Electrophilic peptide analogs as inhibitors of trypsin-like enzymes
First Claim
Patent Images
1. A compound of formula (I) ##STR526## or a pharmaceutically acceptable salt thereof, wherein:
- R1 isa) --(C1 -C12 alkyl)--X, ab) --(C1 -C12 alkenyl)--X, or ##STR527## x is a) halogen,b) --CN,c) --NO2,d) --CF3,e) --NH2,f) --NHOR2,g) --NHC(═
NH)R2,h) --NHC(═
NH)NHOH,i) --NHC(═
NH)NHNH2,j) --NHC(═
NH)NHCN,k) --NHC(═
NH)NHR2,l) --NHC(═
NH)NHCOR2,m) --C(═
NH)NHR2,n) --C(═
NH)NHCOR2,o) --C(═
O)NHR2,p) --CO2 R2,q) --OR2,r) --OCF3,s) --S(O)r R2,t) --SC(═
NH)NHR2, oru) --SC(═
NH)NHC(═
O)R2 ;
R2 isa) hydrogen, orb) C1 -C4 alkyl;
R3 isa) --C(═
O)--(CH2)p --CR6 R7 --(CH2)q -aryl,b) --C(═
O)--W--CR8 R9 -aryl, with the proviso that W cannot be a bivalent oxygen atom,c) --C(═
O)--CR8 R9 --W--(CH2)r -aryl, with the proviso that W cannot be --NR4 -- or --NC(═
O)R4 --,d) --C(═
O)--W--CR8 R9 -heteroaryl,e) --C(═
O)--CR8 R9 --W--(CH2)r -heteroaryl, with the proviso that W cannot be --NR4 -- or --NC(═
O)R4 --,f) --C(═
O)--W--CR8 R9 -heterocycle,g) --C(═
O)--CR8 R9 --W--(CH2)r -heterocycle, with the proviso that W cannot be --NR4 -- or --NCOR4 --,h) --C(═
O)--(CH2)t --W--(C5 -C7 cycloalkyl), ##STR528## wherein aryl is limited to phenyl, ##STR529## wherein aryl is limited to phenyl, ##STR530## with the proviso that R13 cannot be --N(C1 -C4 alkyl)2 when A is --C(═
O)R14, ##STR531## wherein aryl is limited to phenyl,t) --C(═
O)--(CR8 R9)--NHS(O)r R8, ##STR532## R4 and R5 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl,c) --(C1 -C4 alkyl)-aryl, ord) C5 -C7 cycloalkyl;
R8 and R9 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl,c) C1 -C4 alkoxy,d) aryl,e) --(C1 -C4 alkyl)-aryl,f) --(C1 -C4 alkyl)-heterocycle,g) --O-aryl,h) --(CH2)p --CO2 R4,i) R8 and R9 can be taken together to form a (C2 -C7) alkyl;
R10 is;
phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C1 -C4 alkyl, C1 -C4 alkoxy, C7 -C15 alkylaryl, C7 -C15 alkoxyaryl, methylenedioxy, --NO2, --CF3, --SH, --S(O)r --(C1 -C4 alkyl), CN, --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHCOR4, --(CH2)p --CO2 R4 ;
R11 is;
a) --OR4,b) --NR15 R16,c) --NC(═
O)R15 R16,d) --NR15 C(═
O)OR4,e) aryl,f) --(C1 -C4 alkyl)-aryl,g) heteroaryl,h) --(C1 -C4 alkyl)-heteroaryl,i) --(C1 -C4 alkyl)--CO2 R4,j) heterocycle,k) --(C1 -C4 alkyl)heterocycle, ##STR533## R3 and R11, when taken together to form a ring bonded to the nitrogen;
##STR534## R13 is independently selected at each occurrence from the group consisting of;
a) hydrogenb) halogen,c) C1 -C4 alkyl,d) C1 -C4 alkoxy,e) methylenedioxy,f) --NO2,g) --CF3,h) --SH,i) --S(O)r --(C1 -C4 alkyl),j) --CN,k) --OH,l) --NH2,m) --NH(C1 -C4 alkyl),n) --N(C1 -C4 alkyl)2,o) --NHC(═
