US 5,310,903 AGranted

Imidazolidyl rapamycin derivatives

AssigneeMerck & Co., Inc.

InventorsMark Goulet, William H. Parsons, Matthew J. Wyvratt

Life of this patent

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Abstract

Imidazolidyl rapamycin derivatives of the general structural Formula I: ##STR1## have been prepared from suitable precursors by alkylation and/or arylation at C-42 and/or C-31. These compounds are useful in a mammalian host for the treatment of autoimmune diseases and diseases of inflammation, infectious diseases, the prevention of rejection of foreign organ transplants and the treatment of solid tumors.

Claims5

Dependent claims

A compound of formula I:

##STR20## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is selected from the group consisting of:
##STR21## wherein G is N--R.sup.6, O, S, SO, or SO.sub.2, ##STR22## R.sup.2 is independently selected from:
(1) the definitions of R.sup.1 ;
(2) hydrogen;
(3) phenyl;
(4) substituted phenyl in which the substituents are X, Y and Z;
(5) 1- or 2-naphthyl;
(6) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z;
(7) biphenyl;
(8) substituted biphenyl in which the substituents are X, Y and Z;
(9) C.sub.1-10 alkyl;
(10) substituted C.sub.1-10 alkyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 -alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 -alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently selected from:
(i) hydrogen, or
(ii) C.sub.1-6 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from:
(a') phenyl, which may be substituted with X, Y and Z,
(b') --OH,
(c') C.sub.1-6 alkoxy,
(d') --CO.sub.2 H,
(e') --CO.sub.2 --C.sub.1-6 alkyl,
(f') --C.sub.3-7 cycloalkyl, and
(g') -OR.sup.11,
(iii) or where R.sup.9 and R.sup.10 and the N to which they are attached may form a heterocyclic ring selected from the group consisting of:
morpholine, thiomorpholine, piperidine, and piperazine,
(h)--NR.sup.9 CO--C.sub.1-6 alkyl--R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-napthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(11) C.sub.3-10 alkenyl;
(12) substituted C.sub.3-10 alkenyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 -alkoxy;
(d) phenyl-C.sub.1-3 alkoxy;
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z;
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(13)C.sub.3-10 alkynyl;
(14) substituted C.sub.3-10 alkynyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 -alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --N.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 -alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11 ;
and
(15) --R.sup.11 ;
R.sup.6 is selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1-6 -alkyl, unsubstituted or substituted with:
(a) hydroxy,
(b) C.sub.1-6 alkoxy,
(c) --N.sup.12 R.sup.13, wherein R.sup.12 and R.sup.13 are independently selected from
(i) hydrogen,
(ii) C.sub.1-6 alkyl, or
(iii) C.sub.3-6 alkenyl,
(d) phenyl, unsubstituted or substituted with X, Y and Z,
(e) --OR.sup.11,
(3) C.sub.3-6 alkenyl, unsubstituted or substituted with:
(a) hydroxy,
(b) phenyl, unsubstituted or substituted with X, Y and Z, or
(c) C.sub.1-6 alkoxy,
(4) phenyl, unsubstituted or substituted with X, Y and Z,
(5) --R.sup.11,
(6) X, Y or Z;
R.sup.7 and R.sup.8 independently are selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1-7 alkyl,
(3) C.sub.2-6 alkenyl,
(4) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, and m is 0, 1, 2, and 3,
(5) --CF.sub.3,
(6) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(7) R.sup.14 O(CH.sub.2).sub.m -- wherein R.sup.14 is hydrogen, C.sub.1-6 alkyl, hydroxy--C.sub.2-3 alkyl, --CF.sub.3, phenyl, R.sup.11 or naphthyl and m is as defined above,
(8) ##STR23## wherein R.sup.14 and m are as defined above;
(9) phenyl--(CH.sub.2).sub.m -- wherein m is as defined above and the phenyl is unsubstituted or substituted with X, Y and Z,
(10) napthyl--(CH.sub.2).sub.m -- wherein m is as defined above and the napthyl is unsubstituted or substituted with X, Y and Z,
(11) biphenyl--(CH.sub.2).sub.m -- wherein m is as defined above and the biphenyl is unsubstituted or substituted with X, Y and Z,
(12) heteroaryl--(CH.sub.2).sub.m -- wherein heteroaryl is selected from:
acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinozaline, pyrrazole, indole, imidazole, benzatriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pyrimidine, and pyrrole, m is as defined above and the heteroaryl is unsubstituted or substituted with X, Y, and Z,
(13) morpholinyl, and
(14) --CH.dbd.CH--phenyl wherein the phenyl is unsubstituted or substituted with X, Y and Z;
R.sup.11 is selected from:
(a) --PO(OH)O.sup.- M.sup.+, wherein M.sup.+ is a positively charged inorganic or organic counterion, selected from the group consisting of:
ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine,
