Nova Patents
NZ526003A

Biaryl compounds as serine protease inhibitors

Abstract

Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents.

NZ526003A, drawing sheet 1
Sheet 1 of 371

Term

Term ended

Projected expiry passed 22 October 2021, 4.9 years ago.

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60 claims: 5 independent, 55 dependent

  1. 1
    What is claimed is 1. Compound having the structure (I) shown below:( R 1 )“— E 1 - W- E 2 -B V 1 -|_—v (R 2 ) p ;pharmaceutically acceptable salts thereof;and prodrugs thereof;(I) (A) each E 1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O 2 ) which may be saturated or unsaturated;R is -CH=CH-R 2 , -C^C-R 2 , -C(R 2 )=CH2, -C(R 2 )=C(R 3 ), -CH=NR 2 , -C(R 2 )=N-R 3 ,4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R 1 , R 2 , or R 3 . Preferably, these R, R 1 , R 2 , or R 3 do not include -(C2_4 alkenyl)-CO 2 -Ci-8 alkyl, -(C 2 _4 alkenyl)-CO 2 -Ci.s alkyl-phenyl, and-(C 2 -4 alkenyl)-CO 2 Ci-8 alkyl-O-Ci-4 alkyl;R l is H, -R, -NO2, -CN, -halo, -N3, -C i.8 alkyl, -(CH2)nCO2R 2 , -C2. 8 alkenyl-CO 2 R 2 , -0(CH2)„C02R 2 , -C(O)NR 2 R 3 , -P(O)(OR 2 )2j alkyl substituted tetrazol-5-yl, 287 -(CH 2 ) n O(CH 2 ) n aryl, -NR 2 R 3 , -(CH2)n OR 2 , -(CH2) n SR 2 , -N(R 2 )C(O)R 3 , -S(O2)NR 2 R 3 , -N(R 2 )S(O2)R 3 , -(CHR 2 )n NR 2 R 3 , -C(O)R 3 , (CH2) n N(R 3 )C(O)R 3 , -N(R 2 )CR 2 R 3 substituted or unsubstituted (CH 2 ) n -cycloalkyl, substituted or unsubstituted (CH 2 ) n phenyl, or substituted or unsubstituted (CH 2 ) n -heterocycle which may be saturated or unsaturated;m is 1 except that when E 1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring;R 2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2)i-3-biphenyl, -(CH2)M-PhN(SO2-Ci.2-alkyl)2,-CO(CHR J )n-OR 1 ,-(CHR')n-heterocycle, -(CHR')n-NH-CO-R 1 , -(CHR l )n-NH-SO2R 1 ,-(CHR l )n-Ph-N(SO2-C1.2-alkyl)2, -(CHRVqOXCHR’XNHR 1 , -(CHRYCCSXCHR’XNHR 1 , -(CH2)„O(CH 2 )„CH 3 , -CF 3 , -C 2 . 5 acyl, -(CHR’) n OH, -(CHR^nCOzR 1 , -(CHR’)n-O-alkyl, -(CHR’)„-O-(CH2)„-O-alkyl, -(CHR‘)n-S-alkyl, -CCHR’)n-S(O)-aIkyl, -(CHR')n-S(O2)-aIkyl, -(CHR')n-S(O2)-NHR 3 , -(CHR 3 )n-N 3 , -(CHR 3 )nNHR 4 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted(CHR 3 )n heterocycle, or substituted or unsubstituted-(CHR 3 )n cycloalkyl which may be saturated or unsaturated;when n is more than 1, the substitutions R 1 and R 3 may be same or different;R 3 is H, -OH, -CN, substituted alkyl, -C 2 .8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R ! )R 2 , or 5-6 membered saturated substituted or unsubstituted hetero ring;-NR 2 R 3 may form a ring system having 4 to 7 atoms or may be bicyciic ring;wherein said ring system comprises carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted;288 INTELLECTUAL n F p CE OF - 8 JUN 2005 RECEIVED WO 02/34711 PCT/USO1/32582 W is a direct bond, -CHR 2 -, -CH=CR 2 -, -CR 2 =CH-, -CR 2 =CR 2 -, -C=C-, -O-CHR 2 -, -CHR 2 -O-, -N(R 2 )-C(O)-, -C(O)-N(R 2 )-, -N(R 2 )-CH-(R 3 )-, -CH 2 -N(R 2 )-, -CH(R’)-N(R 2 )-, -S-CHR 2 -, -CHR 2 -S-, -S(O 2 )-N(R 2 )-, -C(O)N(R 2 )-(CHR 2 )n-, -C(R 1 R 2 )n-NR 2 -, -N(R 2 )-S(O 2 )-, -R 2 C(O)NR 2 -, -R 2 NC(O)NR 2 -, -CONR 2 CO-, 5 -C(=NR 2 )NR 2 -, -NR 2 