Patent EA-000924-B1 (EA)
Title: Isoxazoline fibrinogen receptor antagonists
Inventor: WITYAK JOHN
IPC: A61K31/665
Filed: 1996-05-30
Abstract: nyloxy)ethyl-;  l-(cyclohexyloxycarbonyloxy)ethyl-1. A compound of Formula I:   or pharmaceutically noethyl-; diethylaminoethyl-; (5-methyl-1,3-dioxacrom R<2>(R<3>)N(CH2)qZ-, R<2>(R<3>)N(R<2>N=)CN(R<2>)(CH2)qZ-, piperazinyl-(CH2)qZ- or   Z is selecte5-phenyl-cyclopenten-2-one-4-yl)methyl-;  1-(2-(2-independently selected from: H, C1-C10 alkyl, C2-Cf claim 1 of Formula Id:    or a pharmaceutically yl, C6-C10 aryl, C7-C11 arylalkyl, C2-C7 alkylcarbonyl, C6-C10 arylcarbonyl, C2-C10 alkoxycarbonyl, >)N(R<2>N=)C-, R<2>(R<3>)N(R<2>N=)CN(R<2>)-, R<2>(rbonyl, C6-C10 aryloxycarbonyl, aryl(C1-C10 alkoxy)carbonyl, C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl, C6-C10 arylcarbonyloxy(C1-C4 alkoxy)carbony>(R<3>)N(R<5>ON=)C-   Z is selected from a bond, O, S, S(=O) or S(=O)2; R<2> and R<3> are independenkyl)-, -(C2-C7 alkenyl)-,  -(C2-C7 alkynyl)-, -(ar3-C11cycloalkyl, C4-C11cycloalkylalkyl, C6-C10aryl optionally substituted with 0-3 groups selected fingle bond; -(C1-C7 alkyl)-, substituted with 0-3 groups independently selected from R<6> or R<7>; -(C2-C7 alkenyl)-, substituted with 0-3 groups indelly substituted with 0-3 groups selected from hydrynyl)-, substituted with 0-2 groups independently H3, -N(CH3)2, C1-C4haloalkyl, methylenedioxydiyl, with 0-2 groups independently selected from R<6> oarbonyl optionally substituted with 0-3 groups selndependently selected from R<6> or R<7>; or -(pyridazinyl)-, substituted with 0-2 groups independentlenedioxydiyl, ethylenedioxydiyl; C1-C10alkoxycarbonyl; C4-C11cycloalkoxycarbonyl; C7-C11bicycloalko, -(C2-C7 alkynyl)-, or  -(C(R<5>)2)nC(=O)N(R<5a>)ituted with 0-3 groups selected from hydroxy, halogen, C1-C6alkoxy, C1-C6alkyl, CF3, S(O)mCH3, -N(CH3)2, C1-C4haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1-C10alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups bstituted with 0-3 groups independently selected falkyl, CF3, S(O)mCH3, -N(CH3)2, C1-C4haloalkyl, med from hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkylbonyloxy(C1-C4 alkoxy)carbonyl; C6-C10arylcarbonyloxy(C1-C4alkoxy)carbonyl where the aryl group is oyloxy, C2-C10 alkoxycarbonylalkyloxy, C5-C10 cyclom hydroxy, halogen, C1-C6alkoxy, C1-C6alkyl, CF3, yloxyalkyloxy, C5-C10 cycloalkoxycarbonylalkyloxy, C7-C11 aryloxycarbonylalkyloxy, C8-C12 aryloxycarbonyloxyalkyloxy, C8-C12 arylcarbonyloxyalkyloxy, bstituted with 0-2 groups selected from hydroxy, hkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-(CH3)2, C1-C4haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1-C5)alkyl where the heteroaryl group is optionally substituted with 0-2l, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarby, C1-C6alkyl, CF3, S(O)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;  pro11 cycloalkylmethyl, C6-C10 aryl, C7-C11 arylalkyl or C1-C10 alkyl substituted with 0-2 R<4b>; R<5a> is selected from hydrogen, hydroxy, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, C1-C6 alkoxy, benzyloxy, C6-C10 aryl, hetC1-C7alkylene substituted with 0-6 R<6> or R<7>; C2-C7alkenylene substituted with 0-4 R<6> or R<7>; b>; alternately, R<5> and R<5a> can be taken together to be 