(19) TZZ ¥ZZZ_Z_T (11) EP 2 300 010 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 403/12 (2006.01) C07D 241/26 (2006.01) 04.03.2015 Bulletin 2015/10 C07D 401/12 (2006.01) (21) Application number: 09761700.5 (86) International application number: PCT/EP2009/057060 (22) Date of filing: 08.06.2009 (87) International publication number: WO 2009/150137 (17.12.2009 Gazette 2009/51) (54) PYRAZINE DERIVATIVES AS EPITHELIAL SODIUM CHANNEL BLOCKERS PYRAZINDERIVATE ALS BLOCKIERER DES EPITHELIALEN NATRIUMKANALS DÉRIVÉS DE PYRAZINE EN TANT QUE BLOQUEUR DU CANAL SODIQUE EPITHELIAL (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2005/025496 WO-A-2006/023573 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL WO-A-2007/071400 PT RO SE SI SK TR • JH LI ET AL: "Stereoselective blockade of (30) Priority: 10.06.2008 EP 08157980 amphibian epithelial sodium channels by amiloride analogs" JOURNAL OF (43) Date of publication of application: PHARMACOLOGY AND EXPERIMENTAL 30.03.2011 Bulletin 2011/13 THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL (73) Proprietor: Novartis AG THERAPEUTICS, US, vol. 267, no. 3, 1 December 4056 Basel (CH) 1993 (1993-12-01), pages 1081-1084, XP008093856 ISSN: 0022-3565 (72) Inventors: • RUSS T ET AL: "Preparation and diuretic • COLLINGWOOD, Stephen Paul propertiesof novel amiloride analogues" ARCHIV Horsham Sussex RH12 5AB (GB) DER PHARMAZIE, VCH • DEVEREUX, Nicholas James VERLAGSGESELLSCHAFT MBH, WEINHEIM, Horsham Sussex RH12 5AB (GB) DE, vol. 325, no. 12, 1 December 1992 • HOWSHAM, Catherine (1992-12-01), pages 761-767, XP002496825 ISSN: Horsham Sussex RH12 5AB (GB) 0365-6233 • HUNT, Peter Horsham Sussex RH12 5AB (GB) Remarks: • HUNT, Thomas Anthony Thefile contains technical information submitted after Horsham Sussex RH12 5AB (GB) the application was filed and not included in this specification (74) Representative: Mueller, Philippe et al Novartis Pharma AG Patent Department 4002 Basel (CH) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 300 010 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 300 010 B1 Description [0001] This invention relates to organic compounds, their preparation and use as pharmaceuticals. [0002] The compounds of the invention typically include a suitable, negatively-charged counter ion. This may be any 5 suitable counter ion and in particular may be any suitable pharmaceutically acceptable counter ion. Examples of suitable counter ions include, but are not limited to: fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, hexafluoro- phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenylacetate, triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxy- naphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. 10 [0003] In one aspect, there is provided a compound according to the Formula Ia: 15 20 or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein 6 6a R is -(C0-C6 alkylene)-R , wherein the alkylene linker is optionally substituted by one or more groups selected from C1-C3 alkyl, halo and OH; 25 6a 11 12 13 14 R is selected from H, a C 3-C10 carbocyclic group, NR R , C(O)NR R , C6-C10 aryl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl and a group of the formula P-(CH2)m-Q, wherein each of the ring systems is optionally substituted by one or more substituents selected from the List Z; a- a a P is selected from a bond, -O-, -C(O)-, -C(O)O-, -NHC(=N)NH- and -S(O2)-,-S(O2)NR , -NR C(O)-,-NR C(O)O-, a a b -NR S(O2)- and -NR C(O)NR -; 30 a b R and R are each independently selected from H, C 1-C6 alkyl, a C 3-C10 carbocyclic group and -(C 1-C3 alkylene)-C3-C10 carbocyclic; Q is selected from H, C1-C6 alkyl, a C3-C10 carbocyclic group, C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6- membered heterocyclyl, wherein the carbocyclic, C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl groups are each optionally substituted by one or more substituents selected from List Z; 35 m is 0, 1, 2 or 3; 7 8 10 R , R and R are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a C3-C10 carbocyclic group, -(C1-C3 alkylene)-C3-C10 carbocyclic group, C6-C10 aryl, 5- to 6-membered heteroaryl, 5- to 6-membered het- erocyclyl or a group of the formula (CH 2)d-A-(CH2)b-B, wherein the carbocyclic, C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl groups are each optionally substituted by one or more substituents selected from 40 List Z; and wherein the alkyl and alkylene groups are optionally substituted by one or more halogen atoms, OH groups or phenyl groups; or R7 and R8, together with the nitrogen atom to which they are