboxymethyl cellulose or similar dispersing agents maintain Such a constant concentration, a continuous intra which are commonly used in the formulation of pharmaceu venous delivery device may be utilized. An example of such tically acceptable dosage forms including emulsions and Sus a device is the Deltec CADD-PLUSTM model 5400 intrave pensions. Other commonly used surfactants, such as Tweens, 15 nous pump. Spans and other emulsifying agents or bioavailability enhanc Compositions for rectal or vaginal administration are pref ers which are commonly used in the manufacture of pharma erably suppositories which can be prepared by mixing the ceutically acceptable Solid, liquid, or other dosage forms may compounds described herein with Suitable non-irritating also be used for the purposes of injectable formulations. excipients or carriers such as cocoa butter, beeswax, polyeth Oily Suspensions may beformulated by Suspending a com ylene glycolora Suppository wax which are solid at ambient pound of Formula I in a vegetable oil, for example arachis oil, temperature but liquid at body temperature and therefore melt olive oil, Sesame oil or coconut oil, or in mineral oil Such as in the rectum or vaginal cavity and release the active com liquid paraffin. The oily Suspensions may contain a thicken pound. Other formulations Suitable for vaginal administra ing agent, for example beeswax, hard paraffin or cetyl alco tion may be presented as pessaries, tampons, creams, gels, hol. Sweetening agents such as those set forth above, and 25 pastes, foams or sprays. flavoring agents may be added to provide a palatable oral The pharmaceutical compositions described herein may preparation. These compositions may be preserved by the also be administered topically, especially when the target of addition of an anti-oxidant Such as butylated hydroxyanisolor treatment includes areas or organs readily accessible by topi alpha-tocopherol. cal application, including diseases of the eye, the ear, the skin, Aqueous Suspensions of a compound of Formula I contain 30 or the lower intestinal tract. Suitable topical formulations are the active materials in admixture with excipients suitable for readily prepared for each of these areas or organs. the manufacture of aqueous suspensions. Such excipients Dosage forms for topical or transdermal administration of include a Suspending agent, such as Sodium carboxymethyl a compound described herein include ointments, pastes, cellulose, croScarmellose, povidone, methylcellulose, creams, lotions, gels, powders, Solutions, sprays, inhalants or hydroxypropyl methylcellulose, Sodium alginate, polyvi 35 patches. The active component is admixed under sterile con nylpyrrolidone, gum tragacanth and gum acacia, and dispers ditions with a pharmaceutically acceptable carrier and any ing or wetting agents such as a naturally occurring phos needed preservatives or buffers as may be required. Oph phatide (e.g., lecithin), a condensation product of an alkylene thalmic formulation, eardrops, and eye drops are also con oxide with a fatty acid (e.g., polyoxyethylene Stearate), a templated as being within the scope of this invention. Addi condensation product of ethylene oxide with a long chain 40 tionally, the present invention contemplates the use of aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a con transdermal patches, which have the added advantage of pro densation product of ethylene oxide with a partial ester viding controlled delivery of a compound to the body. Such derived from a fatty acid and a hexitol anhydride (e.g., poly dosage forms can be made by dissolving or dispensing the oxyethylene Sorbitan monooleate). The aqueous Suspension compound in the proper medium. Absorption enhancers can may also contain one or more preservatives such as ethyl or 45 also be used to increase the flux of the compound across the n-propyl p-hydroxy-benzoate, one or more coloring agents, skin. The rate can be controlled by either providing a rate one or more flavoring agents and one or more Sweetening controlling membrane or by dispersing the compound in a agents, such as Sucrose or saccharin. polymer matrix or gel. Topical application for the lower intes The injectable formulations can be sterilized, for example, tinal tract can be effected in a rectal Suppository formulation by filtration through a bacterial-retaining filter, or by incor 50 (see above) or in a suitable enema formulation. Topically porating sterilizing agents in the form of sterile solid compo transdermal patches may also be used. sitions which can be dissolved or dispersed in sterile water or For topical applications, the pharmaceutical compositions other sterile injectable medium prior to use. may be formulated in a suitable ointment containing the In order to prolong the effect of a compound described active component Suspended or dissolved in one or more herein, it is often desirable to slow the absorption of the 55 carriers. Carriers for topical administration of the compounds compound from Subcutaneous or intramuscular injection. of this invention include, but are not limited to, mineral oil, This may be accomplished by the use of a liquid Suspension of liquid petrolatum, white petrolatum, propylene glycol, poly crystalline or amorphous material with poor water solubility. oxyethylene, polyoxypropylene compound, emulsifying wax The rate of absorption of the compound then depends upon its and water. Alternatively, the pharmaceutical compositions rate of dissolution that, in turn, may depend upon crystal size 60 can beformulated in a Suitable lotion or cream containing the and crystalline form. Alternatively, delayed absorption of a active components suspended or dissolved in one or more parenterally administered compound form is accomplished pharmaceutically acceptable carriers. Suitable carriers by dissolving or Suspending the compound in an oil vehicle. include, but are not limited to, mineral oil, sorbitan Injectable depot forms are made by forming microencapsu monostearate, polysorbate 60, cetyl esters wax, cetearyl alco lated matrices of the compound in biodegradable polymers 65 hol. 2 octyldodecanol, benzyl alcohol and water. Such as polylactide-polyglycolide. Depending upon the ratio For ophthalmic use, the pharmaceutical compositions may of compound to polymer and the nature of the particular be formulated as micronized suspensions in isotonic, pH US 9,309,235 B2 39 40 adjusted Sterile Saline, or, preferably, as Solutions in isotonic, The formulations may be packaged in unit-dose or multi pH adjusted sterile saline, either with or without a preserva dose containers, for example sealed ampoules and vials, and tive such as benzylalkonium chloride. Alternatively, for oph may be stored in a freeze-dried (lyophilized) condition requir thalmic uses, the pharmaceutical compositions may be for ing only the addition of the sterile liquid carrier, for example mulated in an ointment Such as petrolatum. For treatment of 5 water, for injection immediately prior to use. Extemporane the eye or other external tissues, e.g., mouth and skin, the ous injection Solutions and Suspensions are prepared from formulations may be applied as a topical ointment or cream sterile powders, granules and tablets of the kind previously containing the active ingredient(s) in an amount of for described. Preferred unit dosage formulations are those con example, 0.075 to 20% w/w. When formulated in an oint taining a daily dose or unit daily Sub-dose, as herein above 10 recited, or an appropriate fraction thereof, of the active ingre ment, the active ingredients may be employed with either an dient. oil-based, paraffinic or a water-miscible ointment base. In another aspect, a compound of Formula I or a pharma Alternatively, the active ingredients may be formulated in ceutically acceptable salt thereof may be formulated in a a cream with an oil-in-water cream base. If desired, the aque Veterinary composition comprising a veterinary carrier. Vet ous phase of the cream base may include a polyhydric alco 15 erinary carriers are materials useful for the purpose of admin hol, i.e. an alcohol having two or more hydroxyl groups such istering the composition and may be solid, liquid or gaseous as propylene glycol, butane 1,3-diol, mannitol, Sorbitol, glyc materials which are otherwise inert or accepFormula In the erol and polyethylene glycol (including PEG 400) and mix Veterinary art and are compatible with the active ingredient. tures thereof. The topical formulations may desirably include These veterinary compositions may be administered a compound which enhances absorption or penetration of the parenterally, orally or by any other desired route. active ingredient through the skin or other affected areas. Therapeutic Methods Examples of such dermal penetration enhancers include dim The present disclosure relates to stimulators of soluble ethyl Sulfoxide and related analogs. guanylate cyclase (sGC), pharmaceutical formulations The oily phase of emulsions prepared using a compound of thereof and their use, alone or in combination with one or Formula I may be constituted from known ingredients in a 25 more additional agents, for treating and/or preventing various known manner. While the phase may comprise merely an diseases, wherein an increase in the concentration of NO oran emulsifier (otherwise known as an emulgent), it desirably increase in the concentration of c(GMP might be desirable. comprises a mixture of at least one emulsifier with a fat oran The diseases that can be treated include but are not limited oil or with both a fat and an oil. A hydrophilic emulsifier may topulmonary hypertension, arterial hypertension, heart fail be included together with a lipophilic emulsifier which acts as 30 ure, atherosclerosis, inflammation, thrombosis, renal fibrosis a stabilizer. In some embodiments, the emulsifier includes and failure, liver cirrhosis, erectile dysfunction and other both an oil and a fat. Together, the emulsifier(s) with or related cardiovascular disorders. without stabilizer(s) make up the so-called emulsifying wax, Increased concentration of c(CMP leads to vasodilation, and the wax together with the oil and fat make up the so-called inhibition of platelet aggregation and adhesion, anti-hyper emulsifying ointment base which forms the oily dispersed 35 tensive effects, anti-remodeling effects, anti-apoptotic phase of the cream formulations. Emulgents and emulsion effects, anti-inflammatory effects and neuronal signal trans stabilizers suitable for use in the formulation of a compound mission effects. Thus, sGC stimulators may be used to treat of Formula I include TweenTM-60, SpanTM-80, cetostearyl and/or prevent a range of diseases and disorders, including alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono but not limited to a peripheral, pulmonary, hepatic, liver, Stearate and sodium lauryl Sulfate. 40 cardiac or cerebralvasculariendothelial disorders or condi The pharmaceutical compositions may also be adminis tions, a urogenital-gynecological disorder or condition, a tered by nasal aerosol orby inhalation. Such compositions are thromboembolic disease, a fibrotic disorder, a pulmonary or prepared according to techniques well-known in the art of respiratory disorder, a renal or hepatic disorder, a metabolic pharmaceutical formulation and may be prepared as solutions disorder, atherosclerosis, or a lipid related disorder. in Saline, employing benzyl alcohol or other Suitable preser 45 In other embodiments, the compounds here disclosed are Vatives, absorption promoters to enhance bioavailability, sGC stimulators that may be useful in the prevention and/or fluorocarbons, and/or other conventional Solubilizing or dis treatment of diseases and disorders characterized by undesir persing agents. Formulations suitable for intrapulmonary or able reduced bioavailability of and/or sensitivity to NO, such nasal administration have a particle size for example in the as those associated with conditions of oxidative stress or range of 0.1 to 500 micros (including particles in a range 50 nitrosative stress. between 0.1 and 500 microns in increments microns such as Throughout this disclosure, the terms “hypertension'. 0.5, 1, 30, 35 microns, etc) which is administered by rapid “arterial hypertension” or “high blood pressure (HBP) are inhalation through the nasal passage or by inhalation through used interchangeable and refer to an extremely common and the mouth so as to reach the alveolar sacs. highly preventable chronic condition in which blood pressure The pharmaceutical composition (or formulation) for use 55 (BP) in the arteries is higher than normal. If not properly may be packaged in a variety of ways depending upon the controlled, it represents a significant risk factor for several method used for administering the drug. Generally, an article serious cardiovascular and renal conditions. Hypertension for distribution includes a container having deposited therein may be a primary disease, called “essential hypertension” or the pharmaceutical formulation in an appropriate form. Suit "idiopathic hypertension', or it may be caused by other dis able containers are well-known to those skilled in the art and 60 eases, in which case it is classified as 'secondary hyperten include materials such as bottles (plastic and glass), Sachets, sion”. Essential hypertension accounts for 90-95% of all ampoules, plastic bags, metal cylinders, and the like. The CaSCS. container may also include a tamper-proof assemblage to As used herein, the term “resistant hypertension” refers to prevent indiscreet access to the contents of the package. In hypertension that remains above goal blood pressure (usually addition, the container has deposited thereon a label that 65 less than 140/90 mmHg, although a lower goal of less than describes the contents of the container. The label may also 130/80 mmHg is recommended for patients with comorbid include appropriate warnings. diabetes or kidney disease), in spite of concurrent use of three US 9,309,235 B2 41 42 antihypertensive agents belonging to different antihyperten hypertension and thyroid disease are more common, while sive drug classes. People who require four or more drugs to men more commonly Suffer from chronic obstructive pulmo control their blood pressure are also considered to have resis nary disease (COPD), peripheral vascular disease, coronary tant hypertension. artery disease and renal insufficiency. Depression is a fre Hypertension is an extremely common comorbid condition 5 quent comorbidity of heart failure and the two conditions can in diabetes, affecting --20-60% of patients with diabetes, and often do complicate one another. Cachexia has long been depending on obesity, ethnicity, and age. This type of hyper recognized as a serious and frequent complication of heart tension is herein referred to as “diabetic hypertension'. In failure, affecting up to 15% of all heart failure patients and type 2 diabetes, hypertension is often present as part of the being associated with poor prognosis. Cardiac cachexia is metabolic syndrome of insulin resistance also including cen 10 defined as the nonedematous, nonvoluntary loss of at least 6% tral obesity and dyslipidemia. In type 1 diabetes, hyperten of body weight over a period of six months. sion may reflect the onset of diabetic nephropathy. The term “sleep apnea refers to the most common of the "Pulmonary hypertension (PH), as used herein, is a dis sleep-disordered breathing disorders. It is a condition char ease characterized by sustained elevations of blood pressure acterized by intermittent, cyclical reductions or total cessa in the pulmonary vasculature (pulmonary artery, pulmonary 15 tions of airflow, which may or may not involve obstruction of vein and pulmonary capillaries), which results in right heart the upper airway. There are three types of sleep apnea: hypertrophy, eventually leading to right heart failure and obstructive sleep apnea, the most common form, central sleep death. Common symptoms of PH include shortness of breath, apnea and mixed sleep apnea. dizziness and fainting, all of which are exacerbated by exer “Central sleep apnea (CSA), is caused by a malfunction in tion. Without treatment, median life expectancy following the brain's normal signal to breathe, rather than physical diagnosis is 2.8 years. PH exists in many different forms, blockage of the airway. The lack of respiratory effort leads to which are categorized according to their etiology. Categories an increase in carbon dioxide in the blood, which may rouse include pulmonary arterial hypertension (PAH). PH with left the patient. CSA is rare in the general population, but is a heart disease, PH associated with lung diseases and/or relatively common occurrence in patients with systolic heart hypoxaemia, PH due to chronic thrombotic and/or embolic 25 failure. disease and miscellaneous PH. PAH is rare in the general As used herein, the term “metabolic syndrome'. “insulin population, but the prevalence increases in association with resistance syndrome' or “syndrome X, refers to a group or certain common conditions such as HIV infection, Sclero clustering of metabolic conditions (abdominal obesity, derma and sickle cell disease. Other forms of PH are gener elevated fasting glucose, “dyslipidemia' (i.e., elevated lipid ally more common than PAH, and, for instance, the associa 30 levels) and elevated blood pressure (HBP)) which occur tion of PH with chronic obstructive pulmonary disease together more often than by chance alone and that together (COPD) is of particular concern. Current treatment for pull promote the development of type 2 diabetes and cardiovas monary hypertension depends on the stage and the mecha cular disease. Metabolic syndrome is characterized by a spe nism of the disease. cific lipid profile of increased triglycerides, decreased high As used herein “heart failure' is a progressive disorder of 35 density lipoprotein cholesterol (HDL-cholesterol) and in left ventricular (LV) myocardial remodeling that culminates Some cases moderately elevated low-density lipoprotein cho in a complex clinical syndrome in which impaired cardiac lesterol (LDL-cholesterol) levels, as well as accelerated pro function and circulatory congestion are the defining features, gression of “atherosclerotic disease' due to the pressure of and results in insufficient delivery of blood and nutrients to the component risk factors. There are several types of dys body tissues. The condition occurs when the heart is damaged 40 lipidemias: “hypercholesterolemia' refers to elevated levels or overworked and unable to pump out all the blood that of cholesterol. Familial hypercholesterolemia is a specific returns to it from the systemic circulation. As less blood is form of hypercholesterolemia due to a defect on chromosome pumped out, blood returning to the heart backs up and fluid 19 (19p 13.1-13.3). “Hyperglyceridemia' refers to elevated builds up in other parts of the body. Heart failure also impairs levels of glycerides (e.g., “hypertrigliceridemia' involves the kidneys’ ability to dispose of Sodium and water, compli 45 elevated levels of triglycerides). “Hyperlipoproteinemia cating fluid retention further. Heart failure is characterized by refers to elevated levels of lipoproteins (usually LDL unless autonomic dysfunction, neurohormonal activation and over otherwise specified). production of cytokines, which contribute to progressive cir As used herein, the term “peripheral vascular disease culatory failure. Symptoms of heart failure include: dyspnea (PVD)', also commonly referred to as “peripheral arterial (shortness of breath) while exercising or resting and waking 50 disease (PAD) or “peripheral artery occlusive disease at night due to sudden breathlessness, both indicative of pull (PAOD)', refers to the obstruction of large arteries not within monary edema; general fatigue or weakness, edema of the the coronary, aortic arch vasculature, or brain. PVD can result feet, ankles and legs, rapid weight gain, chronic cough, from atherosclerosis, inflammatory processes leading to including that producing mucus or blood. Depending on its Stenosis, an embolism, or thrombus formation. It causes clinical presentation, heart failure is classified as de novo, 55 either acute or chronic “ischemia (lack of blood supply). transient or chronic. Acute heart failure, i.e. the rapid or Often PVD is a term used to refer to atherosclerotic blockages gradual onset of symptoms requiring urgent therapy, may found in the lower extremity. PVD also includes a subset of develop de novo or as a result of chronic heart failure becom diseases classified as microvascular diseases resulting from ing decompensated. Diabetes is a common comorbidity in episodal narrowing of the arteries (e.g., “Raynaud's phenom patients with heart failure and is associated with poorer out 60 enon'), or widening thereof (erythromelalgia), i.e. vascular comes as well as potentially compromising the efficacy of Spasms. treatments. Other important comorbidities include systemic The term “thrombosis” refers to the formation of a blood hypertension, chronic airflow obstruction, sleep apnea, cog clot (“thrombus’) inside a blood vessel, obstructing the flow nitive dysfunction, anemia, chronic kidney disease and arthri of blood through the circulatory system. When a blood vessel tis. Chronic left heart failure is frequently associated with the 65 is injured, the body uses platelets (thrombocytes) and fibrinto development of pulmonary hypertension. The frequency of form a blood clot to prevent blood loss. Alternatively, even certain comorbidities varies by gender: among women, when a blood vessel is not injured, blood clots may form in the US 9,309,235 B2 43 44 body if the proper conditions present themselves. If the clot levels of sexual excitement, causing personal distress. FSAD ting is too severe and the clot breaks free, the traveling clot is encompasses both the lack of Subjective feelings of excite now known as an "embolus'. The term “thromboembolism’ ment (i.e., Subjective sexual arousal disorder) and the lack of refers to the combination of thrombosis and its main compli Somatic responses such as lubrication and Swelling (i.e., geni cation, "embolism'. When a thrombus occupies more than 5 tal/physical sexual arousal disorder). FSAD may be strictly 75% of surface area of the lumen of an artery, blood flow to psychological in origin, although it generally is caused or the tissue Supplied is reduced enough to cause symptoms complicated by medical or physiological factors. Hypoestro because of decreased oxygen (hypoxia) and accumulation of genism is the most common physiologic condition associated metabolic products like lactic acid (“gout”). More than 90% with FSAD, which leads to urogenital atrophy and a decrease obstruction can result in anoxia, the complete deprivation of 10 in vaginal lubrication. oxygen, and “infarction', a mode of cell death. As used herein, "erectile dysfunction (ED) is a male An "embolism' (plural embolisms) is the event of lodging sexual dysfunction characterized by the inability to develop of an embolus (a detached intravascular mass capable of or maintain an erection of the penis during sexual perfor clogging arterial capillary beds at a site far from its origin) mance. A penile erection is the hydraulic effect of blood into a narrow capillary vessel of an arterial bed which causes 15 entering and being retained in Sponge-like bodies within the a blockage (vascular occlusion) in a distant part of the body. penis. The process is often initiated as a result of sexual This is not to be confused with a thrombus which blocks at the arousal, when signals are transmitted from the brain to nerves site of origin. in the penis. Erectile dysfunction is indicated when an erec A “stroke', or cerebrovascular accident (CVA), is the rapid tion is difficult to produce. The most important organic causes loss of brain function(s) due to disturbance in the blood Sup are cardiovascular disease and diabetes, neurological prob ply to the brain. This can be due to “ischemia' (lack of blood lems (for example, trauma from prostatectomy Surgery), hor flow) caused by blockage (thrombosis, arterial embolism), or monal insufficiencies (hypogonadism) and drug side effects. a hemorrhage (leakage of blood). As a result, the affected area Specific diseases of disorders which may be treated and/or of the brain cannot function, which might result in an inability prevented by administering an sGC stimulator of the inven to move one or more limbs on one side of the body, inability 25 tion, include but are not limited to: hypertension (e.g., dia to understand or formulate speech, or an inability to see one betic hypertension, arterial hypertension, pulmonary hyper side of the visual field. Risk factors for stroke include old age, tension, resistant hypertension, peripheral artery disease, hypertension, previous stroke or transient ischemic attack etc), heart failure (e.g., left ventricular diastolic dysfunction (TIA), diabetes, high cholesterol, cigarette Smoking and atrial (LVDD) and left ventricular systolic dysfunction (LVSD), fibrillation. High blood pressure is the most important modi 30 sleep apnea associated with heart failure), arteriosclerotic fiable risk factor of stroke. An "ischemic stroke' is occasion disease (e.g., atherosclerosis), thromboembolic disorders ally treated in a hospital with thrombolysis (also known as a (e.g., chronic thromboembolic pulmonary hypertension, “clot buster), and some hemorrhagic strokes benefit from thrombosis, stroke, embolism, pulmonary embolism), renal neurosurgery. Prevention of recurrence may involve the diseases (e.g., renal fibrosis, ischemic renal disease, renal administration of antiplatelet drugs such as aspirin and dipy 35 failure, renal insufficiency, chronic kidney disease), hepatic ridamole, control and reduction of hypertension, and the use disease (e.g., liver fibrosis or cirrhosis), respiratory disease of statins. Selected patients may benefit from carotid endart (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmo erectomy and the use of anticoagulants. nary disease, interstitial lung disease), sexual disorders (e.g., “Ischemia' is a restriction in blood Supply to tissues, caus erectile dysfunction, male and female sexual dysfunction, ing a shortage of oxygen and glucose needed for cellular 40 vaginal atrophy), sickle cell anemia, neuro inflammatory dis metabolism (to keep tissue alive). Ischemia is generally eases or disorders and metabolic disorders (e.g., lipid related caused by problems with blood vessels, with resultant dam disorders). age to or dysfunction of tissue. It also means local anemia in The compounds of Formula I as well as pharmaceutically a given part of a body sometimes resulting from congestion acceptable salts thereof, as stimulators of sGC, are useful in (such as vasoconstriction, thrombosis or embolism). 