Patent EA-004807-B1 (EA)
Title: Amine derivatives as protease inhibitors
Inventor: LINK JOHN O
IPC: A61K31/4725
Filed: 2000-03-15
Abstract: 1. A compound of Formula I: in which: A comprises a benzooxadole or naphthooxazole ring, each ring is substituted with R<7> and with R<8> if necessary, wherein R<7> is hydrogen, halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, nitro or phenyl; R<8> in each case is independently halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, nitro or trifluoromethyl; n is 0,1,2 or 3; X<1> is =C; X<2> is a bond or a divalent group of Formula (a): wherein: X<3> is -C(O)- or -CH2S (O)2-; R<9> is hydrogen, R<11> is hydrogen or methyl and R<12> is (C1-6)alkyl substituted with SR<14>, -C(O)R<14>, -C(O)2R<14>, wherein R<14> is (C6-C12)aryl(C0-C6)alkyl or hetero(C5-C12)aryl(C0-C6)alkyl, wherein in R<12> aromatic ring system can be extra substituted with 1-5 radicals, independently selected from (C1-C6)alkyl, (C1-C6)alkylidene, cyano with halo-substituted (C1-C4)alkyl, nitro, -X<5>NR<14>R<14>, -X<5>NR<14>C(O)OR<14>, -X<5>NR<14>C(O)NR<14>R<14>, -X<5>NR<14>C(NR<14>)NR<14>R<14>, -X<5>OR<14>, -X<5>SR<14>, X<5>C(O)OR<14>, -X<5>C(O)NR<14>R<14>, -X<5>S(O)2NR<14>R<14>, -X<5>P(O)(OR<14>)OR<14>, -X<5>OP(O)(OR<14>)OR<14>, -X<5>NR<14>C(O)R<15>, -X<5>S(O)R<15>, -X<5>S(O)2R<15>, wherein X<5> is a bond or (C10-C6)alkylene; R<14> for each case independently is hydrogen, (C1-6)alkyl or substituted with halo (C1-C3)alkyl and R<15> is (C1-C6)alkyl or substituted with halo (C1-C3)alkyl; R<1> is -X<6>X<7>R<20>, wherein X<6> is -C(O)-, or -S(O)2-, X<7> is a bond, -O- or -NR<21>-, wherein R<21> is hydrogen or (C1-6)alkyl, and R<20> is (i) (C1-6)alkyl optionally substituted by -C(O)OR<14> or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero-(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero-(C5-12)aryl(C0-6alkyl, or (iii) (C3-6)cycloalkyl-C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted with X<5>R<24>, -X<5>(O)R<24>, -X<5>C(O)R<24>, -X5C(O)OR<24>, -X<5>C(O)NR<24>R<25>, -X<5>NR<24>R<25>, -X<5>NR<25>RC(O)24, -X<5>NR<25>C(O)OR<24>, -X<5>NR<25>C(O)NR<24>R<25> or -X<5>NR<25>C(NR<25>)NR<24>R<25>, wherein X<5> is a bond or (C1-6)alkylene, R<24> is (C3-6)cycloalkyl-(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl (C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl and R<25> at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R<1> any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, halo, halo-substituted(C1-4)alkyl, -OR<14> and -C(O)OR<14>, wherein R<14> is ad defined above; or when X<2> is a divalent group of formula (a) or (b) then R<1> may also represent hydrogen or oxalo; R<2> is hydrogen; R<3> is hydrogen, (C1-6)alkyl optionally substituted with cyano, halo, nitro, -SR<24>, -C(O)OR<24>, -C(O)NR<24>R<24>, -P(O)(OR<24>)OR<24>, -OP(O)(OR<24>)OR<24>, -S(O)R<25>, -S(O)2R<25> or -C(O)R<25>, wherein R<24> at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted(C1-3)alkyl, R<25> is halo, (C1-6)alkyl or halo-substituted(C1-3)alkyl or (C6-12)aryl(C2-3)alkyl, wherein said aryl optionally substituted by 1 to 5 radicals, optionally selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted, (C1-4)alkyl, nitro, -X<5>NR<14>C(O)OR<14>, -X<5>NR<14>C(O)NR<14>R<14>, X<5>NR<14>C(NR<14>)NR<14>R<14>, -X<5>OR<14>, -X<5>SR<14>, -X<5>C(O)OR<14>, -X<5>C(O)NR<14>R<14>, -X<5>S(O)2NR<14>R<14>, -X<5>P(O)(OR<14>)OR<14>, -X<5>OP(O)(OR<14>)OR<14>, -X<5>NR<14>C(O)R<15>, -X<5>S(O)R<15>, -X<5>S(O)2R<15> and -X<5>C(O)R<15>, wherein X<5> is a bond or (C1-6)alkylene, R<14> and R<15> are as defined above, or R<3> and R<4> together with hydrogen atom, to which are attached both R<3> and R<4>, form cyclopropylene, cyclobutylen, cyclopenthylene, or cyclohexylene; R<4> is hydrogen or as defined above; R<5> and R<6> together form oxo; and the N-oxide derivative, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof. 2. The compound of claim 1, in which: A is