(b) --SO.sub.3.sup.- M.sup.+,
(c) --CO(CH.sub.2).sub.q CO.sub.2.sup.- M.sup.+, wherein q is 1 to 3, and
(d) --CO--C.sub.1-6 alkyl--NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from:
(i) hydrogen,
(ii) C.sub.1-6 alkoxy,
(iii) --NR.sup.12 R.sup.13, wherein R.sup.12 and R.sup.13 are as defined above,
(iv) --COOR.sup.6, wherein R.sup.6 is as defined above,
(v) phenyl,
(vi) substituted phenyl in which the substituents are X, Y and Z,
(vii) imidazolidyl,
(viii) indolyl,
(ix) --SH, and
(x) --S--C.sub.1-6 alkyl;
A is selected from the group consisting of:
(1) a bond,
(2) C.sub.1-10 alkyl;
(3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l ) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(4) --C.sub.1-10 alkyl wherein one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.9 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, --NR.sup.9 CONR.sup.10 --;
(5) --C.sub.3-10 alkenyl wherein alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.9 --, --O--, --S(O).sub.n --, --CO.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, and --NR.sup.9 CONR.sup.10 --;
##STR24## wherein s is 0 to 6 and t is 0 to 6, ##STR25## wherein r is 1 to 3 and s, and t are as defined above;
X, Y and Z are independently selected from the group consisting of:
(a) hydrogen,
(b) C.sub.1-10 alkyl, unsubstituted or substituted with one or more substituents selected from:
(i) aryl, wherein aryl is selected from the group consisting of phenyl and naphthyl,
(ii) substituted aryl wherein aryl is as defined above and in which the substituents are X', Y' and Z',
(iii) heteroaryl, wherein heteroaryl is as defined above,
(iv) substituted heteroaryl wherein heteroaryl is as defined above in which the substituents are X', Y', and Z',
(v) unsubstituted or substituted aryloxy, wherein aryl is as defined above and in which the substituents on aryl are X', Y' and Z',
(vi) --OR.sup.9,
(vii) --OR.sup.11,
(viii) --OCOR.sup.9,
(ix) --OCO.sub.2 R.sup.9,
(x) --NR.sup.9 R.sup.10,
(xi) --CHO,
(xii) --NR.sup.9 COC.sub.1-6 alkyl-R.sup.10,
(xiii) --NR.sup.9 CO.sub.2 C.sub.1-6 alkyl-R.sup.10,
(xiv) --NR.sup.9 CONR.sup.9 R.sup.10,
(xv) --OCONR.sup.9 R.sup.10,
(xvi) --CONR.sup.9 R.sup.10,
(c) C.sub.1-10 alkyl wherein one or more of the alkyl carbons is replaced by a group selected from --NR.sup.9 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, --NR.sup.9 CONR.sup.10 --, --CO--, --CH(OH)--, alkenyl or alkynyl and the alkyl may be unsubstituted or substituted with one or more substituents selected from:
(i) aryl, wherein aryl is as defined above,
(ii) substituted aryl wherein aryl is as defined above and in which the substituents are X', Y' and Z',
(iii) heteroaryl, wherein heteroaryl is as defined above,
(iv) substituted heteroaryl wherein heteroaryl is as defined above and in which the substituents are X', Y', and Z',
(v) unsubstituted or substituted aryloxy, in which the substituents on aryl are X', Y', and Z',
(vi) --OR.sup.9,
(vii) --OR.sup.11,
(viii) --OCOR.sup.9,
(ix) --OCO.sub.2 R.sup.9,
(x) --NR.sup.9 R.sup.10,
(xi) --CHO,
(xii) --NR.sup.9 COC.sub.1-6 alkyl-R.sup.10,
(xiii) --NR.sup.9 CO.sub.2 C.sub.1-6 alkyl-R.sup.10,
(xiv) --NR.sup.9 CONR.sup.9 R.sup.10,
(xv) --OCONR.sup.9 R.sup.10,
(xvi) --CONR.sup.9 R.sup.10,
(d) halogen,
(e) --NR.sup.9 R.sup.10,
(f) --CN,
(g) --CHO,
(h) --CF.sub.3,
(i) --SR.sup.15, wherein R.sup.15 is hydrogen, C.sub.1-6 alkyl, trifluoromethyl, or phenyl,
(j) --SOR.sup.15,
(k) --SO.sub.2 R.sup.15,
(l) --CONR.sup.9 R.sup.10,
(m) R.sup.16 O(CH.sub.2).sub.m -- wherein R.sup.16 is hydrogen, C.sub.1-6 alkyl, hydroxy-C.sub.2-3 alkyl, --CF.sub.3, phenyl, R.sup.11 or naphthyl and m is 0, 1, 2, or 3,
(n) --CH(OR.sup.17)(OR.sup.18), wherein R.sup.17 and R.sup.18 are C.sub.1-3 alkyl or taken together form an ethyl or propyl bridge,
(o) ##STR26## wherein R.sup.16 and m are as defined above, (p) ##STR27## wherein R.sup.16 and m are as defined above, and (q) --R.sup.11 ;
or any two of X, Y and Z may be joined to form a saturated ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon;
X', Y' and Z' independently are selected from:
(a) hydrogen,
(b) C.sub.1-7 alkyl,
(c) C.sub.2-6 alkenyl,
(d) halogen,
(e) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein R.sup.9, R.sup.10 and m are as defined above,
(f) --CN,
(g) --CHO,
(h) --CF.sub.3,
(i) --SR.sup.15, wherein R.sup.15 is as defined above,
(j) --SOR.sup.15, wherein R.sup.15 is as defined above,
(k) --SO.sub.2 R.sup.15, wherein R.sup.15 is as defined above,
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(m) R.sup.16 O(CH.sub.2).sub.m --, wherein R.sup.16 and m are as defined above,
(n) --CH(OR.sup.17)(OR.sup.18), wherein R.sup.17 and R.sup.18 are as defined above,
(o) ##STR28## wherein R.sup.16 and m are as defined above, (p) ##STR29## wherein R.sup.16 and m are as defined above, and (q) --R.sup.11.