45 the prevention and/or treatment of the following types of According to the American Psychiatric Association’s diseases, conditions and disorders which can benefit from Diagnostic and Statistical Manual of Mental Disorders, sGC stimulation: Fourth Edition (DSM-IV), the term “sexual dysfunction” (1) Peripheral, pulmonary, hepatic, liver, cardiac or cerebral encompasses a series of conditions "characterized by distur vascular/endothelial disorders/conditions: bances in sexual desire and in the psychophysiological 50 disorders related to high blood pressure and decreased changes associated with the sexual response cycle; while coronary blood flow Such as increased acute and chronic problems of this type are common, sexual dysfunction is only coronary blood pressure, arterial hypertension and vascular considered to exist when the problems cause distress for the disorder resulting from cardiac and renal complications (e.g. patient. Sexual dysfunction can be either physical or psycho heart disease, stroke, cerebral ischemia, renal failure); resis logical in origin. It can exist as a primary condition, generally 55 tant hypertension, diabetic hypertension, congestive heart hormonal in nature, although most often it is secondary to failure; diastolic or sistolic dysfunction; coronary insuffi other medical conditions or to drug therapy for said condi ciency; arrhythmias. tions. All types of sexual dysfunction can be further classified thromboembolic disorders and ischemias such as myocar as life-long, acquired, situational or generalized (or combi dial infarction, stroke, transient ischemic attacks (TIAS); nations thereof). 60 stable or unstable angina pectoris; The DSM-IV-TR specifies five major categories of “female peripheral arterial disease, peripheral occlusive arterial sexual dysfunction’: sexual desire/interest disorders; “sexual disease; arousal disorders (including genital, Subjective and com pulmonary/respiratory conditions such as pulmonary bined); orgasmic disorder, dyspareunia and vaginismus; and hypertension, pulmonary arterial hypertension, and associ persistent sexual arousal disorder. 65 ated pulmonary vascular remodeling (e.g. localized thrombo “Female sexual arousal disorder (FSAD) is defined as a sis and right heart hypertrophy); pulmonary hypertonia; pri persistent or recurring inability to attain or maintain Sufficient mary pulmonary hypertension, secondary pulmonary US 9,309,235 B2 45 46 hypertension, familial pulmonary hypertension, sporadic pull As used herein, the terms “subject' and “patient” are used monary hypertension, pre-capillary pulmonary hypertension, interchangeably. The terms “subject' and “patient” refer to an idiopathic pulmonary hypertension, thrombotic pulmonary animal (e.g., a bird Such as a chicken, quail or turkey, or a arteriopathy, plexogenic pulmonary arteriopathy; mammal), specifically a “mammal’ including a non-primate pulmonary hypertension associated with or related to: left (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, Ventricular dysfunction, hypoxemia, mitral valve disease, and mouse) and a primate (e.g., a monkey, chimpanzee and a constrictive pericarditis, aortic Stenosis, cardiomyopathy, human), and more specifically a human. In some embodi mediastinal fibrosis, pulmonary fibrosis, anomalous pulmo ments, the Subject is a non-human animal Such as a farm nary venous drainage, pulmonary venooclusive disease, pull animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog. monary vasculitis, collagen vascular disease, congenital heart 10 cat, guinea pig or rabbit). In some embodiments, the Subject is disease, pulmonary venous hypertension, interstitial lung dis a human. ease, sleep-disordered breathing, sleep apnea, alveolar The invention also provides a method for treating one of the hypoVentilation disorders, chronic exposure to high altitude, above diseases, conditions and disorders in a subject, com neonatal lung disease, alveolar-capillary dysplasia, sickle cell prising administering a therapeutically effective amount of a disease, other coagulation disorders, chronic thromboembo 15 compound of Formula I, or a pharmaceutically acceptable salt lism, pulmonary embolism (due to tumor, parasites or foreign thereof, to the subject in need of the treatment. Alternatively, material), connective tissue disease, lupus, Schitosomiasis, the invention provides the use of a compound of Formula I, or sarcoidosis, chronic obstructive pulmonary disease, asthma, a pharmaceutically acceptable salt thereof, in the treatment of emphysema, chronic bronchitis, pulmonary capillary heman one of these diseases, conditions and disorders in a subject in giomatosis; histiocytosis X, lymphangiomatosis and com need of the treatment. The invention further provides a pressed pulmonary vessels (such as due to adenopathy, tumor method of making or manufacturing a medicament useful for or fibrosing mediastinitis); treating one of these diseases, conditions and disorders com arterosclerotic diseases or conditions such as atherosclero prising using a compound of Formula I, or a pharmaceutically sis (e.g., associated with endothelial injury, platelet and acceptable salt thereof. monocyte adhesion and aggregation, Smooth muscle prolif 25 The term “biological sample, as used herein, refers to an eration and migration); restenosis (e.g. developed after in vitro or ex vivo sample, and includes, without limitation, thrombolysis therapies, percutaneous transluminal angio cell cultures or extracts thereof biopsied material obtained plasties (PTAS), percutaneous transluminal coronary angio from a mammal or extracts thereof blood, saliva, urine, plasties (PTCAs) and bypass); inflammation; faeces, semen, tears, lymphatic fluid, ocular fluid, vitreous cardiovascular disease associated with metabolic syn 30 humour, or other body fluids or extracts thereof. drome (e.g., obesity, dyslipidemia, diabetis, high blood pres “Treat”, “treating or “treatment” with regard to a disorder sure); lipid related disorders such as dyslipidemia, hypercho or disease refers to alleviating or abrogating the cause and/or lesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver the effects of the disorder or disease. As used herein, the terms disease, and hepatitis; “treat”, “treatment” and “treating refer to the reduction or liver cirrhosis, associated with chronic liver disease, 35 amelioration of the progression, severity and/or duration of hepatic fibrosis, hepatic stellate cell activation, hepatic an sGC, cQMP and/or NO mediated condition, or the ame fibrous collagen and total collagen accumulation; liver dis lioration of one or more symptoms (preferably, one or more ease of necro-inflammatory and/or of immunological origin; discernable symptoms) of said condition (i.e. “managing andurogenital system disorders, such as renal fibrosis and without "curing the condition), resulting from the adminis renal failure resulting from chronic kidney diseases or insuf 40 tration of one or more therapies (e.g., one or more therapeutic ficiency (e.g. due to accumulation/deposition and tissue agents such as a compound or composition of the invention). injury, progressive Sclerosis, glomerunephritis); prostate In specific embodiments, the terms “treat”; “treatment and hypertrophy; “treating refer to the amelioration of at least one measurable (2) sexual disorders of conditions: erectile dysfunction; physical parameter of an sGC, c0MP and/or NO mediated female sexual dysfunction (e.g., female sexual arousal dys 45 condition. In other embodiments the terms “treat”, “treat function), vaginal atrophy and incontinence. ment” and “treating refer to the inhibition of the progression In other embodiments of the invention, the compounds of of an sGC, cQMP and/or NO mediated condition, either Formula I as well as pharmaceutically acceptable salts physically by, e.g., stabilization of a discernable symptom or thereof are useful in the prevention and/or treatment of the physiologically by, e.g., stabilization of a physical parameter, following types of diseases, conditions and disorders which 50 or both. can benefit from sGC stimulation: hypertension, resistant The term “preventing as used herein refers to administer hypertension, diabetic hypertension, pulmonary hyperten ing a medicament beforehand to avert or forestall the appear sion (PH), pulmonary arterial hypertension, PH associated ance of one or more symptoms of a disease or disorder. The with COPD, chronic airflow obstruction, asthma or pulmo person of ordinary skill in the medical art recognizes that the nary fibrosis, thrombosis, embolism, thromboembolic disor 55 term “prevent' is not an absolute term. In the medical art it is ders, atherosclerosis, right heart hypertrophy, heart failure, understood to refer to the prophylactic administration of a diastolic dysfunction, systolic dysfunction, sleep apnea asso drug to substantially diminish the likelihood or seriousness of ciated with heart failure, liver cirrhosis, renal fibrosis, renal a condition, or symptom of the condition and this is the sense failure resulting from chronic kidney diseases or insuffi intended in this disclosure. The Physician's Desk Reference, ciency, metabolic disorder, dyslipidemia, hypercholester 60 a standard text in the field, uses the term “prevent hundreds olemia, hypertriglyceridemia, sitosterolemia, fatty liver dis of times. As used therein, the terms “prevent”, “preventing ease, hepatitis, erectile dysfunction, female sexual and “prevention' with regard to a disorder or disease, refer to dysfunction, female sexual arousal dysfunction and vaginal averting the cause, effects, symptoms or progression of a atrophy. disease or disorder prior to the disease or disorder fully mani The terms, “disease”, “disorder and “condition” may be 65 festing itself. used interchangeably here to refer to an sGC, c0MP and/or In one embodiment, the methods of the invention are a NO mediated medical or pathological condition. preventative or “pre-emptive' measure to a patient, specifi US 9,309,235 B2 47 48 cally a human, having a predisposition (e.g. a genetic predis therapeutic dose, while the additional therapeutic agent, for position) to developing an sGC, c0MP and/or NO related example, a suitable cancer-therapeutic agent is administered disease, disorder or symptom. in an effective amount. In other embodiments, the methods of the invention are a As used herein, the terms “in combination' or “co-admin preventative or “pre-emptive' measure to a patient, specifi istration' can be used interchangeably to refer to the use of cally a human, Suffering from a disease, disorder or condition more than one therapy (e.g., one or more prophylactic and/or that makes him at risk of developing an sGC, c0MP or NO therapeutic agents). The use of the terms does not restrict the related disease, disorder or symptom. order in which therapies (e.g., prophylactic and/or therapeu The compounds and pharmaceutical compositions tic agents) are administered to a subject. 10 Co-administration encompasses administration of the first described herein can be used alone or in combination therapy and second amounts of the compounds in an essentially for the treatment or prevention of a disease or disorder medi simultaneous manner, such as in a single pharmaceutical ated, regulated or influenced by sGC, c0MP and/or NO. composition, for example, capsule or tablet having a fixed Compounds and compositions here disclosed are also use ratio of first and second amounts, or in multiple, separate ful for veterinary treatment of companion animals, exotic 15 capsules or tablets for each. In addition, such co administra animals and farm animals, including, without limitation, tion also encompasses use of each compound in a sequential dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, manner in either order. When co-administration involves the horses, pigs and cattle. separate administration of the first amount of a compound of In other embodiments, the invention provides a method of Formula I and a second amount of an additional therapeutic stimulating sGC activity in a biological sample, comprising agent, the compounds are administered Sufficiently close in contacting said biological sample with a compound or com time to have the desired therapeutic effect. For example, the position of the invention. Use of a sGC stimulator in a bio period of time between each administration which can result logical sample is useful for a variety of purposes knownto one in the desired therapeutic effect, can range from minutes to of skill in the art. Examples of such purposes include, without hours and can be determined taking into account the proper limitation, biological assays and biological specimen storage. 25 ties of each compound Such as potency, solubility, bioavail Combination Therapies ability, plasma half-life and kinetic profile. For example, a The compounds and pharmaceutical compositions compound of Formula I and the second therapeutic agent can described herein can be used in combination therapy with one be administered in any order within about 24 hours of each or more additional therapeutic agents. For combination treat other, within about 16 hours of each other, within about 8 ment with more than one active agent, where the active agents 30 hours of each other, within about 4 hours of each other, within are in separate dosage formulations, the active agents may be about 1 hour of each other or within about 30 minutes of each administered separately or in conjunction. In addition, the other. administration of one element may be prior to, concurrent to, More, specifically, a first therapy (e.g., a prophylactic or or Subsequent to the administration of the other agent. therapeutic agent such as a compound described herein) can When co-administered with other agents, e.g., when co 35 be administered prior to (e.g., 5 minutes, 15 minutes, 30 administered with another pain medication, an “effective minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 amount of the second agent will depend on the type of drug hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 used. Suitable dosages are known for approved agents and weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 can be adjusted by the skilled artisan according to the condi weeks before), concomitantly with, or Subsequent to (e.g., 5 tion of the Subject, the type of condition(s) being treated and 40 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, the amount of a compound described herein being used. In 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 cases where no amount is expressly noted, an effective hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, amount should be assumed. For example, compounds 8 weeks, or 12 weeks after) the administration of a second described herein can be administered to a Subject in a dosage therapy (e.g., a prophylactic or therapeutic agent such as an range from between about 0.01 to about 10,000 mg/kg body 45 anti-cancer agent) to a Subject. weight/day, about 0.01 to about 5000 mg/kg body weight/day, Examples of other therapeutic agents that may be com about 0.01 to about 3000 mg/kg body weight/day, about 0.01 bined with a compound of this disclosure, either administered to about 1000 mg/kg body weight/day, about 0.01 to about separately or in the same pharmaceutical composition, 500 mg/kg body weight/day, about 0.01 to about 300 mg/kg include, but are not limited to: body weight/day, about 0.01 to about 100 mg/kg body 50 (1) Endothelium-derived releasing factor (EDRF); weight/day. (2) NO donors such as a nitrosothiol, a nitrite, a Sydnonimine, When “combination therapy” is employed, an effective a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a amount can be achieved using a first amount of a compound nitrosimine, nitrotyrosine, a diazetine dioxide, an oXatriazole of Formula I or a pharmaceutically acceptable salt thereofand 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a second amount of an additional Suitable therapeutic agent. 55 a hydroxyurea or a furoxan. Some examples of these types of In one embodiment of this invention, a compound of For compounds include: glyceryl trinitrate (also known as GTN, mula I and the additional therapeutic agent are each admin nitroglycerin, nitroglycerine, and trinitrogylcerin), the nitrate istered in an effective amount (i.e., each in an amount which ester of glycerol; sodium nitroprusside (SNP), wherein a mol would be therapeutically effective if administered alone). In ecule of nitric oxide is coordinated to iron metal forming a another embodiment, the compound of Formula I and the 60 square bipyramidal complex; 3-morpholinosydnonimine additional therapeutic agent are each administered in an (SIN-1), a Zwitterionic compound formed by combination of amount which alone does not provide a therapeutic effect (a a morpholine and a Sydnonimine; S-nitroso-N-acetylpenicil Sub-therapeutic dose). In yet another embodiment, the com lamine (SNAP), an N-acetylated amino acid derivative with a pound of Formula I can be administered in an effective nitrosothiol functional group; diethylenetriamine/NO amount, while the additional therapeutic agent is adminis 65 (DETA/NO), a compound of nitric oxide covalently linked to tered in a sub-therapeutic dose. In still another embodiment, diethylenetriamine; and NCX4016, an m-nitroxymethylphe the compound of Formula I can be administered in a sub nyl ester of acetyl salicylic acid. More specific examples of US 9,309,235 B2 49 50 some of these classes of NO donors include: the classic nitro HMR-1766 (ataciguat sodium, see patent publication vasodilators, such as organic nitrate and nitrite esters, includ WO2000002851) ing nitroglycerin, amyl nitrite, isosorbide dinitrate, isosor bide 5-mononitrate, and nicorandil; Isosorbide (Dilatrate(R)- SR, Imdur R, Ismo (R), Isordil(R), Isordil(R), Titradose(R), Monoket(R), FK 409 (NOR-3); FR 144420 (NOR-4): 3-mor O O O pholinosydnonimine; Linsidomine chlorohydrate ("SIN-1); M V/ S-nitroso-N-acetylpenicillamine (“SNAP); AZD3582 (CI NOD lead compound), NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015, NCX 950, NCX 1000, NCX 1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216, and NCX 10 4040 (all available from NicOx S.A.), S-nitrosoglutathione (GSNO), Sodium Nitroprusside, S-nitrosoglutathione mono ethyl-ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitroso S 3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy hydrazino)-N-methyl-1-hexanamine (NOC-9) or diethy N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (see lamine NONOate. Nitric oxide donors are also as disclosed in 15 patent publications DE19830430 and WO2000002851) U.S. Pat. Nos. 5,155,137, 5,366,997, 5,405,919, 5,650,442, 5,700,830, 5,632,981, 6,290,981, 5,691423 5,721,365, 5,714,511, 6,511,911, and 5,814,666, Chrysselis et al. (2002) OV/ O V/ J Med Chem. 45:5406-9 (such as NO donors 14 and 17), and S S Nitric Oxide Donors for Pharmaceutical and Biological r- O HN1 Research, Eds: Peng George Wang, Tingwei Bill Cai, Naoyuki Taniguchi, Wiley, 2005; su N Cl; (3) Other substances that enhance coMP concentrations such H as protoporphyrin IX, arachidonic acid and phenyl hydrazine o1 derivatives; (4) Nitric Oxide Synthase substrates: for example, n-hydrox 25 yguanidine based analogs, such as NG-hydroxy-L-arginine On (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3- hydroxyguanidine, and PR5 (1-(3,4-dimethoxy-2-chloroben and HMR-1069 (Sanofi-Aventis). Zylideneamino)-3-hydroxyguanidine); L-arginine deriva (7) Heme-dependent sGC stimulators including, but not lim tives (such as homo-Arg, homo-NOHA. N-tert-butyloxy- and 30 ited to: N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon YC-1 (see patent publications EP667345 and guanidine-carpoic acid, agnatine, hydroxyl-agmatine, and DE19744026) L-tyrosyl-L-arginine); N-alkyl-N'-hydroxyguanidines (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hy droxyguanidine), N-aryl-N'-hydroxyguanidines (such as 35 N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives which bear —F. —Cl, -methyl, —OH substitu ents, respectively); guanidine derivatives such as 3-(trifluo rmethyl) propylguanidine; and others reviewed in Cali et al. (2005, Current Topics in Medicinal Chemistry 5:721-736) 40 and disclosed in the references cited therein; (5) Compounds which enhance eNOS transcription: for example those described in WO 02/064146, WO 02/064545, WO 02/064546 and WO 02/064565, and corresponding patent documents such as US2003/0008915, US2003/ 45 0022935, US2003/0022939 and US2003/0055093. Other eNOS transcriptional enhancers including those described in US20050101599 (e.g. 2,2-difluorobenzo. 1,3 dioxol-5-car boxylic acid indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)- benzamide), and Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schäfer et al., 50 BAY 41-2272 (see patent publications DE 19834.047 and Journal of Thrombosis and Homeostasis 2005; Volume 3, DE19942809) Supplement 1: abstract number P1487); (6) NO independent heme-independent sGC activators, including, but not limited to: BAY 58-2667 (see patent pub lication DE 1994.3635) 55

