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WO 2016/010538 Al 21 January 2016 (21.01.2016) P O P C T

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WO 2016/010538 Al 21 January 2016 (21.01.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/010538 Al 21 January 2016 (21.01.2016) P O P C T (51) International Patent Classification: (74) Agents: RUTT, Steven, J. et al; The Marbury Law Group, C07C 69/712 (2006.01) C07D 307/20 (2006.01) PLLC, 11800 Sunrise Valley Drive, 15th Floor, Reston, C07D 453/02 (2006.01) C07C 59/72 (2006.01) Virginia 20191 (US). C07D 257/06 (2006.01) A61K 31/215 (2006.01) (81) Designated States (unless otherwise indicated, for every C07D 235/06 (2006.01) A61K 31/192 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 263/22 (2006.01) A61K 31/165 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 493/00 (2006.01) A61K 31/341 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 295/088 (2006.01) A61P 9/12 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 14/046920 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 16 July 2014 (16.07.2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (71) Applicant: CORSAIR PHARMA, INC. [US/US]; 400 kind of regional protection available): ARIPO (BW, GH, Oyster Point Boulevard, South San Francisco, California GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 94080 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors: BECKER, Cyrus K.; 4675 Frontenac Park TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Court, Fremont, California 94538 (US). RESCOURIO, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Gwenaella; 10 De Sabla Road, Apt. #509, San Mateo, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, California 94402 (US). PFISTER, Jiirg; 1500 Oak Aven TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). ue, Los Altos, California 94024 (US). VENKATRAMAN, Meenakshi; 34202 Gannon Terrace, Fremont, California Published: 94555 (US). ZHANG, Xiaoming; 1089 Remsen Court, — with international search report (Art. 21(3)) Sunnyvale, California 94087 (US). 00 o © v o (54) Title: TREPROSTINIL DERIVATIVE COMPOUNDS AND METHODS OF USING SAME (57) Abstract: Compounds represented by formulae I, II, III, and IV including pro-drugs for treprostinil and prostacyclin analogs. Uses include treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH). The structures of the compounds can be adapted to the particular application for a suitable treatment dosage. Transdermal applications can be used. TREPROSTINIL DERIVATIVE COMPOUNDS AND METHODS OF USING SAME CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part application of U.S. Application Serial No. 14/153,498 filed on January 13, 2014, which claims priority to U.S. Provisional Application No. 61/751,608 filed on January 11, 2013, each of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is a disease which can result in death and is characterized by increased pulmonary artery pressure and pulmonary vascular resistance. A need exists for better compounds and methods for treating PH and PAH. See, for example, US Patent Publication No. 2013/0274261 . Many valuable pharmacologically active compounds, including some of interest with respect to PH and PAH, cannot be effectively administered orally for various reasons and are generally administered via intravenous or intramuscular routes. These routes of administration generally require intervention by a physician or other health care professional, and can entail considerable discomfort as well as potential local trauma to the patient. One example of such a compound is treprostinil and derivatives thereof, which has been used in the treatment of PH and PAH. See, for example, WO 2005/007081. Treprostinil (herein also called Compound A) has the following structure: Treprostinil can exist as a salt, such as a sodium salt. Accordingly, there is a clinical need in providing treprostinil by improved formulations and methods, e.g., either orally or transdermally. More particularly, there is a need for a safe and effective method for increasing the systemic availability of treprostinil via administration of treprostinil or derivatives (including prodrugs) or analogs thereof. The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this are disclosed in numerous technical journals and patents. U.S. Pat. Nos. 3,598,122; 4,144,317; 4,201,21 1; 4,262,003; and 4,379,454, all of which are incorporated herein by reference, are representative of various transdermal drug delivery systems of the prior art, which systems have the ability of delivering controlled amounts of drugs to patients for extended periods of time ranging in duration from several hours to several days. None of the above patents describes a transdermal delivery system which is intended to deliver treprostinil or its derivatives. SUMMARY Embodiments described herein include compounds, compositions, and devices, as well as methods of making and methods of using the same. One embodiment provides a compound represented by Formula (I) wherein, R20, R2], R22, R23, R24, R25, R26, R27, 28, R29, R30, R31, R32, R33, R34, R35, and R36 are independently H or deuterium; Z is -OH, -OR11, -N(Ru)Ri2, -SR , or P Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyi, substituted alkylcycloheteroalkyi, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyi, aryl, or heteroaryl; Pi is selected from the group consisting of: wherein, m is 1, 2, 3, or 4; Ru and R15 are independently in each occunence selected from the group consisting of , alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R14 and 1 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; Rig and Ri9 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), - CONH2, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy; Ri4 and Ri taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; R14 and R 19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; Ri5 and Retaken together with the atoms to which they attach optionally form a 5- to 7- membered ring; Ri5 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; and, and R2 are independently H or P2, wherein at least one of Ri and R2 is P2, wherein P2 is selected from the group consisting of: wherein, m is 1, 2, 3, or 4; Ri4 and R15 are as defined above; R14 and R 5 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl and methoxy; Ri6 and Ri7 are independently in each occurrence H or alkyl; Ri6 and R taken together with the atoms to which they attach optionally form a 3- to 6- membered ring; R 8 and R1 are as defined above; Ri4 and R 8 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; Ri4 and R1 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; wherein Formula I includes enantiomers, pharmaceutically acceptable salts, solvates and polymorphs of the compounds of Formula I. In another embodiment, the parameters of Formula I are defined as follows: R20, R21, R22, R23, R24, R2 2 , R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are independently H or deuterium; Z is -OR„, -N(R )R12 , -SR , or P,; Rn is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl,
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