222 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula I:

##STR20## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is selected from the group consisting of:
##STR21## wherein G is N--R.sup.6, O, S, SO, or SO.sub.2, ##STR22## R.sup.2 is independently selected from:
(1) the definitions of R.sup.1 ;
(2) hydrogen;
(3) phenyl;
(4) substituted phenyl in which the substituents are X, Y and Z;
(5) 1- or 2-naphthyl;
(6) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z;
(7) biphenyl;
(8) substituted biphenyl in which the substituents are X, Y and Z;
(9) C.sub.1-10 alkyl;
(10) substituted C.sub.1-10 alkyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 -alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 -alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently selected from:
(i) hydrogen, or
(ii) C.sub.1-6 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from:
(a') phenyl, which may be substituted with X, Y and Z,
(b') --OH,
(c') C.sub.1-6 alkoxy,
(d') --CO.sub.2 H,
(e') --CO.sub.2 --C.sub.1-6 alkyl,
(f') --C.sub.3-7 cycloalkyl, and
(g') -OR.sup.11,
(iii) or where R.sup.9 and R.sup.10 and the N to which they are attached may form a heterocyclic ring selected from the group consisting of:
morpholine, thiomorpholine, piperidine, and piperazine,
(h)--NR.sup.9 CO--C.sub.1-6 alkyl--R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-napthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(11) C.sub.3-10 alkenyl;
(12) substituted C.sub.3-10 alkenyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 -alkoxy;
(d) phenyl-C.sub.1-3 alkoxy;
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z;
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(13)C.sub.3-10 alkynyl;
(14) substituted C.sub.3-10 alkynyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 -alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --N.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 -alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11 ;
and
(15) --R.sup.11 ;
R.sup.6 is selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1-6 -alkyl, unsubstituted or substituted with:
(a) hydroxy,
(b) C.sub.1-6 alkoxy,
(c) --N.sup.12 R.sup.13, wherein R.sup.12 and R.sup.13 are independently selected from
(i) hydrogen,
(ii) C.sub.1-6 alkyl, or
(iii) C.sub.3-6 alkenyl,
(d) phenyl, unsubstituted or substituted with X, Y and Z,
(e) --OR.sup.11,
(3) C.sub.3-6 alkenyl, unsubstituted or substituted with:
(a) hydroxy,
(b) phenyl, unsubstituted or substituted with X, Y and Z, or
(c) C.sub.1-6 alkoxy,
(4) phenyl, unsubstituted or substituted with X, Y and Z,
(5) --R.sup.11,
(6) X, Y or Z;
R.sup.7 and R.sup.8 independently are selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1-7 alkyl,
(3) C.sub.2-6 alkenyl,
(4) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, and m is 0, 1, 2, and 3,
(5) --CF.sub.3,
(6) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(7) R.sup.14 O(CH.sub.2).sub.m -- wherein R.sup.14 is hydrogen, C.sub.1-6 alkyl, hydroxy--C.sub.2-3 alkyl, --CF.sub.3, phenyl, R.sup.11 or naphthyl and m is as defined above,
(8) ##STR23## wherein R.sup.14 and m are as defined above;
(9) phenyl--(CH.sub.2).sub.m -- wherein m is as defined above and the phenyl is unsubstituted or substituted with X, Y and Z,