O)R4, orp) --(CH2)p --CO2 R4 ;
R14 is;
a) --CF3,b) --CHF2,c) --CH2 F,d) --CH2 Cl,e) --C(═
O)OR4,f) --C(═
O)NR15 R16,g) --C(═
O)R4,h) --C(═
O)COOR4,i) --C(═
O)C(═
O)NR15 R16,j) --C(═
O)C(═
O)R4,k) --CY3 Y4 COOR4,l) --CY3 Y4 C(═
O)NR15 R16, orm) --CY3 Y4 C(═
O)R4 ;
R15 and R16 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl,c) --(C1 -C4 alkyl)-aryl,d) C5 -C7 cycloalkyl, ore) phenyl, unsubstituted or substituted by R13 ;
R15 and R16 taken together to form a ring can also include;
##STR535## R17 is;
a) hydrogen,b) C1 -C4 alkyl,c) aryl,d) --(C1 -C4 alkyl)-aryl, ore) C5 -C7 cycloalkyl;
R18 is;
a) hydrogen,b) --(C1 -C5) alkyl, orc) --(C1 -C5) haloalkyl,d) --(C1 -C5) alkoxy;
R19 is;
a) hydrogen,b) --(C1 -C5) alkyl,c) halo, ord) --(C1 -C5) haloalkyl,e) --NO2,f) --NR4 R5,g) --CN,h) --(C1 -C5) alkoxy;
A is;
--BY1 Y2 ;
W isa) --O--,b) --S(O)r --,c) --NR4 --, ord) --NC(═
O)R4 --;
Y1 and Y2 area) --OH,b) --F,c) --NR4 R5,d) C1 -C8 alkoxy, or when taken together Y1 and Y2 form;
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
Y3 and Y4 area) --OH orb) --F;
n is 0 or 1;
p is 0 to 3;
q is 0 to 4;
r is 0 to 2;
t is 1 to 3;
v is 1 to 17;
wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;
heteroaryl is 2-, or 3-, or 4-pyridyl;
2- or 3-furyl;
2- or 3-benzofuranyl;
2-, or 3-thiophenyl;
2- or 3-benzo[b]thiophenyl;
2-, or 3-, or 4-quinolinyl;
1-, or 3-, or 4-isoquinolinyl;
2- or 3-pyrrolyl;
1- or 2- or 3-indolyl;
2-, or 4-, or 5-oxazolyl;
2-benzoxazolyl;
2- or 4- or 5-imidazolyl;
1- or 2-benzimidazolyl;
2- or 4- or 5-thiazolyl;
2-benzothiazolyl;
3- or 4- or 5-isoxazolyl;
3- or 4- or 5-pyrazolyl;
3- or 4-or 5-isothiazolyl;
3- or 4-pyridazinyl;
2- or 4- or 5-pyrimidinyl;
2-pyrazinyl;
2-triazinyl;
3- or 4-cinnolinyl;
1-phthalazinyl;
2- or 4-quinazolinyl;
or 2-quinoxalinyl ring;
said ring(s) may be unsubstituted or include optional substitution with one to three substituents;
heterocycle is tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholino;
said ring(s) may be unsubstituted or include optional substitution with one to three substituents;
the substituents that may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group consisting of;
halogen, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --SH, --S(O)r --(C1 -C4 alkyl)--CN, --OH, --NH2, --NH(C1 -C4 alkyl) --N(C1 -C4 alkyl)2, --NHC(═
O)R4, --(CH2)p --CO2 R4, phenyl which may be unsubstituted or substituted with R13.
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Abstract
This invention relates to electrophilic dipeptide analogs conjugated to an N,N-disubstituted α-amino acid as inhibitors of trypsin-like serine protease enzymes.