~so 60 HO

65 US 9,309,235 B2 51 52 BAY 41-8543 (see patent publication DE 19834044) (8) Compounds that inhibit the degradation ofcGMP, such as: PDE5 inhibitors, such as, for example, Sildenafil (ViagraR) and other related agents such as Avanafil. Lodenafil. Mirodenafil. Sildenafil citrate (RevatioR), Tadalafil (Cialis(R) or AdcircaR), Vardenafil (Levitra) and Udenafil; Alprostadil; and Dipyridamole; (9) Calcium channel blockers such as: Dihydropyridine calcium channel blockers: Amlodipine (Norvasc), Aranidipine (Sapresta), AZelnidipine (Callblock), 10 Barnidipine (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Dilt iazem, Efonidipine (Landel), Felodipine (Plendil), Lacid ipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine 15 (Calslot, Madipine), Nicardipine (Cardene, Carden SR), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimo dipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), Pranidipine (Acalas), Isradipine (Lomir); BAY 63-2521 (see patent publication DE 19834044) Phenylalkylamine calcium channel blockers: Verapamil CFM-1571 (see patent publication WO2000027394) (Calan, Isoptin)

A350-619 25 N

HN Crs N No 19 cO

H 35 N1-1-N N Gallopamil (Procorum, D600); Benzothiazepines: Diltiazem (Cardizem); O S.

40 OCH: Cl; A-344.905 n1n-1-N-N". N 45 O S. /- O X-Olt, Cl; H2O-N O A-778935 50 OH HO Nonselective calcium channel inhibitors such as: mibefradil, NH bepridil and fluspirilene, fendiline; (10) Endothelin receptor antagonists (ERAs): for instance the dual (ET, and ET) endothelin receptor antagonist Bosentan (marketed as TracleerR); Sitaxentan, marketed under the name Thelin R; Ambrisentanis marketed as Letairis(R in U.S.; dual/nonselective endothelin antagonist Actelion-1, that 60 entered clinical trials in 2008; (11) Prostacyclin derivatives or analogues: for instance pros tacyclin (prostaglandin I2), Epoprostenol (synthetic prosta cyclin, marketed as Flolan R); Treprostinil (Remodulin(R), Iloprost (Ilomedin R), Iloprost (marketed as Ventavis(R); oral 65 and inhaled forms of Remodulin(R) that are under develop and other compounds disclosed in Tetrahedron Letters ment; Beraprost, an oral prostanoid available in Japan and (2003), 44(48): 8661-8663. South Korea; US 9,309,235 B2 53 54 (12) Antihyperlipidemics such as: bile acid sequestrants (e.g., (18) Antiarrhythmic agents such as the following types: Cholestyramine, Colestipol, Colestilan and Colesevelam): Type I (Sodium channel blockers): Quinidine, Lidocaine, statins such as Atorvastatin, Simvastatin, Lovastatin, Fluvas Phenytoin, Propafenone tatin, Pitavastatin, Rosuvastatin and Pravastatin; cholesterol Type III (potassium channel blockers): Amiodarone, absorption inhibitors such as EZetimibe; other lipid lowering 5 Dofetilide, Sotalol agents such as Icosapent ethyl ester, Omega-3-acid ethyl Type V: Adenosine, Digoxin esters, Reducol, fibric acid derivatives such as Clofibrate, (19) Diuretics such as: Thiazide diuretics, e.g., Chlorothiaz Bezafibrate, Clinofibrate, Gemfibrozil, Ronifibrate, Binifi ide, Chlorthalidone, and Hydrochlorothiazide, Bendroflume brate, Fenofirate, Ciprofibrate, Choline fenofibrate; nicotinic thiazide, Cyclopenthiazide, Methyclothiazide, Polythiazide, 10 QuinethaZone, Xipamide, MetolaZone, Indapamide, Cicleta acid derivatives such as AcipimoX and Niacin; also combina nine; Loop diuretics, such as Furosemide and Toresamide; tions of Statins, niacin, intestinal cholesterol absorption-in potassium-sparing diuretics such as Amiloride, Spironolac hibiting Supplements (eZetimibe and others) and fibrates; tone, Canrenoate potassium, Eplerenone and Triamterene; antiplatelet therapies such as Clopidogrel bisulfate; combinations of these agents; other diuretics Such as Aceta (13) Anticoagulants, such as the following types: 15 Zolamid and Carperitide Coumarines (Vitamin Kantagonists): Warfarin R (Couma (20a) Direct acting vasodilators such as Hydralazine hydro din) mostly used in the US and UK; Acenocoumarol(R) chloride, Diazoxide, Sodium nitroprusside, Cadralazine: and Phenprocoumon R, mainly used in other countries; other vasodilators such as Isosorbide dinitrate and Isosorbide Phenindione(R): 5-mononitrate; Heparin and derivative Substances such as: Heparin; low (20b) Exogenous vasodilators such as: molecular weight heparin, Fondaparinux and Adenocard(R), an adenosine agonist, primarily used as an Idraparinux: anti-arrhythmic; Direct thrombininhibitors such as: Argatroban, Lepirudin, Alpha blockers (which block the vasoconstricting effect of Bivalirudin and Dabigatran; Ximelagatran (ExantaR), adrenaline): not approved in the US; 25 Alpha-1-adrenoceptor antagonists such as PraZosin, Tissue plasminogen activators, used to dissolve clots and Indoramin, Urapidil, BunaZosin, TeraZosin, Doxazosin unblock arteries, such as Alteplase; Atrial natriuretic peptide (ANP); (14) Antiplatelet drugs: for instance thienopyridines Such as Ethanol: Lopidogrel and Ticlopidine; Dipyridamole: Aspirin; Histamine-inducers, which complement proteins C3a, C4a (15) ACE inhibitors, for example the following types: 30 and C5a work by triggering histamine release from mast Sulfhydryl-containing agents such as Captopril (trade cells and basophil granulocytes; name Capoten(R), the first ACE inhibitor and Zofeno Tetrahydrocannabinol (THC), major active chemical in pril; marijuana which has minor vasodilatory effects; Dicarboxylate-containing agents such as Enalapril (Vaso Papaverine, an alkaloid found in the opium poppy papaver 35 somniferum; b tec/RenitecR); Ramipril (Altace/Tritace/Ramace/ (21) Bronchodilators: there are two major types of bronchodi Ramiwin R); Quinapril (Accupril.R.), Perindopril (Cov lator, Bagonists and anticholinergics, exemplified below: ersyl/Aceon(R); Lisinopril (Lisodur/Lopril/Novatec/ B2 agonists: Salbutamol(R) or albuterol (common brand Prinivil/Zestril.R) and Benazepril (Lotensin(R): name: Ventolin) and Terbutaline(R) are short acting B Phosphonate-containing agents such as: Fosinopril; 40 agonists for rapid relief of COPD symptoms. Long act Naturally occurring ACE inhibitors such as: Casokinins ing Bagonists (LABAS) Such as Salmeterol.R and For and lactokinins, which are breakdown products of casein moterol R; and whey that occur naturally after ingestion of milk anticholinergics: Ipratropium(R) is the most widely pre products, especially cultured milk; The Lactotripeptides scribed short acting anticholinergic drug. Tiotropium R Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic 45 is the most commonly prescribed long-acting anticho Lactobacillus helveticus or derived from casein also linergic drug in COPD; have ACE-inhibiting and antihypertensive functions: Theophylline(R), a bronchodilator and phosphodiesterase Other ACE inhibitors such as Alacepril, Delapril, Cilaza inhibitor; pril, Imidapril, Trandolapril, Temocapril, Moexipril, (22) Corticosteroids: such as beclomethasone, methylpred Spirapril, 50 nisolone, betamethasone, prednisone, prenisolone, triamci (16) Supplemental oxygen therapy; nolone, dexamethasone, fluticasone, flunisolide and hydro (17) Beta blockers, such as the following types: cortisone, and corticosteroid analogs such as budesonide Non-selective agents: Alprenolol R, Bucindolol.R., Car (23) Dietary Supplements such as, for example: omega-3 oils; teolol R, Carvedilol R (has additional C-blocking activ folid acid, niacin, Zinc, copper, Korean red ginseng root, ity), Labetalol R (has additional C.-blocking activity), 55 ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, Nadolol R, Penbutolol R (has intrinsic sympathomi horny goat weed, maca root, muirapuama, saw palmetto, and metic activity), Pindolol R (has intrinsic sympathomi Swedish flower pollen: Vitamin C, Vitamin E. Vitamin K2: metic activity), Oxpremonol, Acebutolol, Sotalol, Testosterone Supplements, Testosterone transdermal patch; Mepindolol, Celiprolol, Arotinolol, Tertatolol. Amosu Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Mel lalol, Nipradilol, Propranolol.R and Timolol R; 60 anotan II, hMaxi-K; Prelox: a Proprietary mix/combination f-Selective agents: Acebutolol R (has intrinsic sympatho of naturally occurring ingredients, L-arginine aspartate and mimetic activity), Atenolol R, Betaxolol R, Biso Pycnogenol; prolol R, Celiprolol R, Dobutamine hydrochloride, (24) PGD2 receptor antagonists including, but not limited to, Irsogladine maleate, Carvedilol, Talinolol, Esmolol R, compounds described as having PGD2 antagonizing activity Metoprolol.R and Nebivolol R; 65 in United States Published Applications US20020022218, B-Selective agents: ButaxamineR (weak C.-adrenergic US20010051624, and US20030055077, PCT Published agonist activity); Applications WO9700853, WO9825919, WO03066046, US 9,309,235 B2 55 56 WO03066047, WO03101961, WO03101981, WOO4007451, isoxicam, piroxicam, Sudoxicam and tenoxican), Salicylates WO0178697, WOO4032848, WO03097042, WO03097598, (e.g., acetyl salicylic acid and Sulfasalazine) and the pyrazo WO03022814, WO03022813, and WOO4058164, European lones (e.g., apaZone, bezpiperylon, feprazone, mofebutaZone, Patent Applications EP945450 and EP944614, and those oxyphenbutaZone and phenylbutaZone); listed in: Torisu et al. 2004 Bioorg Med Chem Lett 14:4557. (28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib Torisu et al. 2004 Bioorg Med Chem Lett 2004 14:4891, and (CelebrexR), rofecoxib (Vioxx(R), Valdecoxib, etoricoxib, Torisu et al. 2004 Bioorg & Med Chem 2004 12:4685; parecoxib and lumiracoxib; (opioid analgesics such as (25) Immunosuppressants such as cyclosporine (cyclospo codeine, fentanyl, hydromorphone, levorphanol, meperidine, rine A, Sandimmune(R) Neoral(R), tacrolimus (FK-506, Pro methadone, morphine, oxycodone, oxymorphone, pro graf R), rapamycin (sirolimus, Rapamune(R) and other 10 poxyphene, buprenorphine, butorphanol, dezocine, nalbu FK-506 type immunosuppressants, and mycophenolate, e.g., phine and pentazocine; and mycophenolate mofetil (CellCept(R): (29) Anti-diabetic agents such as insulin and insulin mimet (26) Non-steroidal anti-asthmatics such as B2-agonists (e.g., ics, Sulfonylureas (e.g., Glyburide, Glybenclamide, Glipiz terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, ide, Gliclazide, Gliquidone, Glimepiride, Meglinatide, Tolb salmeterol, bitolterol and pirbuterol) and B2-agonist-corti 15 utamide, Chlorpropamide, Acetohexamide, TolaZamide), costeroid combinations (e.g., Salmeterol-fluticasone (Ad biguanides, e.g., metformin (GlucophageR), C-glucosidase vairR), formoterol-budesonid (Symbicort(R)), theophylline, inhibitors (such as Acarbose, Epalrestat, Voglibose, Miglitol), cromolyn, cromolyn Sodium, nedocromil, atropine, ipratro thiazolidinone compounds, e.g., rosiglitaZone (AVandia.(R), pium, ipratropium bromide, leukotriene biosynthesis inhibi troglitaZone (ReZulin(R), ciglitaZone, pioglitaZone (Actos(R) tors (zileuton, BAY1005): and englitaZone; insulin sensitizers such as PioglitaZone and (27) Non-steroidal anti-inflammatory agents (NSAIDs) such RosiglitaZone; Insulin secretagogues such as Repaglinide, as propionic acid derivatives (e.g., alminoprofen, benoxapro Nateglinide and Mitiglinide; Incretin mimetics such as fen, bucloxic acid, carprofen, fenbufen, fenoprofen, flupro Exanatide and Liraglutide; Amylin analogues such as Pram fen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miro lintide; glucose lowering agents such as Chromiumm picoli profen, naproxen, oxaprozin, pirprofen, pranoprofen, 25 nate (optinally combined with biotin); dipeptidyl peptidase Suprofen, tiaprofenic acid and tioxaprofen), acetic acid IV inhibitors such as Sitagliptin, Vildagliptin, Saxagliptin, derivatives (e.g., indomethacin, acemetacin, alclofenac, clid Alogliptin and Linagliptin; vaccines currently being devel anac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furo oped for the treatment of diabetes; AVE-0277, Alum-GAD, fenac, ibufenac, isoxepac, oXpinac, Sulindac, tiopinac, tol BHT-3021, IBC-VS01; cytokine targeted therapies in devel metin, Zidometacin and Zomepirac), fenamic acid derivatives 30 opment for the treatment of diabetes such as Anakinra, (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, Canakinumab, Diacerein, Gevokizumab, LY-218.9102, niflumic acid and tolfenamic acid), biphenylcarboxylic acid MABP-1, GIT-027; drugs in development for the treatment of derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., diabetes:

Drugs in development for the treatment of diabetes Mechanism of Drug Name Organization Action Status Dapagliflozin AstraZeneca Bristol- SGLT-2 Inhibitors Recommende Myers Squibb Approval Alogliptin Takeda Insulin Sensitizers Pre-Registere benzoate? metformin Dipeptidyl Peptidase hydrochloride IV (CD26; DPP-IV: DP-IV) Inhibitors Anagliptin Kowa Sanwa Dipeptidyl Peptidase Pre-Registere IV (CD26; DPP-IV: DP-IV) Inhibitors Insulin degludec Novo Nordisk Pre-Registere Insulin degludec insulin Novo Nordisk Pre-Registere aspart Insulin human (rDNA MannKind Pre-Registere origin) inhalation powder Lixisenatide Sanofi Insulin Pre-Registere Secretagogues/GLP 1 Receptor Agonists Recombinant human Biodel Pre-Registere insulin Teneligliptin Mitsubishi Tanabe Dipeptidyl Peptidase Pre-Registere Pharma IV (CD26; DPP-IV: DP-IV) Inhibitors AVE-O277 Andromeda Biotech Phase III Tewa Albiglutide GlaxoSmithKline GLP-1 Receptor Phase III Agonists Aleglitazar Roche PPARalpha Agonists. Phase III PPARgamma Agonists Atorvastatin GlaxoSmithKline K(ATP) Channel Phase III calcium glimepiride Blockers/Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV) Inhibitors. HMG-CoA US 9,309,235 B2 57 58 -continued Drugs in development for the treatment of diabetes Mechanism of Drug Name Organization Action Status Reductase Inhibitors TNFSF6 Expression Inhibitors BYK-324677 Nycomed Phase BalaglitaZone Dr. Reddy's Insulin Sensitizers Phase Laboratories PPARgamma Partial Agonists CSG-452 Chugai SGLT-2 Inhibitors Phase Pharmaceutical Canagliflozin ohnson & Johnson SGLT-2 Inhibitors Phase Mitsubishi Tanabe Pharma Canagliflozin metformin ohnson & Johnson SGLT-2 Inhibitors Phase hydrochloride Insulin Sensitizers Dapagliflozin Metformin AstraZeneca Bristol SGLT-2 Inhibitors Phase hydrochloride Myers Squibb Insulin Sensitizers Dulaglutide Lilly Insulin Phase Secretagoguest GLP-1 Receptor Agonists Empagliflozin Boehringer Ingelheim SGLT-2 Inhibitors Phase Lilly Empagliflozinilinagliptin Boehringer Ingelheim SGLT-2 Inhibitors Phase Lilly Dipeptidyl Peptidase IV (CD26; DPP-IV: DP-IV) Inhibitors Gemigliptin LG Life Sciences Dipeptidyl Peptidase Phase IV (CD26; DPP-IV: DP-IV) Inhibitors Hepatic-directed vesicle Diasome Phase insulin Pharmaceuticals Human isophane insulin Wockhardt Phase N-105 Biocon Phase insulin Novo Nordisk Insulin Phase degludecliraglutide Secretagoguest GLP-1 Receptor Agonists insulin glargine Sanofi Phase pragliflozin L-proline Astellas Pharma SGLT-2 Inhibitors Phase Kotobuki LY-2605541 Lilly Phase LY-2963O16 Lilly Phase Lixisenatide. Insulin Sanofi Insulin Phase glargine Secretagoguest GLP-1 Receptor Agonists LobeglitaZone sulfate Chong Kun Dang PPARalpha Agonists Phase Pharm (CKD Pharm) PPARgamma Agonists. Insulin Sensitizers Luseogliflozin Taisho SGLT-2 Inhibitors Phase Otelixizumab Tolerx Anti-CD3 Phase Ranolazine Gilead Sodium Channel Phase Blockers Recombinant human National Institute of Phase insulin Health Sciences Sitagliptin phosphate Merck & Co. PPARgamma Phase monohydrate pioglitazone Agonists. Insulin hydrochloride Sensitizers Dipeptidyl Peptidase V (CD26; DPP-IV: DP-IV) Inhibitors Sitagliptinatorvastatin Merck & Co. Dipeptidyl Peptidase Phase III calcium V (CD26; DPP-IV: DP-IV) Inhibitors/ HMG-CoA Reductase inhibitorSTNFSF6 Expression Inhibitors TAK-875 Takeda Free Fatty Acid Phase III Receptor 1 (FFAR1; GPR40) Agonists insulin Secretagogues TT 401 7TM Pharma Cannabinoid CB Phase I Antagonists TT 401 Transition Phase I Therapeutics US 9,309,235 B2 59 60 -continued Drugs in development for the treatment of diabetes Mechanism of Drug Name Organization Action Status ZYH-2 Cadilla Healthcare PPARalpha Ligands Phase I (d/b/a Zydus Cadila) PPARgamma Ligands ZYO-1 Cadilla Healthcare Cannabinoid CB1 Phase I (d/b/a Zydus Cadila) Antagonists 701645 Cellonis Phase I Biotechnologies 701499 Cellonis Phase I Biotechnologies 7433OO University of Phase I California, San Francisco 448661 University of Phase I Pittsburgh AD-1 National Institute Clinical Pharma Res Dev Colesevelam Daiichi Sankyo Bile Acid Clinical hydrochloride Sequestrants DBPR-108 National Health IND Filed Research Institutes ScinoPharm Nodlin Biolaxy IND Filed PSN-491 Prosidion Glucose-Dependent IND Filed Insulinotropic Receptor (GDIR, GPR119) Agonists Dipeptidyl Peptidase IV (CD26; DPP-IV: DP-IV) Inhibitors Tolimidone Melior Discovery Lyn Kinase Activators IND Filed ZYD-1 Cadilla Healthcare GLP-1 Receptor IND Filed (d/b/a Zydus Cadila) Agonists ZYOG-1 Cadila Healthcare GLP-1 Receptor IND Fled (d/b/a Zydus Cadila) Agonists

35 (30) HDL cholesterol-increasing agents such as Anacetrapib, CP-404, HPP-404, ISIS-FGFR4RX, Insulinotropin, MK-524A, CER-001, DRL-17822, Dalcetrapib, JTT-302, KD-3010PF, 05212389, PP-1420, PSN-842, Peptide YY3 RVX-000222, TA-8995; 36, Resveratrol, S-234462; S-234.462, Sobetirome, (31) Antiobesity drugs such as Methamphetamine hydrochlo TM-38837, Tetrahydrocannabivarin, ZYO-1, beta-Lapa chone; ride, Amfepramone hydrochloride (TenuateR), Phentermine 40 (32) Angiotensin receptor blockers such as Losartan, Valsar (Ionamin R), Benzfetamine hydrochloride (Didrex(R), Phen tan, Candesartan cilexetil, Eprosaran, Irbesartan, Telmisar dimetrazine tartrate (Bontril.R., Prelu-2(R), Plegine(R), Mazin tan, Olmesartran medoxomil, AZilsartan medoxomil: dol (Sanorex(R), Orlistat(Xenical(R), Sibutramine hydrochlo (33) Renin inhibitors such as Aliskiren hemifumirate; ride monohydrate (MeridiaR), Reductil(R), Rimonabant (34) Centrally acting alpha-2-adrenoceptor agonists such as (AcompliaR), Amfepramone, Chromium picolinate, 45 Methyldopa, Clonidine, Guanfacine; RM-493, TZP-301; combination such as Phentermine/Topi (35) Adrenergic neuron blockers such as Guanethidine, Gua ramate, Bupropion/Naltrexone, Sibutramine/Metformin, nadrel; Bupropion SR/Zonisamide SR, Salmeterol, Xinafoate/fluti (36) Imidazoline I-1 receptor agonists such as Rimenidine casone propionate; Lorcaserin hydrochloride, Phentermine? dihydrogen phosphate and Moxonidine hydrochloride topiramate, Bupropion/naltrexone, Cetilistat, Exenatide, 50 hydrate; KI-0803, Liraglutide, Metformin hydrochloride, Sibutra (37) Aldosterone antagonists Such as Spironolactone and mine/Metformin, 876167, ALS-L-1023, Bupropion Eplerenone SR/Zonisamide SR, CORT-108297, Canagliflozin, Chro (38) Potassium channel activators such as Pinacidil mium picolinate, GSK-1521498, LY-377604, Metreleptin, (39) Dopamine D1 agonists Such as Fenoldopam mesilate; Obinepitide, P-57AS3, PSN-821, Salmeterolxinafoate/fluti 55 Other dopamine agonists Such as Ibopamine, Dopexamine casone propionate, Sodium tungstate, Somatropin (recombi and Docarpamine; nant), TM-30339, TTP-435, Tesamorelin, Tesofensine, Vel (40) 5-HT2 antagonists such as Ketanserin; neperit, Zonisamide, BMS-830216, ALB-127158, AP-1030, (41) Drugs that are currently being developed for the treat ATHX-105, AZD-2820, AZD-8329, Beloranib hemioxalate, ment of arterial hypertension:

Mechanism of Drug Name Organization Action Status AZilsartan Takeda Angiotensin AT1 Registered Antagonists Angiotensin AT2 US 9,309,235 B2 61 62 -continued

Mechanism of Drug Name Organization Action Status Antagonists Insulin Sensitizers Amlodipine besylate?irbesartan Dainippon Sumitomo Angiotensin AT1 Pre-Registered Pharma Antagonists Calcium Channel Blockers AZilsartan amlodipine besilate Takeda Angiotensin AT1 Phase III Antagonists Insulin Sensitizers Calcium Channel Blockers Cilnidipinefvalsartan Ajinomoto/Mochida Angiotensin AT1 Phase III Antagonists Calcium Channel Blockers Fimasartan Boryung Angiotensin AT1 Phase III Antagonists Irbesartanatorvastatin Hanmi Angiotensin AT1 Phase III Antagonists Dipeptidyl Peptidase IV (CD26; DPP-IV: DP-IV) Inhibitors. HMG CoA Reductase Inhibitors Expression Inhibitors Irbesartantrichlorimethiazide Shionogi Angiotensin AT1 Phase III Antagonists Losartan Merck & Co. Angiotensin AT1 Phase III potassium hydrochlorothiazide? Antagonists amlodipine besylate Calcium Channel Blockers Pratosartan Boryung Angiotensin AT1 Phase III Antagonists ACT-280.778 Actellion Phase II Amiloride Hemodynamic Mineralocorticoid Phase II hydrochloridespironolactone Therapeutics Receptor (MR) Antagonists Exchanger (NHE) inhibitors Epithelial Sodium Channels (ENaC) Blockers K(V)1.5 Channel Blockers K(V)4.3 Channel Blockers Angiotensin vaccine CoVaccine HT BTG Phase II CYTOO6-Angob Cytos Biotechnology Anti-Angiotensin Phase II I Cholecalciferol Emory University Phase II Cobiprostone Sucampo CIC-2 Channel Phase II Pharmaceuticals Activators INTOO1 IntelGenx Phase II LCZ-696 Novartis Angiotensin AT1 Phase II Antagonists Neprilysin (Enkephalinase, Neutral Endopeptidase, NEP) Inhibitors LFF-269 Novartis Phase II Octreotide acetate Chiasma Growth Hormone Phase II Release Inhibitors Somatostatin Agonists US 9,309,235 B2 63 64 -continued