3-azabicyclononyl, l-piperidinyl, l-morpholinyl or 1-piperazinyl, each being optionally substituted with C1-C6 alkyl, C6-C10 aryl, heteroaryl, C7-C11 arylalkyl, C1-C6 alkylcarbonyl, C3-C7 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, C7-C11 ary<8> or R<15>; C2-C7alkenylene substituted with 0-4lsulfonyl; R<5b> is selected from C1-C8 alkyl, C2- with 0-4 R<4>, R<8> or R<15>; Y is selected from:thyl, C6-C10 aryl, C7-C11 arylalkyl or C1-C10 alky-C10aryloxy, C7-C11aralkyloxy, C3-C10alkylcarbonyloxyalkyloxy, C3-C10alkoxycarbonyloxyalkyloxy, C2-C10alkoxycarbonylalkyloxy, C5-C10cycloalkylcarbonyl CF3, CHO, CO2R<5>, C(=O)R<5a>, CONR<5>R<5a>, OC(= C5-C10cycloalkoxycarbonylalkyloxy, C7-C11aryloxycarbonylalkyloxy, C8-C12aryloxycarbonyloxyalkyloxy,NR<5a>C(=O)OR<5b>, NR<5a>C(=O)NR<5>R<5a>, NR<5a>SOarbonyloxyalkyloxy, C5-C10(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-C14(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R<2>)(R<3>)N-( C1-C10alkoxy)-;  R<14> and W are attached to the s, C1-C6 alkyl, CF3, S(O)mMe, or -NMe2; C7-C11 arylalkyl, said aryl being optionally substituted with    D, E, F and G are each independently selected from: C(R<6a>)2; carbonyl; a heteroatom moiety sel when R<6> is a substituent on aryl; or a 5-10 membered heterocyclic ring containing 1-3 N, O or S h=O); alternatively, the bond between D and E, E ansaturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R<7>; R<6a> is selected from C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2 or NR<12>R<13>;  R<7> is selected from H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, -N(R<12>)R<13>, cyano, halo, CF3, CHO, CO2R<5>, C(=O)R<5a>, CONR<5>R<5a>, OC(=O)R<5a>, OC(=O)R<5b>, OR<5a>, OC(=O)NRNHR<5a>, CON(R<12>)2, OC(=O)R<5a>; OC(=O)OR<5a>; O(=O)R<5a>, NR<5a>C(=O)OR<5b>, NR<5a>C(=O)NR<5> R<5a>, NR<5a>SO2NR<5>R<5a>, NR<5a>SO2R<5>, S(O)pR<5a>R<5a>, NR<12>C(=O)N(R<12>)2, NR<12>SO2N(R<12>)2, NR<12>SO2R<5a>, S(O)pR<5a>, SO2N(R<12>)2, C2-C6alkeylalkyl; R<8> is selected from: H; R<6>; C1-C10 alkyl, substituted with 0-3 R<6>; C2-C10 alkenyl, suected from halogen, C1-C6alkoxy, C1-C6alkyl, CF3, ed with 0-3 R<6>; C3-C8 cycloalkyl, substituted with 0-3 R<6>; C5-C6 cycloalkenyl, substituted with 0-2 R<6>; aryl, substituted with 0-2 R<6>; 5-10 meor -NMe2;  methylenedioxy, when R<6> is a substituent on aryl; R<6a> is selected from C1-C4alkyl, C1 saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted withwith 0-8 R<6>; C2-C10alkenyl, substituted with 0-6 R<6>; C2-C10alkynyl, substituted with 0-6 R<6>; C3-C8cycloalkyl, substituted with 0-6 R<6>;  C5-C6 cycloalkenyl, substituted with 0-5 R<6>; aryl, substituted with 0-5 R<6>; 5-6 membered heterocyclic ring containing 1-2 N, O or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, moreover said heterocyclic ring being substituted with 0-5 R<6>; R<12> and R<13> are independently H, C1-C10alkyl, > is selected from H, C1-C10 alkyl, C2-C10 alkenyllkylsulfonyl, aryl(C1-C10alkyl)sulfonyl, arylsulfonyl, aryl, C2-C6alkenyl, C3-C11cycloalkyl, C4-C11cycloalkylalkyl, C7-C11arylalkyl, C2-C7alkylcarbonykyl, substituted with 0-8 R<6>; C2-C10 alkenyl, substituted with 0-6 R<6>; C1-C10 alkoxy, substituted with 0-6 R<6>; aryl, substituted with 0-5 R<6>; 5-6 membered heterocyclic ring containing 1-2 N, O or S heteroatoms, wherein said heterocyclic ring teroaryl groups are optionally substituted with 0-saturated, said heterocyclic ring being substituted with 0-5 R<6>; C1-C10 alkoxycarbonyl substituted with 0-8 R<6>; CO2R<5>; or  -C(=O)N(R<5>)R<5a>;   C3-C11cycloalkyl, C4-C11cycloalkylmethyl, C6-C10aryl, C7-C11arylalkyl or C1-C10alkyl substituted wir is 0-3;  provided that n, q, and r are chosen suC10alkyl, substituted with 0-8 R<6>; C2-C10alkenyland Y is in the range of 8-18. 