benzooxazol-2-yl each substituted by a group R<7>, wherein R<7> is hydrogen, halo, (C1-4)alkoxy, (C1-4) alkoxycarbonyl or nitro and R<8> at each occurrence independently is halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or trifluoromethyl; X<2> is a bond or a divalent group of Formula (a), wherein within Formula (a) X<3> is -C(O)-, R<11> is hydrogen and R<12> is a group of the Formula: in which q is 0,1,2,4 or 5 and R<33> at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted(C1-4)alkyl, nitro, -X<5>NR<14>R<14>, -X<5>OR<14>, -X<5>SR<14>, -X<5>C(O)NR<14>R<14>, -X<5>C(O)OR<14>, -X<5>S(O)R<15>, -X<5>S(O)2R<15> and -X<5>C(O)R<15>, wherein X<5> is a bond or (C1-6) alkylene, R<14> at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3) alkyl and R<15> is(C1-3) alkyl or halo-substituted (C1-3) alkyl; R<1> is selected from a group consisting of acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo [2.2.2] hept-2-ylcarbonyl, bicyclo [2.2.1] hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di (2-methoxyethyl) carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; R<3> is selected from hydrogen, (C1-4)alkyl, phenyl (C2-3) alkyl or (C1-4) alkylsulfonyl (C2-4) alkyl or R<3> and R<4> taken together with the carbon atom to which both R<3> and R<4> are attached form(C3-6) cycloalkylene; R<4> is hydrogen or as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 3. The compound of claim 2, in which: q is 0,1 or 2, R<1> is morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R<3> is methyl, ethyl, n-propyl, n-butyl, 2-methylsulfonylethyl or phenylethyl or R<3> and R<4> taken together with the carbon atom to which both R<3> and R<4> are attached form cyclobutylene and R<33> at each occurrence independently is (C1-4) alkyl, cyano, halo, halo-subsituted (C1-4) alkyl, nitro, -OR<14>, -SR<14> or -C (O) OR<14>, wherein R<14> at each occurrence independently is hydrogen, (C1-3) alkyl or halo-substituted (C1-3) alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 4. The compound of Claim 3 in which R<33> at each occurrence independently is selected from a group consisting of (C1-4) alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 5. The compound of Claim 1 in which within Formula (a) R<12> is benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 6. A compound of Formula II: in which: A comprises a benzooxadole or naphthooxazole ring, in which X<1> is a ring of carbon atoms; N is 0, 1, 2 or 3; X<1> is C or -CH-; X<8> is (C1-2)alkylene; R<1> is hydrogen, carboxy, oxalo, carbamoylor-X<6>X<7>R<20>, wherein X<6> is-C (O)-, -C (O) C (O)- or -S(O)2-, X<7> is a bond, -O- or -NR<21>-, wherein R<21> is hydrogen or (C1-6) alkyl, and R<20> is (i) (C1-6)alkyl optionally substituted by cyano, halo, nitro, -NR<14>R<14>, -NR<14>C(O)OR<14>, -NR<14>C(O)NR<14>R<14>, -NR<14>C(NR<14>)NR<14>R<14>, -OR<14>, -SR<14>, -C(O)OR<14>, -C(O)NR<14>, -S(O)2NR<14>R<14>, -P(O)(OR<14>)OR<14>, -OP(O)(OR<14>)OR<14>, -NR<14>C(O)R<15>, -S(O)R<15>, -S(O)2R<15>, -C(O)R<15>, -OR<22>, -SR<22>, -S(O)R<22>, --S(O)2R<22>, -C(O)R<22>, -C(O)OR<22>, -C(O)NR<22>R<23>, -NR<22>R<23>, -NR<23>C(O)R<22>, -NR<23>C(O)OR<22>, -NR<23>C(O)NR<22>R<23> or -NR<23>C(NR<23>)NR<22>R<23>, wherein R<14> at each occurrence independently is hydrogen, (C1-6) alkyl or halo-substituted (C1-3) alkyl, R<15> is (C1-6) alkyl or halo-substituted (C1-3) alkyl, R<22> is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C9-12) bicycloaryl (C0-6) alkyl or hetero(C8-12) bicycloaryl(C0-6) alkyl and R<23> at each occurrence independently is hydrogen or (C1-6) alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, (C9-12) bicycloaryl (C0-6) alkyl or hetero (C8-12) bicycloaryl (C0-6) alkyl or (iii) (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6) cycloalkyl (C0-6) alkyl, phenyl (C0-6) alkyl or hetero(C5-6) aryl (C0-6) alkyl substituted by X<5>OR<24>, -X<5>SR<24>, -X<5>S(O)R<24>, -X<5>S(O)2R<24>, -X<5>C(O)R<24>, -X<5>C(O)OR<24>, -