Mechanism of Drug Name Organization Action Status PL-3994 Palatin Technologies Atrial Natriuretic Phase II Peptide A (NPR1; Guanylate Cyclase A) Receptor Agonists Rostafuroxime Sigma-Tau Phase II SLX-2101 NT Life Sciences Phosphodiesterase Phase II V (PDE5A) inhibitors TBC-3711 Encysive Endothelin ETA Phase II Pharmaceuticals Receptor Antagonists Udenafil Dong-A/Falk Pharma Phosphodiesterase Phase II V (PDE5A) inhibitors Atorvastatin calcium losartan HanAll BioPharma Angiotensin AT1 Phase I potassium Antagonists Dipeptidyl Peptidase IV (CD26; DPP-IV: DP-IV) inhibitors. HMG CoA Reductase inhibitors TNFSF6 Expression inhibitors BLA-S-1058 BIAL Dopamine beta- Phase monooxygenase inhibitors CS-31SO Daiichi Sankyo Phase DSP-9599 Dainippon Sumitomo Renin Inhibitors Phase Pharma MK-1597 Actellion Merck & Co. Renin Inhibitors Phase MK-4618 Merck & Co. Phase MK-S478 Merck & Co. Phase MK-7145 Merck & Co. Phase MK-8266 Merck & Co. Phase MK-8457 Merck & Co. Phase MP-157 Mitsubishi Tanabe Angiotensin AT2 Phase Pharma Agonists MT-3995 Mitsubishi Tanabe Mineralocorticoid Phase Pharma Receptor (MR) Antagonists Mirodenafil hydrochloride SK Chemicals Phosphodiesterase Phase V (PDE5A) Inhibitors NV-04 Novogen Antioxidants Phase Nifedipine/Candesartan cilexetil Bayer Angiotensin AT1 Phase Antagonists Calcium Channel Blockers Antioxidants QGC-001 Quantum Genomics Glutamyl Phase I Aminopeptidase (Aminopeptidase A) Inhibitors RDX-S791 Ardelyx Na+ H+ Phase I Exchanger type 3 (NHE-3) Inhibitors TAK-272 Takeda Renin Inhibitors Phase I TAK-591 Takeda Angiotensin AT2 Phase I Antagonists VTP-27999 Vitae Pharmaceuticals Renin Inhibitors Phase I VaSomera PhaseBio VPAC2 (VIP2) Phase I Agonists Tylerdipine hydrochloride Sihuan Calcium Channel IND Filled Pharmaceutical Blockers

(42) Vasopressin antagonists Such as Tolvaptan; (44) PDE-3 inhibitors such as Amrinone, Milrinone, Enoxi 65 mone, Vesnarinone, Pimobendan, Olprinone; (43) Calcium channel sensitizers such as Levosimendan or (45) Adenylate cyclase activators such as Colforsindapropate activators such as Nicorandil; hydrochloride: US 9,309,235 B2 65 66 (46) Positive inotropic agents such as Digoxin and Metil -continued digoxin; metabolic cardiotonic agents such as Ubide carenone; brain naturetic peptides such as Nesiritide; Drugs in development for the treatment of heart failure (47) Drugs that are currently in development for the treatment of heart failure: Mechanism of Drug Name Organization Action Status PL-3994 Palatin Atrial Natriuretic Phase II Drugs in development for the treatment of heart failure Technologies Peptide A (NPR1; Guanylate Cyclase Mechanism of A) Receptor Drug Name Organization Action Status 10 Agonists Remestemcel-L Osiris Phase Bucindolol ARCA beta-Adrenoceptor Pre TRV-120027 Trevena Angiotensin AT1 Phase hydrochloride Antagonists Registered Receptor Ligands Aliskiren Novartis Renin Inhibitors Phase III Urocortin 2 Neurocrine CRF2 Agonists Phase hemifumarate Biosciences Ferric Vilfor Phase III 15 AAV6-CMV imperial College Phase II carboxymaltose SERCA2a LCZ-696 Novartis Angiotensin AT1 Phase III Anakinra IL-1 Receptor Phase II Antagonists Antagonists Neprilysin LipiCell Bioheart Institute Phase II (Enkephalinase, de Medicina Neutral Regenerativa Endopeptidase, ALD-2O1 Cytomedix/Texas Phase NEP) Inhibitors Heart Institute Neuregulin-1 ZenSun Phase III BAY-1021,189 Bayer Phase Olmesartan Tohoku University Angiotensin AT1 Phase III BAY-10671.97 Bayer Adenine Receptor Phase medoxomil Antagonists Agonists C3BS-CQR-1 Cardio3 Phase II III BAY-86-8050 Bayer Drugs Acting on Phase BioSciences 25 Vasopressin MyoCell Bioheart Phase II III (AVP) Receptors Serelaxin Novartis Phase II III BIA-S-1058 BIAL Dopamine beta Phase AAV1. AmpliPhi Phase II monooxygenase SERCA2a Biosciences Inhibitors Celladon Mount CSCs University of Phase Sinai School of 30 Louisville Medicine Calcitonin gene VasoGenix Phase Albiglutide GlaxoSmithKline GLP-1 Receptor Phase related peptide Agonists JVS-100 uwentaS Phase Allogeneic Mesoblast Phase Therapeutics mesenchymal MyoCell SDF Bioheart Phase precursor cells 35 1 AlsterMACS Miltenyi Biotec Phase Myoblast Advanced Cell Phase BAY-94-8862 Bayer Mineralocorticoid Phase Technology (ACT) Receptor (MR) RO-1160367 Serodus 5-HT4 Phase Antagonists Antagonists COR-1 Corimmun Phase Recombinant Acorda Vanderbilt Phase CXL-102O Cardioxyl Nitric Oxide Phase 40 human glial University Pharmaceuticals Donors growth factor 2 Cenderitide Nile Therapeutics Guanylate Phase 18FILMI Lantheus Medical Phase Cyclase 11.95 Imaging Activators 677950 Kyoto Prefectural Phase Endometrial ERCell Medlistem Phase University of regenerative Medicine cells 45 JN-39588.146 Johnson & Johnson Phase Omecamtiv Amgen, Cytokinetics Cardiac Myosin Phase mecarbil Activators (48) Drugs currently in development for the treatment of pulmonary hypertension:

Drugs in development for the treatment of pulmonary hypertension Mechanism o Drug Name Organization Action Status Imatinib Novartis Breast Cancer-Resistant Protein (BCRP; Pre-Registered meSylate ABCG2) Inhibitors Abl Kinase Inhibitors Angiogenesis Inhibitors, Bcr-Abl Kinase Inhibitors/CSF1R (c-FMS) Inhibitors/KIT (C-KIT) Inhibitors/Apoptosis Inducers PDGFRalpha Inhibitors/PDGFRbeta Inhibitors. Inhibitors of Signal Transduction Pathways Treprostinil United Prostacyclin Analogs Pre-Registered diethanolamine Therapeutics GSK-132576OA GlaxoSmithKline Phase III Macitentan Actellion Endothelin ETA Receptor Antagonists Phase III Endothelin ETB Receptor Antagonists Riociguat Bayer Guanylate Cyclase Activators Phase III US 9,309,235 B2 67 68 -continued Drugs in development for the treatment of pulmonary hypertension Mechanism of Drug Name Organization Action Status Selexipag Actellion/Nippon Prostanoid IP Agonists Phase III Shinyaku Udenafil Dong-A Phosphodiesterase V (PDE5A) Inhibitors Phase III L-Citrulline Nat Heart, Lung, Phase II III and Blood Institute? Wanderbilt University BQ-123 Brigham & Endothelin ETA Receptor Antagonists Phase II Women's Hospital Cicletanine Gilead Phase II Fasudil Asahi Kasei Rho Kinase Inhibitors, Calcium Phase II hydrochloride Sensitizers Nilotinib Novartis Bcr-Abl Kinase Inhibitors Apoptosis Phase II hydrochloride Inducers/Inhibitors of Signal monohydrate Transduction Pathways PRX-08066 Clinical Data 5-HT2B Antagonists Phase II Terguride ErgoNex 5-HT2A Antagonists, 5-HT2B Phase II Pharma Antagonists. Dopamine Autoreceptor Agonists/Dopamine D2 Receptor Partial Agonists/Prolactin Secretion Inhibitors Tezosentan Actellion Endothelin ETA Receptor Antagonists Phase II disodium Endothelin ETB Receptor Antagonists Anakinra Virginia L-1 Receptor Antagonists Phase III Commonwealth University (VCU) Simvastatin Imperial College HDL-Cholesterol Increasing Agents Phase III HMG-CoA Reductase Inhibitors 99mTC- Montreal Heart Phase Pulmosind Institute (MHI) APD-811 Arena Prostanoid IP Agonists Phase Sorafenib Bayer Rafkinase B Inhibitors. Rafkinase C Phase inhibitors Angiogenesis Inhibitors/Flt3 (FLK2/STK1) Inhibitors/VEGFR-1 (Flt-1) inhibitors/KIT (C-KIT) Inhibitors VEGFR-2 (FLK-1/KDR) Inhibitors/VEGFR 3 (FLT4) Inhibitors/PDGFRbeta inhibitors. RET Inhibitors. Inhibitors of Signal Transduction Pathways Triplelastat Proteo Biotech Elastase Inhibitors Phase I 2586881 Apeiron Preclinical Biologies C-122 Corridor Caspase 3 Activators/Dopamine D1 Preclinical Pharmaceuticals Antagonists, 5-HT2B Antagonists/5-HT7 Antagonists. Caspase 8 Activators Dopamine D2 Antagonists. Dopamine D3 Antagonists. Histamine H1 Receptor Antagonists. Caspase 9 Activators Apoptosis Inducers PLX-I United Angiogenesis Inducers Preclinical Therapeutics

(49) Drugs in current development for the treatment of female -continued sexual dysfunction: Drugs in active development for the treatment Drugs in active development for the treatment 55 of female sexual dysfunction of female Sexual dysfunction Mechanism of Mechanism of Drug Name Organization Action Status Drug Name Organization Action Status Bremelanotide Palatin Melanocortin Phase II Alprostadil Apricus Phase III Technologies MC3 Receptor Biosciences 60 Agonists VIVUS Melanocortin Prasterone EndoCeutics, HSD11B1 Phase III MC4 Receptor Monash Expression Agonists University Inhibitors Pill-Plus Pantarhei Phase II Testosterone BioSante Androgen Phase III BioScience transdermal gel Receptor 65 Testosterone MDTS Acrux Androgen Phase II Agonists Receptor Agonists US 9,309,235 B2 69 70 -continued -continued Drugs in active development for the treatment Drugs in active development for the of female sexual dysfunction treatment of erectile dysfunction 5 Mechanism of Mechanism of Drug Name Organization Action Status Drug Name Organization Action Status Estradiotestosterone BioSante Estrogen Phase I Receptor (ER) Mount Sinai Agonists School of Androgen 10 Medicine Receptor KH-204 KMSI Clinical Agonists CKD-533 Chong Kun Dang Phosphodiesterase Preclinical LGD-2941 Ligand Selective Phase I Pharm (CKD V (PDE5A) Androgen Pharm) Inhibitors Receptor MP-52 Biopharm Preclinical Modulators 15 TGHW01AP Fabre-Kramer Dopamine D1 Preclinical (SARM) Agonists Lidocaine, heparin Urigen Phase I Dopamine D2 Onabotulinumtoxin.A Allergan Phase I Agonists S1P-104 S1 Biopharma IND Filed PL-6983 Palatin Preclinical Technologies S1P-401 S1 Biopharma Preclinical 2O (51) Drugs in development for the treatment of sleep apnea:

(50) Drugs used for the treatment of erectile dysfunction such Drugs in development for the treatment of sleep apnea as Alprostadil, Aviptadil, Phentolamine mesilate, Weige, Alprostadil; 25 Mechanism of (51) Drugs currently in development for the treatment of male Drug Name Organization Action Status sexual dysfunction: CX-1739 Cortex AMPA Receptor Phase II Modulators Phentermine/topiramate VIVUS AMPA Phase II Antagonists Drugs in active development for the 30 Kainate treatment of erectile dysfunction Antagonists Sodium Channel Mechanism of Blockers Drug Name Organization Action Status Carbonic Anhydrase Type Fluvastatin Novartis Phase III Apoptosis 35 II Inhibitors Sodium Inducers HMG AVE-0118 Sanofi Potassium Phase I CoA Reductase Channel Inhibitors Blockers Lodenafil Cristalia Phosphodiesterase Phase III Suvorexant Merck & Co. Orexin Receptor Phase I carbonate V (PDE5A) Inhibitors Antagonists 40 COL-132 Collegium Clinical EFLA-4OO Chonbuk Phase II III Pharmaceutical National University Hospital Apomorphine Vectura Dopamine D2 Phase II (52) Drugs currently in development for the treatment of hydrochloride Agonists metabolic syndrome: LY-900010 Lilly Phosphodiesterase Phase II 45 V (PDE5A) Inhibitors Selective Antiobesity drugs under active development for the Androgen treatment of patients with metabolic Syndrome Receptor Modulators 50 Mechanism of (SARM) Drug Name Organization Action Status Nitroglycerin Futura Medical Phase II RX-10100 Rexahn Drugs Acting on Phase II Chromium University of Phase II Dopaminergic picolinate Pennsylvania Transmission RM-493 Ipsen Melanocortin MC4 Preclinical Receptor Agonists Drugs Acting on 55 Serotonergic TZP-301 Tranzyme GHS Receptor Preclinical Transmission Antagonists YHD-1023 Yuhan Phase II INT007 IntelGenx Phase I LY-2452473 Lilly Selective Phase I Androgen Receptor 60 Antihyperlipidemic drugs under active development for Modulators the treatment of patients with metabolic Syndrome (SARM) hMaxi-K Albert Einstein Phase I Mechanism of College of Drug Name Organization Action Status Medicine Ion Channel 65 GFT-505 Genfit PPARalpha Phase II Innovations Agonists US 9,309,235 B2 71 72 -continued vehicle or diluent; and b) a container or packaging. The kits may optionally comprise instructions describing a method of Antihyperlipidemic drugs under active development for using the pharmaceutical compositions in one or more of the the treatment of patients with metabolic Syndrome methods described herein (e.g. preventing or treating one or Mechanism of more of the diseases and disorders described herein). The kit Drug Name Organization Action Status may optionally comprise a second pharmaceutical composi PPARdelta tion comprising one or more additional agents described Agonists hereinforco therapy use, a pharmaceutically acceptable car MBX-802S Metabolex PPARdelta Phase II rier, vehicle or diluent. The pharmaceutical composition Agonists 10 Pitavastatin Kowa APOA1 Phase I comprising the compound described herein and the second calcium Expression pharmaceutical composition contained in the kit may be Enhancers optionally combined in the same pharmaceutical composi HMG-CoA tion. Reductase Inhibitors 15 A kit includes a container or packaging for containing the SPP1 pharmaceutical compositions and may also include divided (Osteopontin) Expression containers such as a divided bottle or a divided foil packet. Inhibitors The container can be, for example a paper or cardboard box, CDX-085 Cardax Antioxidants Preclinical a glass or plastic bottle or jar, a re-sealable bag (for example, Pharmaceuticals to hold a “refill of tablets for placement into a different container), or ablisterpack with individual doses for pressing (53) Antiobesity drugs: out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to marketa single dosage form. For example, Drugs marketed for the treatment of obesity 25 tablets may be contained in a bottle which is in turn contained within a box. Year and Orga- Mechanism of country of An example of a kit is a so-called blisterpack. Blisterpacks Drug Name nization Action first launch are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage Methamphetamine Abbott Noradrenergic, alpha- 943 (U.S.) 30 hydrochloride and beta forms (tablets, capsules, and the like). Blister packs generally (Desoxyn) adrenoceptor agonist consist of a sheet of relatively stiff material covered with a foil Amfepramone Sanofi Noradrenergic release 959 (U.S.) of a preferably transparent plastic material. During the pack hydrochloride stimulant aging process, recesses are formed in the plastic foil. The (Tenuate) Phentermine UCB Noradrenergic release 959 (U.S.) recesses have the size and shape of individual tablets or cap (Ionamin) Celltech stimulant 35 Sules to be packed or may have the size and shape to accom Benzfetamine Pfizer Noradrenergic release 960 (U.S.) modate multiple tablets and/or capsules to be packed. Next, hydrochloride stimulant the tablets or capsules are placed in the recesses accordingly (Didrex) Phendimetrazine Pfizer Noradrenergic release 961 (U.S.) and the sheet of relatively stiff material is sealed against the artrate (Bontril, stimulant plastic foil at the face of the foil which is opposite from the Prelu-2, Plegine) 40 direction in which the recesses were formed. As a result, the Mazindol (Sanorex) Novartis Noradrenergic 973 (U.S.) tablets or capsules are individually sealed or collectively reuptake inhibitor Orlistat (Xenical) Roche Pancreatic lipase 998 sealed, as desired, in the recesses between the plastic foil and inhibitor (New Zealand) the sheet. Preferably the strength of the sheet is such that the Sibutramine Abbott Norepinephrine and 5- 1998 (U.S.) tablets or capsules can be removed from the blister pack by hydrochloride HT reuptake inhibitor (withdrawn 45 manually applying pressure on the recesses whereby an open monohydrate 2010) (Meridia, Reductil) ing is formed in the sheet at the place of the recess. The tablet Rimonabant Sanofi Cannabinoid CB1 2006 (U.K.) or capsule can then be removed via said opening. (Acomplia) antagonist (withdrawn It may be desirable to provide written memory aid contain 2008) ing information and/or instructions for the physician, phar 50 macist or Subject regarding when the medication is to be Kits taken. A "daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When The compounds and pharmaceutical formulations the kit contains separate compositions, a daily dose of one or described herein may be contained in a kit. The kit may more compositions of the kit can consist of one tablet or include single or multiple doses of two or more agents, each 55 capsule while a daily dose of another or more compositions of packaged or formulated individually, or single or multiple the kit can consist of several tablets or capsules. A kit can take doses of two or more agents packaged or formulated in com the form of a dispenser designed to dispense the daily doses bination. Thus, one or more agents can be present in first one at a time in the order of their intended use. The dispenser container, and the kit can optionally include one or more can be equipped with a memory-aid, so as to further facilitate agents in a second container. The container or containers are 60 compliance with the regimen. An example of such a memory placed within a package, and the package can optionally aid is a mechanical counter which indicates the number of include administration or dosage instructions. A kit can daily doses that have been dispensed. Another example of include additional components such as Syringes or other Such a memory-aid is a battery-powered micro-chip memory means for administering the agents as well as diluents or other coupled with a liquid crystal readout, or audible reminder means for formulation. Thus, the kits can comprise: a) a 65 signal which, for example, reads out the date that the last daily pharmaceutical composition comprising a compound dose has been taken and/or reminds one when the next dose is described herein and a pharmaceutically acceptable carrier, to be taken. US 9,309,235 B2 73 74 EXAMPLES times). The combined organics are washed with brine, dried over MgSO filtered, and concentrated in vacuo. The result All references provided in the Examples are herein incor ing pyrazole C is then purified by SiO2 chromatography using porated by reference. As used herein, all abbreviations, sym an appropriate gradient of EtOAC/hexanes. bols and conventions are consistent with those used in the 5 Step 3: Amidine Formation: contemporary Scientific literature. See, e.g. Janet S. Dodd, To a suspension of NHCl (e.g., 5 eq) in toluene cooled to ed., The ACS Style Guide: A Manual for Authors and Editors, about 0° C. is added AlMe (e.g., 5 eq, 2.0M solution in 2" Ed., Washington, D.C.: American Chemical Society, toluene) dropwise, e.g., via a syringe. The reaction mixture is 1997, herein incorporated in its entirety by reference. allowed to warm to room temperature, and stirred until no 10 more bubbling is observed. Pyrazole C is added in 1 portion to Example 1 the reaction mixture, heated to about 110° C., and stirred at this temperature until judged complete (e.g., using either TLC Syntheses of the Compounds of Table 1 or LC/MS analysis). Once complete, the reaction mixture is cooled, treated with excess methanol, and stirred vigorously General Procedure A 15 for about 1 hour at room temperature. The thick slurry is filtered, and the resulting solid cake is washed with methanol. The filtrate is concentrated in vacuo, and the resulting Solids O Step 1 are re-suspended in an ethyl acetate:isopropyl alcohol. 5:1 LHMDS -- V:V, solvent mixture. The reaction mixture is further treated THF/toluene 2O R Me O with a saturated sodium carbonate solution, and stirred for A about 10 minutes before the layers are separated. The aqueous OEt layer is extracted with the ethyl acetate:isopropyl alcohol. 5:1 EtO V:V, Solvent mixture (3x), and the combined organics are washed with brine. The organics are further dried over O 25 MgSO4, filtered, and the solvent is removed in vacuo. The O OLi Step 2 product amidine D is used as-is in Subsequent steps without 1N 2 OE H2NHN R further purification. R HCI Preparation of Compound I-2 EtOH 30 O 700 C.