C(=NR 2 )NR 2 -, -NR 2 O-, -N=NCHR 2 -, or -C(O)NR 2 SO 2 -;E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Cy alkyl, C 2 -8 alkenyl, C 2 „s alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino;each X individually is a direct bond, substituted or unsubstituted Cm methylene chain, O, S, NR 2 , S(O), S(O 2 ), or N(O) containing one or two Cm substituted or unsubstituted methylene chains;X at different places may be same or different;B is H, -halo, -CN, -NH 2 , -(CH 2 )„-C(=NR 4 )NHR 5 , -(CH2)n-NHR 4 , (CH2) n NHC(=NR 4 )NR 5 , -(CH 2 )„-OR 4 , Ci-g substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated;B 1 is selected from Β;B 1 and B may be same or different;'Tfiere may be more than one similar or different R 2 groups present on E 2 , when E 2 is a Λ cyclic group of more than 5 atoms;p is 1 except ihat when E 2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring;n is 0-4;A is selected from R 1 ;o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending 3 0 upon the size of the ring;289 each V and V 1 individually is selected from R 1 and N-alkyl substituted carboxamidyl (CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;N,Ndisubstituted carboxamidyl of the formula -CONRiR 2 where Ri and R 2 may be 5 substituted or unsubstituted alkyl or aryl and may be the same or different;mono- or disubstituted sulfonamides of the formula SO2NHR or -SO2NR1R2;and methylene- or polymethylene chain-extended variants thereof;each R 4 and R 5 individually is H, -(CH2)„OH, -C(O)OR 6 , -C(O)SR 6 , -(CH2) n 10 C(O)NR 7 R 8 , -O-C(O)-O-R 7 , an amino acid or a dipeptide;each R 6 is H, R 7 , -C(R 7 )(R 8 )-(CH2)n-O-C(O)-R 9 , -(CH2)„-C(R 7 )(R 8 )-O-C(O)R 9 , -(CH2)„C(R 7 )(R 8 )-O-C(O)-O-R 9 , or-C(R 7 )(R 8 )-(CH2) n -O-C(O)-O-R 9 ;and 15 each R 7 , R 8 and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH 2 CO 2 alkyl. INTELLECTUAL PROPERTY OFFICE OF i\|.Z -8 JUN 2005 RECEIVE 290 WO 02/34711 PCT/US01/32582
  2. 3
    3 ,-CO 2 MEM, CH, O CH 3 ΛΑ . W N0H _ CH, H ,N· 0¾ H ,N. 0¾ 3oc 9¾ ,N. CH, , and -CH2NH2;and pharmaceutically acceptable salts thereof;and prodrugs thereof. 291 WO 02/34711 PCT/USO1/32582 3. The compound of claim 1 represented by the structure 10 wherein R is selected from the group consisting of -OCH 3 ;and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM;and 30 pharmaceutically acceptable salts thereof;and prodrugs thereof. 292
  3. 9
    12. wherein R is -CH3 and R’ is selected from the group consisting of 305 WO 02/34711 PCT/US01/32582 and pharmaceutically acceptable salts thereof;and prodrugs thereof. 306 WO 02/34711 PCT/US01/32582
  4. 12
    15 -CH(OH)CH 2 OH, -CH=O, -CH 2 OH, -CO 2 H, -OCH 3 , -CH=CH 2 ;and -CH=CH 2 ;and pharmaceutically acceptable salts thereof;and prodrugs thereof. INTELLECTUAL^PROPERTY OFFICE “ 8 JUN 2005 315 D P“ λ
  5. 30
    37. wherein R is -OCH 3 , -OH, -OSO 2 CF 3 , -C(=NH)NH 2 , and -H;or -NH 2 ;and R is halo, -CH=CH 2 , -CO 2 CH 3 , and 15 ,NH '/ NH 2 and pharmaceutically acceptable salts thereof;and prodrugs thereof.
  6. 58
    65. A use as claimed in any one of claims 48 to 53, 55 and 58 substantially as herein described with reference to any example thereof.
Independent claims6