27 Citations
12 Claims
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1. A compound of formula (I) ##STR526## or a pharmaceutically acceptable salt thereof, wherein:
- R1 is
a) --(C1 -C12 alkyl)--X, a b) --(C1 -C12 alkenyl)--X, or ##STR527## x is a) halogen, b) --CN, c) --NO2, d) --CF3, e) --NH2, f) --NHOR2, g) --NHC(═
NH)R2,h) --NHC(═
NH)NHOH,i) --NHC(═
NH)NHNH2,j) --NHC(═
NH)NHCN,k) --NHC(═
NH)NHR2,l) --NHC(═
NH)NHCOR2,m) --C(═
NH)NHR2,n) --C(═
NH)NHCOR2,o) --C(═
O)NHR2,p) --CO2 R2, q) --OR2, r) --OCF3, s) --S(O)r R2, t) --SC(═
NH)NHR2, oru) --SC(═
NH)NHC(═
O)R2 ;R2 is a) hydrogen, or b) C1 -C4 alkyl; R3 is a) --C(═
O)--(CH2)p --CR6 R7 --(CH2)q -aryl,b) --C(═
O)--W--CR8 R9 -aryl, with the proviso that W cannot be a bivalent oxygen atom,c) --C(═
O)--CR8 R9 --W--(CH2)r -aryl, with the proviso that W cannot be --NR4 -- or --NC(═
O)R4 --,d) --C(═
O)--W--CR8 R9 -heteroaryl,e) --C(═
O)--CR8 R9 --W--(CH2)r -heteroaryl, with the proviso that W cannot be --NR4 -- or --NC(═
O)R4 --,f) --C(═
O)--W--CR8 R9 -heterocycle,g) --C(═
O)--CR8 R9 --W--(CH2)r -heterocycle, with the proviso that W cannot be --NR4 -- or --NCOR4 --,h) --C(═
O)--(CH2)t --W--(C5 -C7 cycloalkyl), ##STR528## wherein aryl is limited to phenyl, ##STR529## wherein aryl is limited to phenyl, ##STR530## with the proviso that R13 cannot be --N(C1 -C4 alkyl)2 when A is --C(═
O)R14, ##STR531## wherein aryl is limited to phenyl,t) --C(═
O)--(CR8 R9)--NHS(O)r R8, ##STR532## R4 and R5 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl, c) --(C1 -C4 alkyl)-aryl, or d) C5 -C7 cycloalkyl; R8 and R9 are independently selected at each occurrence from the group consisting of; a) hydrogen, b) C1 -C4 alkyl, c) C1 -C4 alkoxy, d) aryl, e) --(C1 -C4 alkyl)-aryl, f) --(C1 -C4 alkyl)-heterocycle, g) --O-aryl, h) --(CH2)p --CO2 R4, i) R8 and R9 can be taken together to form a (C2 -C7) alkyl; R10 is; phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C1 -C4 alkyl, C1 -C4 alkoxy, C7 -C15 alkylaryl, C7 -C15 alkoxyaryl, methylenedioxy, --NO2, --CF3, --SH, --S(O)r --(C1 -C4 alkyl), CN, --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHCOR4, --(CH2)p --CO2 R4 ; R11 is; a) --OR4, b) --NR15 R16, c) --NC(═
O)R15 R16,d) --NR15 C(═
O)OR4,e) aryl, f) --(C1 -C4 alkyl)-aryl, g) heteroaryl, h) --(C1 -C4 alkyl)-heteroaryl, i) --(C1 -C4 alkyl)--CO2 R4, j) heterocycle, k) --(C1 -C4 alkyl)heterocycle, ##STR533## R3 and R11, when taken together to form a ring bonded to the nitrogen;
##STR534## R13 is independently selected at each occurrence from the group consisting of;a) hydrogen b) halogen, c) C1 -C4 alkyl, d) C1 -C4 alkoxy, e) methylenedioxy, f) --NO2, g) --CF3, h) --SH, i) --S(O)r --(C1 -C4 alkyl), j) --CN, k) --OH, l) --NH2, m) --NH(C1 -C4 alkyl), n) --N(C1 -C4 alkyl)2, o) --NHC(═