B

R N - Step 3 R N - Y AIMe, NHCI Y. / toluene A 110° C. OEt NH2 O HN C D

General Procedure A Step 1: Dione Enolate Formation: To a solution of ketone A in THF cooled to -78° C., LiHMDS (e.g., 0.9eq 1.0 M in toluene) is added dropwise, for example using a syringe. The reaction mixture is then allowed to warm to about 0°C., then charged with diethyl oxalate (1.2 eq). At this time, the reaction mixture is warmed to room temperature and stirred at that temperature until judged complete (e.g., using either TLC or LC/MS analysis). Once the reaction is complete (reaction time typically about I-2 45 minutes), the product dione enolate B is used as-is in Step 55 2, i.e., the cyclization step, without any further purification. Step 2: Pyrazole Formation: Intermediate D-1 was accessed via General Procedure A in Dione enolate B is diluted with ethanol and consecutively 58% yield from 1-(isoxazol-3-yl)ethanone using (thiophen charged with HCl (e.g., 3 eq, 1.25M solution in ethanol) and 3-ylmethyl)hydrazine hydrochloride in the second step. Inter arylhydrazine hydrate (e.g., 1.15 eq). The reaction mixture is 60 mediate D1: 'H-NMR (400 MHz, DMSO-d) 89.23-9.16 (m, heated to about 70° C. and stirred at this temperature until 1H), 8.76(brs, 3H), 7.73-7.81 (m, 1H), 7.49 (dt, 1H), 7.31 (br cyclization is deemed complete (e.g., by LC/MS analysis, s, 1H), 7.08-6.98 (m, 2H), 5.79 (s. 2H). typically about 30 minutes). Once complete, the reaction A suspension of sodium (E.Z)-3-ethoxy-2-fluoro-3-oxo mixture is treated carefully with solid sodium bicarbonate prop-1-en-1-olate (257 mg, 1.65 mmol) and Intermediate D-1 (e.g., 4 eq) and diluted with dichloromethane and water. The 65 (150 mg. 0.55 mmol) in ethanol (2.7 mL) was stirred at 90° C. organic layer is separated, and the aqueous layer is further for 18 hours. The contents were diluted with ethyl acetate (10 diluted with water before extraction with dichloromethane (3 mL) and water (10 mL). The mixture was treated carefully US 9,309,235 B2 75 76 with HCl (1.32 mL, 1.66 mmol. 1.25M solution in ethanol). -continued Layers were separated, and the aqueous layer was extracted with dichloromethane (3x10 mL). The organics were washed with brine (10 mL), dried over MgSO4, filtered, and the solvent was removed in vacuo. Purification by silica gel chro matography (0-20% 7:1-acetonitrile:methanol in dichlo romethane) provided impure compound. Purification via reverse phase HPLC provided compound 1-2 (30 mg, 16% yield) as a white solid. I-2: 'H-NMR (400 MHz, DMSO-d) & 13.40-13.17 (brs, 1H), 9.14 (s, 1H), 8.14 (brs, 1H), 7.57 (s, 1H), 7.52-7.45 (m, 10 1H), 7.40 (brs, 1H), 7.29-7.19 (m, 1H), 7.13 (d. 1H), 5.81 (s, 2H). Preparation of Compound I-1

15 I-3 Intermediate D-2 was accessed via General Procedure A in 49% yield from 1-(isoxazol-3-yl)ethanone using ((3-fluo rothiophen-2-yl)methyl)hydrazine hydrochloride in the sec ond step. Intermediate D-2: 'H-NMR (400 MHz, DMSO-d) & 9.22-9.18 (m, 1H), 8.46 (bris, 3H), 7.64-7.58 (m. 1H), 7.53-747 (m. 1H), 7.10 (t, 1H), 6.95 (d. 1H), 5.92 (s. 2H). A suspension of sodium (E.Z)-3-ethoxy-2-fluoro-3-oxo prop-1-en-1-olate (200 mg 0.69 mmol) and Intermediate D-2

(321 mg, 2.06 mmol) in ethanol (3.4 mL) was stirred at 90° C. 25 for 1 hour. The contents were diluted with ethyl acetate (10 mL) and water (10 mL). The mixture was treated carefully with HCl (1.65 mL, 2.06 mmol. 1.25M solution in ethanol). Layers were separated, and the aqueous layer was extracted with dichloromethane (3x20 mL). The organics were washed with brine (10 mL), dried over MgSO4, filtered, and the 30 solvent was removed in vacuo. Purification by silica gel chro matography (0-40% 7:1-acetonitrile:methanol in dichlo romethane) provided compound 1-3 (86 mg, 33% yield) as a white solid. Compound I-3: 'H-NMR (400 MHz, DMSO-d) & 13.29 35 (brs, 1H),9.18 (d. 1H), 8.16 (brs, 1H), 7.59 (s.1H), 7.48 (dd. I-1 1H), 7.23 (brs, 1H), 6.95 (d. 1H), 5.95 (s. 2H). To a solution of Intermediate D-1 (50 mg, 0.55 mmol) in Preparation of Compound I-4 pyridine (2.7 mL) was added a mixture of E- and Z-3-ethoxy acrylonitrile (266 mg, 2.74 mmol) and 1,8-diazabicyclo 5.4.0]undec-7-ene (167 mg, 1.10 mmol). The solution was stirred at 110°C. for 18 hours. The contents were diluted with ethyl acetate (10 mL), and washed with Saturated ammonium chloride solution (3 mL). Layers seperated, and aqueous layer was diluted with additional water (10 mL). The aqueous layer was then extracted with dichloromethane (3x10 mL). Com bined organic layers were washed with brine (10 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatog raphy (0-30% 7:1-acetonitrile:methanol in dichlo romethane) provided compound I-1 (97 mg, 54% yield) as an iridiscent pale brown solid. Compound I-1: 'H-NMR (400 MHz, DMSO) & 9. 13-9.07 (m. 1H), 8.12 (d. 1H), 7.49-7.46 (m, 1H), 7.45 (d. 1H), 7.29 7.26 (m. 1H), 7.24-7.21 (m, 1H), 6.99-6.92 (m,3H), 6.36 (dd. 1H), 5.78 (s. 2H). Preparation of Compound I-3

65 US 9,309,235 B2 77 78 Intermediate D-3 was accessed via General Procedure A in solvent was removed in vacuo. Purification by silica gel chro 57% yield from 1-(isoxazol-3-yl)ethanone using (thiophen matography (0-30% 7:1-acetonitrile:methanol in dichlo 2-ylmethyl)hydrazine hydrochloride in the second step. Inter romethane) provided impure compound. Solids were tritu mediate D-3: 'H-NMR (400 MHz, DMSO-d) & 9.47 (d. rated with ether (5 mL) and dried to yield compound 1-5 (22 J=8.22 Hz, 1H), 9.09-9.26 (m, 1H), 7.66-7.80 (m, 1H), 7.48 mg, 18% yield) as an off-white solid. 1H-NMR (500 MHz, (d. J=5.09 HZ, 1H), 7.29-7.42 (m. 1H), 7.24 (d. J=14.48 Hz, DMSO-d) & 13.28 (brs, 1H), 9.17 (d. 1H), 8.14 (brs, 1H), 1H), 7.04-7.17 (m, 2H), 6.98 (t, J=4.30 Hz, 1H), 5.93-6.06 7.60 (s, 1H), 7.26 (s, 1H), 6.87 (brs, 1H), 6.59 (dd. 1H), 5.87 (m. 1H). (s. 2H). A suspension of sodium (E.Z)-3-ethoxy-2-fluoro-3-oxo prop-1-en-1-olate (484 mg, 3.00 mmol) and intermediate D-3 10 Example 2 (273 mg, 1.0 mmol) in ethanol (10 mL) was stirred at 90° C. for 18 hours. The contents were diluted with ethyl acetate (10 Biological Activity Measurement by the mL) and water (10 mL). The mixture was treated carefully sGC-HEK-cGMP Assay with HCl (1 M aqueous solution). The layers were separated, and the aqueous layer was extracted with dichloromethane 15 (Assay Run with SNP Incubation) (3x10 mL). The organics were washed with brine (10 mL), Human embryonic kidney cells (HEK293), endogenously dried over MgSO filtered, and the solvent was removed in vacuo. The residue was suspended in diethyl ether and filtered expressing soluble guanylate cyclase (sGC), were used to to give compound 1-4 (190 mg, 53% yield) as an off-white evaluate the activity of test compounds. Compounds stimu solid. lating the sGC receptor should cause an increase in the intra Compound I-4: 'H-NMR (400 MHz, DMSO-d) & 13.30 cellular concentration of c(GMP. HEK 293 cells were seeded (br. S., 1H), 9.16 (d. J=1.17 Hz, 1H), 8.16 (br. s., 1H), 7.59 (s. in Dulbecco's Modification of Eagle's Medium supple 1H), 7.45 (d. J–4.70 Hz, 1H), 7.24 (s, 1H), 7.14 (br. S., 1H), mented with fetal bovine serum (10% final) and L-glutamine 6.97 (dd, J=4.70, 3.52 Hz, 1H), 6.00 (s. 2H). (2 mM final) in a 200 uL volume at a density of 1x10 Preparation of Compound I-5 cells/well in a poly-D-lysine coated 96 well flat bottom plate 25 and grown overnight at 37° C. Medium was aspirated and cells were washed with 1x Hank's Buffered Saline Salt Solu tion (200LL). Cells were then incubated for 15 minutes at 37° C. with 200 uL of a 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) solution. Test article and sodium nitroprusside solu tions (xuM concentration for test article solution and 10 uM concentration for SNP solution; wherein X is one of the fol lowing concentrations): 10 M 3 M 1 LM O.3 M O.1 LM

OOOO3 LM OOOO1 LM were then added to the assay mixture (2 LL each) and the resulting mixture incubated at 37°C. for 10 minutes. After the 10 minute incubation, the assay mixture was aspirated and 0.1M HCl (200 u) was added to the cells. The plate was incubated at 4°C. for 30 minutes in the 0.1M HCl to stop the reaction and lyse the cells. The plates were then centrifuged at 50 1,200 g for 5 minutes at room temperature. Supernatants were collected and transferred to a new flat bottom 96 well plate for I-5 analysis by HPLC-MS. Vehicle controls were carried out using DMSO (1%) solutions. A known sGC stimulator, BAY Intermediate D-4 was accessed via General Procedure A in 41-2272, was used as the positive control. Samples were 51% yield from 1-(isoxazol-3-yl)ethanone using ((5-fluo diluted with an equal volume of 1 MAmmonium Acetate (pH rothiophen-2-yl)methyl)hydrazine hydrochloride in the sec 55 7) to neutralize samples for better chromatography. A 2x ond step. "H-NMR (500 MHz, DMSO-d) & 9.25-9.20 (m, cGMP standard solution was prepared in 0.1M HCl and then 1H), 8.81 (brs, 3H), 7.64 (s, 1H), 7.10 (d. 1H), 6.82 (t, 1H), diluted with an equal volume of 1 MAmmonium Acetate, 6.60 (dd. 1H), 5.87 (s. 2H). with the following final concentrations in nM. 1024, 512, A suspension of sodium (E.Z)-3-ethoxy-2-fluoro-3-oxo 256, 128, 64, 32, 16, 8, 4, 2, 1. cGMP concentrations in the prop-1-en-1-olate (146 mg, 0.94 mmol) and Intermediate D-4 60 test plates were determined from each sample using the (91 mg, 0.31 mmol) in ethanol (1.6 mL) was stirred at 90° C. LC/MS conditions shown in Table 2 below and the calculated for 1 hour. The contents were diluted with ethyl acetate (10 cGMP standard curve. ECso values were calculated from mL) and water (10 mL). The mixture was treated carefully concentration-response curves generated with GraphPad with HCl (0.75 mL, 0.94 mmol, 1.25M solution in ethanol). Prism Software. Layers were separated, and the aqueous layer was extracted 65 The biological activities of some of the compounds of with dichloromethane (3x20 mL). The organics were washed Formula I determined with the sGC HEK assay with SNP with brine (10 mL), dried over MgSO4, filtered, and the incubation are summarized in Tables 3A and 3B. US 9,309,235 B2 79 80 TABLE 2 (HPLC LC/MS experimental conditions) MS: Thermo Quantum or Waters LCMS Ion Mode: ESIt Scan Type: MRM

Dwell Collision Retention Time Energy Tube Time Compound: Transition (mSec) (V) Lens (min) cGMP 346 - 152 100 28 139 1.O HPLC: Agilent Technologies 1200 Series with CTC Analytics HTS PAL Column: Thermo Hypersil Gold 2.1 x 50 mm 5 micron particle size Flow Rate: 400 uL/min Column RT Temperature: Autosampler 6° C. Temperature: Injection Volume: 20 uL Mobile Phases: A = 98:2 Water: Acetonitrile + 0.1% Formic Acid B = 2:98 Water:Acetonitrile + 0.1% Formic Acid