2. A compound of claim 1 of Formula II:    wherein:  R<1> is selected from R<2>HN(CH2)qO-, R<2>HN(R<2>N=)CNH(CH2)qO-, p, O or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fullyl; R<8> is selected from H, C1-C10alkyl, C2-C10 alg substituted with 0-5 R<6>; C1-C10alkoxycarbonyl substituted with 0-8 R<6>; CO2R<5>; or  -C(=O)N(R<12>)R<13>;  n is 0-4;  p is 1-3;  q is 1-7;  r is 0-3; provided that n, p, q and r are chosen such that the number of atoms between R<1> and Y is in the range of 8-17. 17. A compound of claim 16 of Focarbonyl, -N(R<12>)R<13>, cyano or halo. 3. A compound of claim 2 wherein: X is selected from: a single bond; -(C1-C7 alkyl)-, substituted with 0-2 groups independently selected from R<4>, R<8> or R<14>; -(C2-C7 alkenyl)-, substituted with 0-2 groups independently selected from R<4>, R<8> or R<14>;  -(C2-C7 alkynyl)-, substituted with 0-2 groups inroxy, halogen, C1-C6 alkoxy, C1-C6alkyl, CF3, S(O)> is selected from H, C1-C6alkyl, C2-C6alkenyl, C3-C8 cycloalkyl, C5-C6cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O or S het 0-3 groups selected from hydroxy, halogen, C1-C6 turated, partially saturated, or fully unsaturatedhaloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C1-C5)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6alkyl, CF3, S(O)mCH3, -N(CH3)2, C1-C4haloalkyl, methyleloxymethoxy-;  cyclohexylcarbonyloxymethoxy-; l-(mbonyl; R<4> is selected from H, C1-C10alkyl, hydroxy, C1-C10alkoxy, nitro, C1-C10alkylcarbonyl or -Nylcarbonyloxy)ethoxy-; isopropyloxycarbonyloxymeth C1-C7 alkylene substituted with 0-6 R<6> or R<7>; C2-C7 alkenylene substituted with 0-4 R<6> or R<7>; C2-C7 alkynylene substituted with 0-4 R<6> or R dimethylaminoethoxy-; diethylaminoethoxy-;  (5-mepyridylene substituted with 0-3 R<6> or R<7>; pyridazinylene substituted with 0-3 R<6> or R<7>; X isxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-one-4-yl)methoxy-;  1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R<4> is -NR<12>R<13>; R<12> is H, C1-C4alkoxycarbonyl, C1-C4alkylcarbonyl, C1-C4 alkylsulfonyl, arC7-C11aralkyloxy, C3-C10alkylcarbonyloxyalkyloxy, C3-C10alkoxycarbonyloxyalkyloxy, C2-C10alkoxycarbonylalkyloxy, C5-C10cycloalkylcarbonyloxyalkyloxy, ethylcarbonyl;  R<13> is H. 5. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, selected from:  5(R,S)-3-[[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid; 5(R,S)-N-(butanesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine; 5(R,S)-N-(&alphn-2-one-yl)methyloxy; Z is selected from O or CH2,xyphenyl]isoxazolin-5-yl)glycine;  5(R,S)-N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidin-4-yl)ethoxyphom N, NH, O,  provided that no more than 2 of D, E)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;  5(R,S)-3-{[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;  2(R,S)-