Patent SG-11201802710Y-A (SG)
Title: 2-phenyl-3,4-dihydropyrrolo[2,1 -f] [1,2,4]triazinone derivatives as phosphodiesterase inhibitors and uses thereof
Inventor: NAEF RETO
IPC: C07D487/04
Filed: 2016-11-15
Abstract: INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau 111111111M 11111111111111111111111111111111111111111111111111111111111111R111111111111111 (10) International Publication Number WO 2017/085056 Al WIPO I PCT (43) International Publication Date 26 May 2017 (26.05.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: as to applicant's entitlement to apply for and be granted a patent (Rule 4.170) (51) International Patent Classification: C07D 487/04 (2006.01) C07D 401/12 (2006.01) A61K 31/53 (2006.01) CO7D 207/50 (2006.01) (21) International Application Number: PCT/EP2016/077720 (22) International Filing Date: 15 November 2016 (15.11.2016) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 15194727.2 16 November 2015 (16.11.2015) EP (71) Applicant: TOPADUR PHARMA AG [CH/CH]; Jur- aweg 14, 4310 Rheinfelden (CH). (72) Inventors: NAEF, Reto; Juraweg 14, 4310 Rheinfelden (CH). TENOR, Hermann; St. Gebhardstrasse 38, 78467 Konstanz (DE). (74) Agent: SPERRLE, Martin; Austrasse 24, 4051 Basel (CH). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, [Continued on next page] (54) Title: 2-PHENYL-3,4-DIHYDROPYRROLO[2,1 -F] [1,2,4]TRIAZINONE DERIVATIVES AS PHOSPHODIESTERASE INHIBITORS AND USES THEREOF O W O 20 17 /085 05 6 Al (57) : The present invention relates to compounds of formula (I) or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R1 is C,-C3alkyl optionally substituted with F, C3-C6cycloalkyl, Ci-C3alkoxy; X represents a bond or Ci-C3alkylene optionally substituted with OH, ONO, ONO 2 ; R2 is H, OH, ONO, ONO 2 , C(0)OH, C(0)0C I -C 3 alkyl, CHO, CN, C i -C 3 alkoxy, OC(0)H, OC(0)-Ci-C3alkyl, C(0)N(R6)0R7, OCI-C3alkylene-C(0)0H, OC i-C3alkylene-C(0)0Ci-C3alkyl, OCI-C3alkylene- C(0)N(R 6 )0R 7 , S(0 0 _ 2 )C i -C 3 alkyl, CR 8 =N-OR 9 , CR8=N-NRioRi 1, CR8=NR12 or CR 8 =N-ONO 2 ; R3 is Ci-C6alkyl optionally substi- tuted with F, OH, ONO, ONO2, Ci-C3alkoxy, C3-C6cycloalkyl; C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; R4 is C i -C 6 alkyl option- ally substituted with C 3 -C 6 cycloalkyl, Ci-C6alkoxy, F, ONO, ONO 2 ; C 2 -C 6 alkenyl, C2-C6alkynyl, C 3 -C 6 cycloalkyl; R5 is H, 50 2 N- R R i3 14 , NHSO2NR13R14; R6 is H or C,-C 3 alkyl; R7 is H, C i -C 3 alkoxy, C i -C 3 alkyl substituted with phenyl, benzyl or a het- erocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C alkyl, F; 1 -C 3 Rg is H, CH 3 or C2H5; R9: H, Ci-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOCI-C3alkyl, Ci-C3alkoxy, OC(0)H, OC(0)-C i -C 3 alkyl, C(0)N(R 6 )0R 7 , OC i -C 3 alkylene-C(0)OH, OC i -C 3 alkylene-C(0)0C i -C 3 alkyl, OC I -C 3 alkylene- C(0)N(R [Continued on next page] R5 WO 2017/085056 Al MIONIMOREIDEDIDEMHOHERIMIEHOMMEHOHE Published: — with international search report (Art 21(3)) 6)0R7, S(00_2)Ci-C3alkyl; R io and Ril are each independently H, Ci-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOCI-C3, C i -C 3 alkoxy, OC(0)H, OC(0)-C i -C 3 alkyl, C(0)N(R 6 )OR 7 , OC i -C 3 alkylene-C(0)OH, OC I -C 3 alkylene- C(0)0CI-C3alkyl, OCi-C3alkylene-C(0)N(R6)OR7, S(00_2)Ci-C3alkyLi or together with the nitrogen atom to which they are at- tached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C alkyl; 1 -C 3 R 12 is C i -C 3 alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC I -C 3 alkyl, C i -C 3 alkoxy, OC(0)H, OC(0)-C i - C3alkyl, C(0)N(R6)OR7, OCI-C3alkylene-C(0)0H, OCI-C3alkylene-C(0)0CI-C3alkyl, OCI-C3alkylene-C(0)N(R6)OR7, S(00_2)Ci- C 3 alkyl; R 13 and R i4 are each independently H or C i -C 6 alkyl optionally substituted with F, OH, ONO, ONO2, COOH, C I - C3alkoxy, C3-C6Cycloalkyl; or together with the nitrogen atom to which they are attached foiin a heterocyclic ring, wherein prefer - ably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R 15 ; R 15 is C 1 -C 6 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C i -C 3 alkoxy, C i -C 3 haloalkoxy, COOR16, NR(7Ris, C=NR19, or with a tetrazole group which is optionally substituted with C 1 -C 3 alkyl; or a heteroaryl ring which is optionally substi- tuted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen; R 16 is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO2, NR17Ris, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitro - gen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and im- idazole, wherein nitrogen atom is directly bound to C 1 -C 4 alkyl; R 17 and R 18 are each independently H or C 1 -C 4 alkyl optionally substituted with ONO, ONO 2 ; R19 is C 1 -C 4 alkyl optionally substituted with F, ONO, ONO 2 ; C 3 -C 6 Cycloalkyl; and their use in methods of treating or preventing a disease alleviated by inhibition of PDE-5 in a human or in a non-human mammal.