(10) napthyl--(CH.sub.2).sub.m -- wherein m is as defined above and the napthyl is unsubstituted or substituted with X, Y and Z,
(11) biphenyl--(CH.sub.2).sub.m -- wherein m is as defined above and the biphenyl is unsubstituted or substituted with X, Y and Z,
(12) heteroaryl--(CH.sub.2).sub.m -- wherein heteroaryl is selected from:
acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinozaline, pyrrazole, indole, imidazole, benzatriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pyrimidine, and pyrrole, m is as defined above and the heteroaryl is unsubstituted or substituted with X, Y, and Z,
(13) morpholinyl, and
(14) --CH.dbd.CH--phenyl wherein the phenyl is unsubstituted or substituted with X, Y and Z;
R.sup.11 is selected from:
(a) --PO(OH)O.sup.- M.sup.+, wherein M.sup.+ is a positively charged inorganic or organic counterion, selected from the group consisting of:
ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine,
(b) --SO.sub.3.sup.- M.sup.+,
(c) --CO(CH.sub.2).sub.q CO.sub.2.sup.- M.sup.+, wherein q is 1 to 3, and
(d) --CO--C.sub.1-6 alkyl--NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from:
(i) hydrogen,
(ii) C.sub.1-6 alkoxy,
(iii) --NR.sup.12 R.sup.13, wherein R.sup.12 and R.sup.13 are as defined above,
(iv) --COOR.sup.6, wherein R.sup.6 is as defined above,
(v) phenyl,
(vi) substituted phenyl in which the substituents are X, Y and Z,
(vii) imidazolidyl,
(viii) indolyl,
(ix) --SH, and
(x) --S--C.sub.1-6 alkyl;
A is selected from the group consisting of:
(1) a bond,
(2) C.sub.1-10 alkyl;
(3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is(are) selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) substituted phenyl-C.sub.1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,
(f) --OCO--C.sub.1-6 alkyl,
(g) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(h) --NR.sup.9 CO--C.sub.1-6 alkyl, wherein R.sup.9 is as defined above,
(i) --COOR.sup.9, wherein R.sup.9 is as defined above,
(j) --CHO,
(k) phenyl,
(l ) substituted phenyl in which the substituents are X, Y and Z,
(m) 1- or 2-naphthyl,
(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,
(o) biphenyl,
(p) substituted biphenyl in which the substituents are X, Y and Z,
(q) --OR.sup.11, and
(r) --S(O).sub.p --C.sub.1-6 alkyl;
(4) --C.sub.1-10 alkyl wherein one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.9 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, --NR.sup.9 CONR.sup.10 --;
(5) --C.sub.3-10 alkenyl wherein alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons is replaced by a group selected from:
--NR.sup.9 --, --O--, --S(O).sub.n --, --CO.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, and --NR.sup.9 CONR.sup.10 --;
##STR24## wherein s is 0 to 6 and t is 0 to 6, ##STR25## wherein r is 1 to 3 and s, and t are as defined above;
X, Y and Z are independently selected from the group consisting of:
(a) hydrogen,
(b) C.sub.1-10 alkyl, unsubstituted or substituted with one or more substituents selected from:
(i) aryl, wherein aryl is selected from the group consisting of phenyl and naphthyl,
(ii) substituted aryl wherein aryl is as defined above and in which the substituents are X', Y' and Z',
(iii) heteroaryl, wherein heteroaryl is as defined above,