Gradient: Time (min) % A % B

O 100 O O.3 30 70 2.00 30 70 2.01 100 O 4 100 O

TABLE 3A TABLE 3B-continued Whole cell activity in the HEKassay. 30 More whole cell activity in the HEK assay. Compound HEK assay EC50 HEKassay HEK assay HEK assay HEK assay No. unconstrained (IM)# (Percent (Percent (Percent Emax-un- I-3 A. Compound Emax Emax Emax constrained 35 I-4 E No. at 1 iM)* at 10 M)* at 30 M)* (Percent)+ #EC50 values were obtained from the full concentration response curve following two methods: EC50 constrained refers to the value obtained when the top of the curve was fitted I-1 C D E E to 100% (wherein E = 100% was the activity in the HEKassay obtained with the positive I-2 C D D D control.BAY 41-2272 at 10 uM in the presence of 100 MSNP), ECsounconstrained here repored refer to the value obtained from a full concentration-response curve when the top of I-3 D D E D the curve is not fitted to 100%. The EC50 code definition in micromolar (uM) are: 40 0.01&EC50 < 0.1 = A I-4 A. D D E 0.1 seC50 < 0.5 = B 0.5 seC50 < 1.0 = C *Percent Emax was obtained at twelve concentrations of the test compound as explained 1,0s EC50 < 5.0 =D above; the results for three of them (1, 10 and 30 M) are shown in Table 3A. The code 5,0s EC50 < 10,0=E definitions for the sGC enzyme activity values, expressed as%E in the presence of 10M of SNP (wherein E = 100% was the activity in the HEKassay obtained with the positive EC50 & 10,0=F control BAY 41-2272 at 10 uM in the presence of 100 MSNP) are: 45 A = 0 to <10% B = 10 to <20% Example 3A C = 20 to <40% D = 40 to <60 Biological Activity Measurements by the Purified E = 60 or <80% 50 Human sGC Enzyme Activity Assay F = 80 to <100% G = 100 to <1.20% Human soluble guanylate cyclase enzyme (hsGC) H = 120% or higher obtained from Enzo Inc. (P/N: ALX-201-177) was used to — = not determined evaluate the activity of test compounds. The assay reactions +The same code definitions apply for Emax unconstrained, wherein this value is defined as contained 0.1 M Tris (pH 8.0), 0.5 mg/mL BSA (pH 8.0), 2 the maximum activity value obtained from the full concentration-response curve for the 55 compound, relative to the positive control value of 100% obtained as above. Here, the term mM DTT, 2 mM MgCl, 300 uM GTP, 1 mM 3-isobutyl-1- “unconstrained” means that, during analysis of the sGC enzyme activity data, the topportion methylxanthine (IBMX) and 5 ng human soluble guanylate of the concentration-response curve was not fitted to 100%. cyclase enzyme. Test compounds in DMSO were then added (2 uL. 10 or 30 uM final concentration) and incubated (water, TABLE 3B 200 uL. 96-well plate format) at 37° C. for 30 minutes. The 60 controls were carried out using 2 uI, DMSO. After the 30 More whole cell activity in the HEK assay. minute incubation, the reaction was stopped with the addition of 200 uL of cold methanol. The plate was then centrifuged at Compound HEK assay EC50 3,200 rpm for 10 minutes at room temperature. Supernatants No. unconstrained (IM)# (200LL) were collected and transferred to a new 96 well plate I-1 D 65 for analysis by HPLC LC/MS/MS. I-2 C An 8 point cOMP (Sigma-Aldrich P/N: G6129) standard curve was prepared in assay buffer ranging from 0.156-20 US 9,309,235 B2 81 82 uM. Samples for the coMP standard curve were then diluted Example 4 with an equal volume of methanol resulting in final c(GMP concentrations of 0.078-10 uM. Biological Activity Measurement by the Thoracic cGMP concentrations in all samples were determined using LC/MS/MS analysis, using the conditions listed in Aortic Rings Assay Table 4 below. The coMP standard curve was generated using 5 GraphPad Prism Software. Thoracic aortic rings were dissected from anesthetized Calculations: Specific Activity was determined by the (isoflurane) male Sprague-Dawley rats weighing 275-299 g. amount of c(GMP formed (nmoles) per mg of sGC per min. Tissues were immediately transferred to ice-cold Krebs Enzyme “fold-change' was calculated by dividing Specific Henseleit solution, which had been aerated with 95% O2 and Activity for test compounds by Specific Activity of DMSO 10 controls. 5% CO for 30 minutes. Following removal of connective TABLE 4 tissue, aortic sections were cut into 4 rings (~2 mm each) and Suspended on 2 L-shaped hooks, with one hook fixed at the LCMSMS method for detection of c(GMP bottom of the tissue bath (Schuler Organ Bath, Harvard Appa Inlet Method: 15 ratus) and the other connected to a force transducer (F30 Force Transducer, Harvard Apparatus). Baths contained HPLC: Waters Acquity Column: Thermo Hypersile Gold PFP, 2.1 x 30 mm, 3 p.m. Krebs Henseleit solution (10 mL) heated to 37°C. and aerated Guard Column: Thermo Hypersile Gold, 2.1 x 10 mm with 95% O, and 5% CO. Rings were brought to an initial Column Temp: 25o C. tension of 0.3-0.5g and gradually raised to a resting tension of Flow Rate: 0.4 mL/min 1.0 g over 60 minutes. Rings were rinsed with Krebs Auto Sampler: Acquity; 6°C. Injection Volume: 10 uL Henseleit solution (heated to 37° C. and aerated with 95% 02 Mobile Phases: A = 0.1% Acetic Acid (v/v) in 100% water and 5% CO) at 15 minute intervals until a stable baseline was B = 0.1% Acetic Acid (viv) in 100 methanol obtained. Rings were considered to be stable after a resting Gradient: Time (min) %. A 90 B Curve tension of 1.0 g was maintained (for approximately 10 min 25 utes) without need for adjustment. Rings were then con O 95 5 6 tracted with 100 ng/mL phenylephrine by adding 100 uI of a O.S 95 5 6 10 m/mL phenylephrine Stock solution. Tissues achieving a O.6 10 90 6 2.0 10 90 6 stable contraction were then treated in a cumulative, dose 2.1 95 5 6 dependent manner with test compounds prepared in dimeth 4 (end) 30 ylsulfoxide (DMSO). In some cases, tissues were rinsed three MS File:c0MP.exp times over a 5 minute period with Krebs-Heinseleit’s solution Mass Spectrum: Waters Quattro micro (heated to 37° C. and aerated with 95% 02 and 5% CO2), Ionization: ES allowed to stabilize at baseline, and then used for character Source, Desolvation: 150° C., 450° C. ization of other test articles or DMSO effects. All data were MS Function: MRM 35 collected using the HSE-ACAD software provided by Har Collision vard Apparatus. Percent relaxation effects were calculated in Dwell Cone Energy Microsoft Excel using the recorded tension value of 100 Compound Transition (Sec) (V) (eV) ng/mL phenylephrine treatment as 0% inhibition and treat ment with 100 uM 3-isobutyl-1-methylxanthine as 100% cGMP 346 - 152 O.1 35 2O 40 inhibition. ECso values were calculated from concentration response curves generated with GraphPad Prism Software. Example 3B Example 5