attached form a 4- to 10-membered nitrogen-containing heterocyclic group which is optionally substituted by one or more substituents selected from the List Z; or R6 and R 8, together with the atoms to which they are attached form a 4- to 10-membered nitrogen-containing heterocyclic 45 group which is optionally substituted by one or more substituents selected from the List Z; c c A is selected from a bond, -O-, -C(O)-, -C(O)NR-, -C(O)O-, -OC(O)-, -NHC(=N)NH-, -S(O2)- -S(O2)NR -, c c c c c c d c -NR C(O)-,-NR C(O)O-, -OC(O)NR -, -NR S(O2)-,-C(O)NR S(O2)-, -NR C(O)NR -, -NR -, -C6-C10 aryl-, -C3-C10 car- bocyclyl-, -5- to 6-membered heteroaryl-, -5- to 6-membered heterocyclyl-, -C6-C10 aryl-O-, -O-C6-C10 aryl-, -O-C 3-C10 carbocyclyl- and -C3-C10 carbocyclyl-O-, wherein the C6-C10 aryl, carbocyclyl, 5- to 6-membered heteroaryl and 5- to 50 6-membered heterocyclyl groups are each optionally substituted by one or more substituents selected from List Z; x y z B is selected from H, C 1-C6 alkyl, a C 3-C10 carbocyclic group, NR R , C(O)OR , C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, wherein the carbocyclic, C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6- membered heterocyclyl groups are each optionally substituted by one or more substituents selected from List Z; d is 1, 2, 3, 4, 5, 6 or 7; 55 b is 0, 1, 2 or 3; c d x y R , R , R and R are each independently selected from H, 1C-C6 alkyl, a C3-C10 carbocyclic group and -(C1-C3 alkylene)-C3-C10 carbocyclic; z R is H or C1-C6 alkyl; 2 EP 2 300 010 B1 9 R is H or C1-C6 alkyl; or 6 9 R and R , together with the carbon atom to which they are attached, form a C3-C10 carbocyclic group or a 4- to 10- membered 5- to 6-membered heterocyclyl group, wherein each of the ring systems is optionally substituted by one or more substituents selected from the List Z; 5 11 R is selected from H, C1-C6 alkyl, a C3-C10 carbocyclic group and -(C1-C3 alkylene)-C3-C10 carbocyclic; 12 R is selected from H, C 1-C6 alkyl, a C 3-C10 carbocyclic group, -(C 1-C3 alkylene)-C3-C10 carbocyclic, -C(O)C 1-C6 alkyl, -C(O)C3-C10 carbocyclic, -C(O)(C1-C3 alkylene)-C3-C10 carbocyclic, -C(O)(CH2)x C6-C10 aryl, -C(O)(CH2)x 5- to 6- membered heteroaryl, -C(O)(CH2)x 5- to 6-membered heterocyclyl, -C(O)Oalkyl, C(O)OC6-C10 aryl, (CH2)x C6-C10 aryl, (CH2)x 5- to 6-membered heteroaryl and - (CH 2)x 5- to 6-membered heterocyclyl, wherein each of the ring systems 10 is optionally substituted by one or more substituents selected from the List Z; 13 R is selected from H, C1-C6 alkyl, a C3-C10 carbocyclic group and -(C1-C3 alkylene)-C3-C10 carbocyclic; 14 R is selected from H, C 1-C6 alkyl, a C3-C10 carbocyclic group, -(C 1-C3 alkylene)-C3-C10 carbocyclic, - (CH2)z C6-C10 aryl, (CH2)z 5- to 6-membered heteroaryl and (CH 2)z 5- to 6-membered heterocyclyl, wherein each of the ring systems is optionally substituted by one or more substituents selected from the List Z; 15 x is 0, 1, 2 or 3; z is 0, 1, 2 or 3; each Z is independently selected from OH, C6-C10 aryl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, benzyl, C1-C6 alkyl optionally substituted by one or more halogen atoms, CN or OH groups, 1C-C6 alkoxy optionally 15 17 substituted by one or more halogen atoms, CN or OH groups, -OC6-C10 aryl, -Obenzyl, -O(CH 2)aC(O)E, NR (SO2)R , 20 15 16 18 15 17 15 17 15 16 17 15 17 15 17 15 (SO2)NR R , (SO2)R , NR C(O)R , C(O)NR R , NR C(O)NR R , NR C(O)OR , NR R , C(O)OR , 15 15 17 15 OC(O)R , OC(O)NR , C(O)R , SR , CN, NO2, and halogen; and when there are two or more Z substitutents, two Z substituents together with the atoms to which they are attached optionally form a 5- to 7-membered carbocyclic or a 4- to 7-membered heterocyclic substituent fused to the ring system; a is 0, 1, 2, 3 or 4, where the alkylene group is optionally substituted by OH or NH 2 when a is 1, 2, 3 or 4; 25 E is NR15R17 or OR17; 15 16 each R and R is independently selected from H, C 1-C6 alkyl, a C 3-C10 carbocyclic group and -(C 1-C3 alkylene)-C3-C10 carbocyclic; 17 each R is selected from H, C1-C6 alkyl, a C3-C10 carbocyclic group, -(C1-C3 alkylene)-C3-C10 carbocyclic, C6-C10 aryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, where each of the ring systems is optionally 30 substituted by OH, halo, C1-C3 alkyl and C1-C3 alkoxy; and 18 R is selected from H, C1-C6 alkyl, a C3-C10 carbocyclic group, -(C1-C3 alkylene)-C3-C10 carbocyclic, C6-C10 aryl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl and NHC(=NH)NH2, where each of the ring systems is op- tionally substituted by OH, halo, C1-C3 alkyl and C1-C3 alkoxy.