(iv) substituted heteroaryl wherein heteroaryl is as defined above in which the substituents are X', Y', and Z',
(v) unsubstituted or substituted aryloxy, wherein aryl is as defined above and in which the substituents on aryl are X', Y' and Z',
(vi) --OR.sup.9,
(vii) --OR.sup.11,
(viii) --OCOR.sup.9,
(ix) --OCO.sub.2 R.sup.9,
(x) --NR.sup.9 R.sup.10,
(xi) --CHO,
(xii) --NR.sup.9 COC.sub.1-6 alkyl-R.sup.10,
(xiii) --NR.sup.9 CO.sub.2 C.sub.1-6 alkyl-R.sup.10,
(xiv) --NR.sup.9 CONR.sup.9 R.sup.10,
(xv) --OCONR.sup.9 R.sup.10,
(xvi) --CONR.sup.9 R.sup.10,
(c) C.sub.1-10 alkyl wherein one or more of the alkyl carbons is replaced by a group selected from --NR.sup.9 --, --O--, --S(O).sub.p --, --CO.sub.2 --, --O.sub.2 C--, --CONR.sup.9 --, --NR.sup.9 CO--, --NR.sup.9 CONR.sup.10 --, --CO--, --CH(OH)--, alkenyl or alkynyl and the alkyl may be unsubstituted or substituted with one or more substituents selected from:
(i) aryl, wherein aryl is as defined above,
(ii) substituted aryl wherein aryl is as defined above and in which the substituents are X', Y' and Z',
(iii) heteroaryl, wherein heteroaryl is as defined above,
(iv) substituted heteroaryl wherein heteroaryl is as defined above and in which the substituents are X', Y', and Z',
(v) unsubstituted or substituted aryloxy, in which the substituents on aryl are X', Y', and Z',
(vi) --OR.sup.9,
(vii) --OR.sup.11,
(viii) --OCOR.sup.9,
(ix) --OCO.sub.2 R.sup.9,
(x) --NR.sup.9 R.sup.10,
(xi) --CHO,
(xii) --NR.sup.9 COC.sub.1-6 alkyl-R.sup.10,
(xiii) --NR.sup.9 CO.sub.2 C.sub.1-6 alkyl-R.sup.10,
(xiv) --NR.sup.9 CONR.sup.9 R.sup.10,
(xv) --OCONR.sup.9 R.sup.10,
(xvi) --CONR.sup.9 R.sup.10,
(d) halogen,
(e) --NR.sup.9 R.sup.10,
(f) --CN,
(g) --CHO,
(h) --CF.sub.3,
(i) --SR.sup.15, wherein R.sup.15 is hydrogen, C.sub.1-6 alkyl, trifluoromethyl, or phenyl,
(j) --SOR.sup.15,
(k) --SO.sub.2 R.sup.15,
(l) --CONR.sup.9 R.sup.10,
(m) R.sup.16 O(CH.sub.2).sub.m -- wherein R.sup.16 is hydrogen, C.sub.1-6 alkyl, hydroxy-C.sub.2-3 alkyl, --CF.sub.3, phenyl, R.sup.11 or naphthyl and m is 0, 1, 2, or 3,
(n) --CH(OR.sup.17)(OR.sup.18), wherein R.sup.17 and R.sup.18 are C.sub.1-3 alkyl or taken together form an ethyl or propyl bridge,
(o) ##STR26## wherein R.sup.16 and m are as defined above, (p) ##STR27## wherein R.sup.16 and m are as defined above, and (q) --R.sup.11 ;
or any two of X, Y and Z may be joined to form a saturated ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon;
X', Y' and Z' independently are selected from:
(a) hydrogen,
(b) C.sub.1-7 alkyl,
(c) C.sub.2-6 alkenyl,
(d) halogen,
(e) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein R.sup.9, R.sup.10 and m are as defined above,
(f) --CN,
(g) --CHO,
(h) --CF.sub.3,
(i) --SR.sup.15, wherein R.sup.15 is as defined above,
(j) --SOR.sup.15, wherein R.sup.15 is as defined above,
(k) --SO.sub.2 R.sup.15, wherein R.sup.15 is as defined above,
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(m) R.sup.16 O(CH.sub.2).sub.m --, wherein R.sup.16 and m are as defined above,
(n) --CH(OR.sup.17)(OR.sup.18), wherein R.sup.17 and R.sup.18 are as defined above,
(o) ##STR28## wherein R.sup.16 and m are as defined above, (p) ##STR29## wherein R.sup.16 and m are as defined above, and (q) --R.sup.11.

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