Biological Measurement by the Purified Human sGC 45 Biological Activity Measurement by the Thoracic Enzyme Synergy Performed in the Presence of Aortic Rings Assay Sodium Nitroprusside (SNP), a Nitric Oxide Donor As an alternative thoracic aortic rings assay, the procedure Enzyme assays were performed as described above, but the of Example 5 was used except that percent relaxation effects assay was done in the presence of 1 LM sodium nitroprusside 50 were calculated in Microsoft Excel using the recorded tension (SNP). Data for compounds of Table 1 is summarized in Table value of 100 ng/mL phenylephrine treatment as 0% inhibition 5 below. and, after washing the tissue with buffer, the original resting TABLE 5 tension of the tissue was used as 100% inhibition. A number of embodiments have been described. Neverthe Enzyme Data With SNP. 55 less, it will be understood that various modifications may be Compound Enzyme Activity (increase made without departing from the spirit and scope of the No. at 30 M with SNP)* invention. I-1 D I-2 D Example 6 60 *The compounds were tested at a concentration of 30 Minthe presence of 1 MSNP. The code for the fold increase in enzyme activity is: Animal Models Descriptions A = no increase to <2 fold increase B = 2 to <5 fold increase Lamb Model of Pulmonary Hemodynamics Using Inhaled C = 5 to <1.0 fold increase D = 10 or <20 fold increase sGC Stimulator E = 20 to 30 fold increase 65 (“Inhaled Agonists of Soluble Guanylate Cyclase Induce F = -30 fold increase Selective Pulmonary Vasodilation, Oleg V. etal, American J of Resp and Critical Care Medicine, Vol 176, 2007, p 1138) US 9,309,235 B2 83 84 It is possible to test whether inhalation of novel dry-powder was then lowered into a 10 ml tissue bath containing modified microparticle formulations containing sGC stimulators Krebs-Henseleitbuffer, at 37°C., bubbled with Carbogen. A would produce selective pulmonary vasodilation in lambs 1 g tension was applied to each piece of tissue and the tissue with acute pulmonary hypertension by following a published washed, followed by a 1 hour stabilization period. Once the procedure. It is also possible to evaluate the combined admin- 5 tissues had been allowed to stabilize, the apparatus for elec istration of the microparticles of sGC stimulator and inhaled trical field stimulation was set to deliver a stimulation of nitric oxide (iNO) in this system. Finally, it is possible to frequency 80 Hz pulse width 0.1 ms, with a gated, uni-polar examine whether inhaling microparticles of an sGC stimula pulse, every 2 minutes using a DS8000 8 channel digital tor would produce pulmonary vasodilation when the response stimulator (World Precision Instruments Stevenage, UK). A to iNO (inducible nitric oxide synthase) is impaired. 10 Voltage response curve was carried out on each tracheal strip Protocol: Inawake, spontaneously breathing lambs instru at 2, 4, 6, 7, 8, 10, 12 V and a sub-maximal voltage then mented with vascular catheters and a tracheostomy tube, selected to apply to each tissue during the remainder of the U-46619 is infused intravenously to increase mean pulmo experiment. Guinea pig tracheal smooth muscle (GPTSM) nary arterial pressure to 35 mm Hg Inhalation of micropar contraction was induced using Sub-maximal Electrical Field ticles composed of either BAY 41-2272, BAY 41-8543, or 15 Stimulation (EFS) (It is also possible to induce contraction by BAY 58-2667 and excipients (dipalmitoylphosphatidylcho using a spasmogen Substance. Such as methacholine or hista line, albumin, lactose) produced dose dependent pulmonary mine as described in Coleman et al.). Compounds were vasodilation and increased transpulmonary c0MP release dissolved in 100% DMSO at 3x10-2M and aliquots stored at without significant effect on mean arterial pressure Inhalation -200 C. A separate aliquot was used for each experiment. of microparticles containing BAY 41-8543 or BAY 58-2667 20 Tissues were washed with Krebs buffer and stimulated using increased systemic arterial oxygenation. The magnitude and the previously determined sub-maximal voltage for 1 hour to duration of pulmonary vasodilation induced by iNO were establish a stable baseline contraction prior to assessment of augmented after inhaling BAY 41-8543 microparticles. Intra compound activity. venous administration of 1H-1.2.4 oxadiazolo 4.3-aqui *Novel and Versatile Superfusion System. Its use in the Evaluation of Some noxalin-1-one (ODO), which oxidizes the prosthetic heme 25 Spasmogenic and Spasmolytic Agents Using Guinea pig isolated Tracheal group of sGC, markedly reduced the pulmonary vasodilator Smooth Muscle..., R. A. Coleman et al., J. Pharmacol. Methods, 21, 71-86, effect of iNO. In contrast, pulmonary vasodilation and 1989. transpulmonary c0MP release induced by inhaling BAY A cumulative dose response curve (DRC) to each test sub 58-2667 microparticles were greatly enhanced after treat stance was then performed and changes in Smooth muscle ment with ODQ. Thus, inhalation of microparticles contain- 30 contraction measured. The effect of each test substance in ing agonists of sGC may provide an effective novel treatment each experiment was expressed as a percentage inhibition of for patients with pulmonary hypertension, particularly when the baseline contraction, normalized to the relevant vehicle responsiveness to iNO is impaired by oxidation of sGC. Note: controls. The experiment was performed three times, using BAY 41-2272, BAY 41-8543 are sGC stimulators whereas tissue from three different animals. The data from all three BAY 58-2667 is an SGC activator. 35 experiments was pooled, the DRC plotted, and the test sub Electrical Field Stimulated Guinea Pig Tracheal Smooth stance potency and efficacy determined. The potency of Ipra Muscle InVitro (Ex Vivo) Model for the Assessment of Bron tropium bromide was assessed alongside the test compounds chodilation. and the IC50 determined to be 0.86 nM (95% Cl, 0.78-0.94), It is possible to assess the bronchodilating effects of sGC in agreement with data previously produced in the system. stimulators by using the system described below. This system 40 allowed us to determine potency, efficacy and duration of The invention claimed is: action of several sGC stimulators, as well as to assess poten 1. A compound according to Formula I, or a pharmaceuti tial side effects such as blood pressure, or heart rate changes. cally acceptable salt thereof, Animals: Guinea pig, Dunkin Hartley, male, Full barrier bred and certified free of specific micro-organisms on receipt 45 525-609 g on the experimental day, Harlan UK Ltd. Guinea Formula I pigs were housed in a group of 4 in Solid-bottomed cages with Gold Flake bedding in a controlled environment (airflow, temperature and humidity). Food (FD1, Special Diet Ser vices) and water were provided ad libitum. 50 Y. (JP). Guinea Pig Tracheal Smooth Muscle Contraction in / Response to EFS. Assessment of Compound Potency and R4 Efficacy: On each experimental day, a guinea pig was killed by Z N exposure to a rising concentration of CO2 and the trachea 55 removed. The trachea was cleaned of extraneous tissue and \:S. cut open longitudinally in a line opposite the muscle, opened X.)o out and cut into strips 2-3 cartilage rings wide. A cotton loop was attached to one end of each tracheal strip and a length of wherein: cotton to the other end. Tracheal strips were then suspended 60 ring B is a 5-membered heteroaryl ring selected from furan between two platinum electrodes, using tissue holders, in a or thiophene; Myobath system (World Precision Instruments Stevenage, n is an integer selected from 0 to 3: UK). The loop was attached over the hook at the bottom of the each J’ is independently selected from halogen, —CN, a tissue holder and the other end attached to the arm of a Caliphatic, —OR or a Css cycloaliphatic group; FORT10 force transducer (World Precision Instruments 65 wherein each said Caliphatic and each said Cls Stevenage, UK) ensuring that the tissue was positioned cycloaliphatic group is optionally and independently between the two platinum electrodes. The whole assembly substituted with up to 3 instances of R: US 9,309,235 B2 85 86 each R is independently selected from hydrogen, a C wherein each said 4 to 8-membered heterocyclic ring aliphatic or a Cs cycloaliphatic ring; wherein each said and each said 5-membered heteroaryl ring optionally Caliphatic and each said C.s cycloaliphatic ring is contains up to 2 additional heteroatoms independently optionally and independently substituted with up to 3 selected from N, O or S, and wherein each said 4 to instances of R: 8-membered heterocyclic ring and each said 5-mem each R is independently selected from halogen, —CN, bered heteroaryl ring is optionally and independently C. alkyl, Chaloalkyl, —O(C. alkyl) or —O(C- substituted by up to 3 instances of R; or haloalkyl); when JP is N(R)C(O)R’, the RP group together with each R is independently selected from halogen, —CN, the carbon atom attached to the RP group, with the C. alkyl, Chaloalkyl, —O(C. alkyl) or —O(C- 10 nitrogen atom attached to the R group and with the R' haloalkyl); group alternatively form a 4 to 8-membered heterocyclic X is selected from N, C-JP or C H: ring or a 5-membered heteroaryl ring; wherein each said o is an integer selected from 0 to 3: 4 to 8-membered heterocyclic ring and each said each JP is independently selected from halogen, NO. 5-membered heteroaryl ring optionally contains up to 2 ORP, SRP, C(O)RP, C(O)ORP, C(O)N 15 additional heteroatoms independently selected from N. (R), CN, N(R), N(R)C(O)R, N(R)C O or S, and wherein each said 4 to 8-membered hetero (O)ORP, SORP, SON(R), N(R)SORP, a cyclic ring and each said 5-membered heteroaryl ring is C- aliphatic, —(C. aliphatic)-R', a Cas optionally and independently substituted by up to 3 cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to instances of R: 8-membered heterocyclic ring or a 5 to 10-membered when JP is N(R')C(O)ORP, the RP group together with heteroaryl ring; wherein each said 4 to 8-membered the oxygen atom attached to the RP group, with the heterocylic ring and each said 5 to 10-membered het carbon atom of the C(O)—portion of the N(R)C eroaryl ring contains between 1 and 3 heteroatoms inde (O)ORP group, with the nitrogenatomattached to the R' pendently selected from O, N or S; and wherein each group, and with the R group alternatively form a 4 to said Caliphatic, each said Css cycloaliphatic ring, 25 8-membered heterocyclic ring or a 5-membered het each said 6 to 10-membered aryl ring, each said 4 to eroaryl ring; wherein each said 4 to 8-membered hetero 8-membered heterocyclic ring and each said 5 to cyclic ring and each said 5-membered heteroaryl ring 10-membered heteroaryl ring is optionally and indepen optionally contains up to 2 additional heteroatoms inde dently substituted with up to 3 instances of R: pendently selected from N, O or S, and wherein each each RP is independently selected from hydrogen, a C 30 said 4 to 8-membered heterocyclic ring and each said aliphatic, -(C- aliphatic)-R, a Css cycloaliphatic 5-membered heteroaryl ring is optionally and indepen ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 dently substituted by up to 3 instances of R: to 6-membered heteroaryl ring; wherein each said 4 to when JP is N(R)SORP, the RP group together with the 8-membered heterocylic ring and each said 5 to 6-mem oxygen atom attached to the RP group, with the sulfur bered heteroaryl ring contains between 1 and 3 heteroa 35 atom attached to said oxygen atom in the SORP toms independently selected from O, N or S; and portion of the N(R)SORP group, with the nitrogen wherein each said C. aliphatic, each said Cls atom attached to the R group, and with the R group cycloaliphatic ring, each said 4 to 8-membered hetero alternatively form a 4 to 8-membered heterocyclic ring cyclic ring, each said phenyl and each said 5 to 6-mem or a 5-membered heteroaryl ring; wherein each said 4 to bered heteroaryl ring is optionally and independently 40 8-membered heterocyclic ring and each said 5-mem substituted with up to 3 instances of R". bered heteroaryl ring optionally contains up to 2 addi each R" is independently selected from hydrogen, a C tional heteroatoms independently selected from N, O or aliphatic, -(C- aliphatic)-R, a Css cycloaliphatic S, and wherein each said 4 to 8-membered heterocyclic ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 ring and each said 5-membered heteroaryl ring is option to 6-membered heteroaryl ring; wherein each said het 45 ally and independently substituted by up to 3 instances erocylic ring and each said heteroaryl ring contains of R: between 1 and 3 heteroatoms independently selected each R is independently selected from halogen, —CN, from O, N or S; and wherein each said Caliphatic, —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, each said Cls cycloaliphatic ring, each said 4 to 8-mem C. haloalkyl, C. cyanoalkyl, -OR. —SR, bered heterocyclic ring, each said phenyl and each said 5 50 OCOR, COR, C(O)CR, C(O)N(R), to 6-membered heteroaryl ring is optionally and inde N(R)C(O)R, N(R) - SOR, SON(R), pendently substituted by up to 3 instances of R: N(R)SOR, phenyl or an oxo group; wherein each each R is independently selected from a Cas said phenyl group is optionally and independently Sub cycloaliphatic ring, a 4 to 8-membered heterocyclic stituted with up to 3 instances of halogen, —OH, ring, phenyl or a 5 to 6-membered heteroaryl ring; 55 —NH2, —NH(C. alkyl). —N(C. alkyl). —NO, wherein each said heterocylic ring and each said het —CN. C. alkyl, Ca haloalkyl, —O(C. alkyl) or eroaryl ring contains between 1 and 3 heteroatoms inde —O(C- haloalkyl); and wherein each said C. pendently selected from O, N or S; and wherein each aralkyl and each said cycloalkyl group is optionally and said Caliphatic, each said Css cycloaliphatic ring, independently substituted with up to 3 instances of halo each said 4 to 8-membered heterocyclic ring, each said 60 gen, phenyl and each said 5 to 6-membered heteroaryl ring is each R is independently selected from halogen, —CN, optionally and independently substituted by up to 3 —NO2. C. alkyl, a C7-12 aralkyl, Css cycloalkyl ring, instances of R: C. haloalkyl, C. cyanoalkyl, -OR. —SR, when JP is –C(O)N(RP), N(RP) or -SON(R), OCOR, COR, C(O)CR, C(O)N(R), the two instances of RP together with the nitrogenatom 65 N(R)C(O)R, N(R) - SOR, SON(R), attached to the RP, alternatively form a 4 to 8-membered N(R)SOR, phenyl or an oxo group; wherein each heterocyclic ring or a 5-membered heteroaryl ring; said phenyl group is optionally and independently Sub US 9,309,235 B2 87 88 stituted with up to 3 instances of halogen, —OH, haloalkyl, —O(C. alkyl). —O(Chaloalkyl), oxo or —NH, -NH(C. alkyl). —N(C. alkyl). —NO, phenyl; wherein said phenyl is optionally and indepen —CN. C. alkyl, C. haloalkyl, —O(C. alkyl) or dently Substituted by up to three instances of halogen, —O(C- haloalkyl); and wherein each said C. —OH, -NH2, —NH(C. alkyl). —N(C. alkyl). aralkyl and each said cycloalkyl group is optionally and 5 —NO, —CN, C- alkyl, Ca haloalkyl, —O(C- independently substituted with up to 3 instances of halo alkyl) or —O(Chaloalkyl); gen, R is a ring C; ring C is a phenyl ring, a monocyclic 5 or each R is independently selected from halogen, CN, 6-membered heteroaryl ring, a bicyclic 8 to 10-mem —NO.C. alkyl, a Czaralkyl, C.s cycloalkyl ring, bered heteroaryl ring, a monocyclic 3 to 10-membered Cia haloalkyl, C. cyanoalkyl, -OR. -SR, 10 OCOR, COR, C(O)CR, C(O)N(R), cycloaliphatic ring, or a monocyclic 4 to 10-membered N(R)C(O)R, N(R) - SOR, SON(R), heterocycle; wherein said monocyclic 5 or 6-membered - N(R)SO.R. phenyl or an oxo group; wherein each heteroaryl ring, said bicyclic 8 to 10-membered het said phenyl group is optionally and independently Sub eroaryl ring, or said monocyclic 4 to 10-membered het stituted with up to 3 instances of halogen, —OH, 15 erocycle contain between 1 and 4 heteroatoms selected —NH, -NH(C. alkyl). —N(C. alkyl). —NO, from N, O or S.; wherein said monocyclic 5 or 6-mem —CN. C. alkyl, C. haloalkyl, —O(C. alkyl) or bered heteroaryl ring is not a 1.3.5-triazinyl ring; and —O(C- haloalkyl); and wherein each said C. wherein said phenyl, monocyclic 5 to 6-membered het aralkyl and each said cycloalkyl group is optionally and eroaryl ring, bicyclic 8 to 10-membered heteroaryl ring, independently substituted with up to 3 instances of halo or monocyclic 4 to 10-membered heterocycle is option gen, ally and independently substituted with up to 3 instances each R is independently selected from halogen, —CN, of J: —NO.C. alkyl, a Czaralkyl, C.s cycloalkyl ring, each J is independently selected from halogen, —CN, Cia haloalkyl, C. cyanoalkyl, -OR. -SR, - NO, a Caliphatic, OR', SR', N(R'), a OCOR, COR, C(O)CR, C(O)N(R), 25 Cs cycloaliphatic ring or a 4 to 8-membered heterocy N(R)C(O)R, N(R) - SOR, SON(R), clic ring; wherein said 4 to 8-membered heterocyclic - N(R)SO.R. phenyl or an oxo group; wherein each ring contains 1 or 2 heteroatoms independently selected said phenyl group is optionally and independently Sub from N, O or S.; wherein each said Caliphatic, each stituted with up to 3 instances of halogen, —OH, said C.s cycloaliphatic ring and each said 4 to 8-mem —NH, -NH(C. alkyl). —N(C. alkyl). —NO, 30 bered heterocyclic ring, is optionally and independently —CN. C. alkyl, C. haloalkyl, —O(C. alkyl) or substituted with up to 3 instances of R", or alternatively, —O(C. haloalkyl); and wherein each said Cz two J groups attached to two vicinal ring Catoms, taken aralkyl and each said cycloalkyl group is optionally and together with said two vicinal ring C atoms, form a 5 to independently substituted with up to 3 instances of halo 7-membered heterocycle resulting in a fused ring C: gen, 35 wherein said 5 to 7-membered heterocycle contains each R is independently selected from hydrogen, a Ca from 1 to 2 heteroatoms independently selected from N. alkyl, a C2-alkenyl, phenyl, a C7-12 aralkyl or a Cas O or S: cycloalkyl ring; wherein each said C. alkyl, each said each R' is independently selected from hydrogen, a C Calkenyl, each said phenyl, each said C7-2 aralkyl aliphatic, a Cs cycloaliphatic ring or a 4 to 8-membered and each said C.s cycloalkyl group is optionally and 40 heterocyclic ring; wherein each said 4 to 8-membered independently substituted with up to 3 instances of halo heterocylic ring contains between 1 and 3 heteroatoms gen, independently selected from O, N or S; and wherein alternatively, two instances of R linked to the same nitro each said Caliphatic, each said C.s cycloaliphatic gen atom of R, together with said nitrogenatom of R, ring, each said 4 to 8-membered heterocyclic ring, is form a 5 to 8-membered heterocyclic ring or a 5-mem 45 optionally and independently substituted with up to 3 bered heteroaryl ring; wherein each said 5 to 8-mem instances of R'; bered heterocyclic ring and each said 5-membered het alternatively, two instances of R' linked to the same nitro eroaryl ring optionally contains up to 2 additional gen atom of J, together with said nitrogen atom of J. heteroatoms independently selected from N, O or S; or form a 4 to 8-membered heterocyclic ring or a 5-mem alternatively, one instance of R linked to a nitrogen atom 50 bered heteroaryl ring; wherein each said 4 to 8-mem of Randone instance of R linked to a carbon or sulfur bered heterocyclic ring and each said 5-membered het atom of the same R, together with said nitrogen and said eroaryl ring optionally contains up to 2 additional carbon or sulfur atom of the same R, forma5 to 8-mem heteroatoms independently selected from N, O or S, and bered heterocyclic ring or a 5-membered heteroaryl wherein each said 4 to 8-membered heterocyclic ring ring; wherein each said 5 to 8-membered heterocyclic 55 and each said 5-membered heteroaryl ring is optionally ring and each said 5-membered heteroaryl ring option and independently substituted by up to 3 instances of ally contains up to 2 additional heteroatoms indepen R7; or dently selected from N, O or S; each R" is independently selected from halogen, —CN, or, alternatively, two JP groups attached to two vicinal ring —NO, C alkyl, Chaloalkyl, Cs cycloalkyl ring, D atoms, taken together with said two vicinal ring D 60 —OR, SR, N(R), or an oxo group; wherein atoms, form a 5 to 7-membered heterocycle resulting in each said cycloalkyl group is optionally and indepen a fused ring D wherein said 5 to 7-membered hetero dently substituted with up to 3 instances of halogen; cycle contains from 1 to 3 heteroatoms independently each R' is independently selected from halogen, —CN, selected from N, O or S; and wherein said 5 to 7-mem —NO, C alkyl, Chaloalkyl, Cs cycloalkyl ring, bered heterocycle is optionally and independently sub 65 —OR, SR, N(R), or an oxo group; wherein stituted by up to 3 instances of halogen, —OH, -NH2, each said cycloalkyl group is optionally and indepen —NH(C. alkyl). —N(C. alkyl), C alkyl, Ca dently substituted with up to 3 instances of halogen; US 9,309,235 B2 89 90 each R' is independently selected from halogen, CN, 16. The compound of claim 1, or a pharmaceutically —NO. C. alkyl, Chaloalkyl, Cs cycloalkyl ring, acceptable salt thereof, having Formula IIA or IIB: —OR. -SR, N(R), or an oxo group; wherein each said cycloalkyl group is optionally and indepen Formula IIA dently substituted with up to 3 instances of halogen; B each R is independently selected from hydrogen, a C, JSAN S alkyl, Chaloalkyl or a Cs cycloalkyl ring; wherein 7 each said cycloalkyl group is optionally and indepen dently substituted with up to 3 instances of halogen: / Ku alternatively, two instances of R linked to the same nitro 10 gen atom of R", together with said nitrogen atom of R". X form a 5 to 8-membered heterocyclic ring or a 5-mem bered heteroaryl ring; wherein each said 5 to 8-mem bered heterocyclic ring and each said 5-membered het eroaryl ring optionally contains up to 2 additional 15 heteroatoms independently selected from N, O or S; and R" is selected from hydrogen, halogen, C. alkyl or C. Formula IIB haloalkyl. 2. The compound of claim 1, or a pharmaceutically accept able salt thereof, wherein ring B is thiophene. 3. The compound of claim 2, or a pharmaceutically accept able salt thereof, wherein the thiophene ring B is unsubsti tuted and n is 0. 4. The compound of claim 1, or a pharmaceutically accept able salt thereof, wherein n is an integer selected from 1 to 3 25 and wherein each J is independently selected from halogen, a Caliphatic or —OR”. 5. The compound of claim 1, or a pharmaceutically accept (JP), able salt thereof, wherein ring B is a furan. 6. The compound of claim 1, or a pharmaceutically accept 30 able salt thereof, wherein X in ring D is C-J or C H. wherein J” is selected from hydrogen or halogen. 7. The compound of claim 1, or a pharmaceutically accept 17. The compound of claim 16, or a pharmaceutically able salt thereof, wherein X in ring D is N. acceptable salt thereof, whereino is an integer from 1 to 3, n. 8. The compound of claim 6, or a pharmaceutically accept is 2 and each J’ is independently selected from a halogen able salt thereof, wherein o is an integer selected between 1 35 atom or -NH2 or -OH. and 3 and each J’ is independently selected from halogen, a 18. The compound of claim 16, or a pharmaceutically Caliphatic, N(R), N(R)C(O)RP, N(R')C(O) acceptable salt thereof, wherein o is an integer from 1 to 3, n. ORP, N(R)C(O)N(RP). SOR', SON(R), is 1 and JP is NH. N(R)SO.R', SR, ORP or an optionally substituted 19. The compound of claim 16, or a pharmaceutically Cs cycloaliphatic ring. 40 acceptable salt thereof, wherein ring C is a 5-6 membered 9. The compound of claim8, or a pharmaceutically accept heteroaryl ring and it is optionally and independently substi able salt thereof, wherein each JP is independently selected tuted by up to 3 instances of J. from methyl, chloro, fluoro, N(RP), or -ORP. 20. The compound of claim 19, or a pharmaceutically 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said 5 to 6-membered het acceptable salt thereof, wherein each RP is independently 45 eroaryl ring is unsubstituted. selected from hydrogen or C. alkyl. 21. The compound of claim 19, or a pharmaceutically 11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-6 membered acceptable salt thereof, wherein, o is 1 or 2 and each JP is heteroaryl and it is substituted by 1 or 2 instances of J: independently selected from fluoro, hydroxyl or amino. wherein each J is selected from fluoro, chloro, bromo, methyl, -CN, -NH, or—OCH. 12. The compound of claim 1, or a pharmaceutically 50 22. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein ring C is a phenyl, a mono acceptable salt thereof, wherein ring C is an isoxazole and it cyclic 5 or 6-membered heteroaryl ring, a monocyclic 3 to is unsubstituted. 6-membered cycloaliphatic ring or a monocyclic 4 to 6-mem 23. The compound of claim 2, wherein X is N, and R is bered heterocycle; each of them optionally and independently oxazolyl or isoxazolyl. substituted with up to 3 instances of J. 55 13. The compound of claim 12, or a pharmaceutically 24. A pharmaceutical composition comprising the com acceptable salt thereof, wherein ring C is a 5 to 6-membered pound of claim 1, or a pharmaceutically acceptable salt heteroaryl ring, optionally substituted by up to 3 instances of thereof, and at least one pharmaceutically acceptable excipi JC. ent. 14. The compound of claim 13, or a pharmaceutically 60 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said 5 to 6-membered het acceptable salt thereof, wherein o is an integer selected eroaryl ring is selected from thienyl, thiazolyl, oxadiazolyl, between 1 and 3 and each JP is independently selected from oxazolyl, isooxazolyl, tetrazolyl pyrrolyl, triazolyl, furanyl, halogen, a C- aliphatic, N(R'), N(R')C(O)R’. pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. N(R)C(O)OR, N(R)C(O)N(R). SOR, 15. The compound of claim 14, or a pharmaceutically 65 –SON(R') - N(R)SORP, SRP, ORP or an acceptable salt thereof, wherein ring C is an oxazolyl or optionally substituted Cls cycloaliphatic ring. isoxazolyl and it is unsubstituted. ck k k k k.