O)R4, orp) --(CH2)p --CO2 R4 ; R14 is; a) --CF3, b) --CHF2, c) --CH2 F, d) --CH2 Cl, e) --C(═
O)OR4,f) --C(═
O)NR15 R16,g) --C(═
O)R4,h) --C(═
O)COOR4,i) --C(═
O)C(═
O)NR15 R16,j) --C(═
O)C(═
O)R4,k) --CY3 Y4 COOR4, l) --CY3 Y4 C(═
O)NR15 R16, orm) --CY3 Y4 C(═
O)R4 ;R15 and R16 are independently selected at each occurrence from the group consisting of; a) hydrogen, b) C1 -C4 alkyl, c) --(C1 -C4 alkyl)-aryl, d) C5 -C7 cycloalkyl, or e) phenyl, unsubstituted or substituted by R13 ; R15 and R16 taken together to form a ring can also include;
##STR535## R17 is;a) hydrogen, b) C1 -C4 alkyl, c) aryl, d) --(C1 -C4 alkyl)-aryl, or e) C5 -C7 cycloalkyl; R18 is; a) hydrogen, b) --(C1 -C5) alkyl, or c) --(C1 -C5) haloalkyl, d) --(C1 -C5) alkoxy; R19 is; a) hydrogen, b) --(C1 -C5) alkyl, c) halo, or d) --(C1 -C5) haloalkyl, e) --NO2, f) --NR4 R5, g) --CN, h) --(C1 -C5) alkoxy; A is; --BY1 Y2 ; W is a) --O--, b) --S(O)r --, c) --NR4 --, or d) --NC(═
O)R4 --;Y1 and Y2 are a) --OH, b) --F, c) --NR4 R5, d) C1 -C8 alkoxy, or when taken together Y1 and Y2 form; e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O; Y3 and Y4 are a) --OH or b) --F; n is 0 or 1; p is 0 to 3; q is 0 to 4; r is 0 to 2; t is 1 to 3; v is 1 to 17; wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents; heteroaryl is 2-, or 3-, or 4-pyridyl;
2- or 3-furyl;
2- or 3-benzofuranyl;
2-, or 3-thiophenyl;
2- or 3-benzo[b]thiophenyl;
2-, or 3-, or 4-quinolinyl;
1-, or 3-, or 4-isoquinolinyl;
2- or 3-pyrrolyl;
1- or 2- or 3-indolyl;
2-, or 4-, or 5-oxazolyl;
2-benzoxazolyl;
2- or 4- or 5-imidazolyl;
1- or 2-benzimidazolyl;
2- or 4- or 5-thiazolyl;
2-benzothiazolyl;
3- or 4- or 5-isoxazolyl;
3- or 4- or 5-pyrazolyl;
3- or 4-or 5-isothiazolyl;
3- or 4-pyridazinyl;
2- or 4- or 5-pyrimidinyl;
2-pyrazinyl;
2-triazinyl;
3- or 4-cinnolinyl;
1-phthalazinyl;
2- or 4-quinazolinyl;
or 2-quinoxalinyl ring;
said ring(s) may be unsubstituted or include optional substitution with one to three substituents;heterocycle is tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholino;
said ring(s) may be unsubstituted or include optional substitution with one to three substituents;the substituents that may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group consisting of; halogen, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --SH, --S(O)r --(C1 -C4 alkyl)--CN, --OH, --NH2, --NH(C1 -C4 alkyl) --N(C1 -C4 alkyl)2, --NHC(═
O)R4, --(CH2)p --CO2 R4, phenyl which may be unsubstituted or substituted with R13. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
- R1 is
Specification