Patent ID: 6756359
Filing Date: 2004-06-29
Classification: A61P,C07H

Abstract:
A compound having the formula II: or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinV is â€”OCORx, carbonyl, or a cladinose moiety of the formula: â€ƒwherein Rx is H, alkyl, â€”O-alkyl, â€”N(H)-alkyl, or â€”N(alkyl)2; either Y and Z taken together define a group X, wherein X is selected from the group consisting of (1) &boxH;O, (2) &boxH;Nâ€”OH, (3) &boxH;Nâ€”Oâ€”R1 where R1 is selected from the group consisting of (a) C1-C12-alkyl, (b) C1-C12-alkyl substituted with alkoxy, (c) C1-C12-alkyl substituted with aryl, (d) C1-C12-alkyl substituted with substituted aryl, (e) C1-C12-alkyl substituted with heteroaryl, (f) C1-C12-alkyl substituted with substituted heteroaryl, (g) C3-C12-cycloalkyl, and (h) â€”Siâ€”(R2)(R3)(R4) wherein R2, R3, R4 are each independently selected from C1-C12-alkyl and aryl; and (4) &boxH;Nâ€”Oâ€”C(R5)(R6)â€”Oâ€”R1 wherein R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of (a) hydrogen, (b) C1-C12-alkyl, (c) C1-C12-alkyl substituted with aryl, (d) C1-C12-alkyl substituted with substituted aryl, (e) C1-C12-alkyl substituted with heteroaryl, and (f) C1-C12-alkyl substituted with substituted heteroaryl; or R5 and R6 taken together with the atoms to which they are attached form a C3-C12-cycloalkyl ring; or Y and Z are &boxH;Nâ€” when taken together with T to form a moiety of the structure: â€ƒor one of Y and Z is hydrogen and the other is selected from a group consisting of (1) hydroxy, (2) protected hydroxy, and (3) NR7R8 wherein R7 and R8 are independently selected from hydrogen and alkyl, substituted alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of â€”Oâ€”, â€”NH, â€”N(C1-C6-alkyl)-, â€”N(aryl)-, â€”N(aryl-C1-C6-alkyl-)-, â€”N(substituted-aryl-C1-C6-alkyl-)-, â€”N(heteroaryl)-, â€”N(heteroaryl-C1-C6-alkyl-)-, â€”N(substituted-heteroaryl-C1-C6-alkyl-)-, and â€”Sâ€” or S(O)nâ€” wherein n is 1 or 2; T is selected from the group consisting of â€”Oâ€”Rg, â€”Oâ€”, â€”NHâ€”, N(Wâ€”Rf)-, and â€”CH(Wâ€”Rf)-, wherein (1) W is absent or is selected from the group consisting of â€”Oâ€”, NHâ€”COâ€”, â€”N&boxH;CHâ€”, â€”NHâ€” and â€”CH2â€”; and (2) Rf is selected from the group consisting of (a) hydrogen, (b) alkyl, alkenyl or alkynyl, (c) alkyl, alkenyl or alkynyl substituted with one or more substituents selected from the group consisting of (i) aryl, (ii) substituted aryl, (iii) heteroaryl, (iv) substituted heteroaryl, (v) hydroxy, (vi) C1-C6-alkoxy, (vii) â€”NR7R8 wherein R7 and R8 are as defined previously, and (viii) â€”Mâ€”R9, wherein M is selected from the group consisting of: â€ƒ(a) â€”C(O)â€”NHâ€”, â€ƒ(b) â€”NHâ€”C(O)â€”, â€ƒ(c) â€”NHâ€”, â€ƒ(d) â€”N&boxH;, â€ƒ(e) â€”N(CH3)â€”, â€ƒ(f) â€”NHâ€”C(O)â€”Oâ€”, â€ƒ(g) â€”NHâ€”C(O)â€”NHâ€”, â€ƒ(h) â€”Oâ€”C(O)â€”NHâ€”, â€ƒ(i) â€”Oâ€”C(O)â€”Oâ€”, â€ƒ(j) â€”Oâ€”, â€ƒ(k) â€”S(O)nâ€”, wherein n is 0, 1 or 2, â€ƒ(l) â€”C(O)â€”Oâ€”, â€ƒ(m) â€”Oâ€”C(O)â€”, â€ƒ(n) â€”C(O)â€”; and and R9 is selected from the group consisting of: (a) alkyl optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted aryl, (cc) heteroaryl, and (dd) substituted heteroaryl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) substituted heteroaryl, and (f) heterocycloalkyl, R is selected from the group consisting of (1) hydrogen; (2) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) â€”CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) â€”S(O)nR10 â€”, wherein n is 0, 1 or 2 and R10 is as previously defined, (e) â€”NHâ€”C(O) R10, wherein R10 is as previously defined, (f) â€”NHâ€”C(O)N R11 R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl; (3) alkyl; (4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy- C1-C3-alkoxy, (e) oxo, (f) Oâ€”SO2-(substituted C1-C6-alkyl), (g) â€”N3, (h) â€”CHO, (i) â€”NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C2-C12-alkenyl, (v) substituted C2-C12-alkenyl, (vi) C2-C12-alkynyl, (vii) substituted C2-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloaryl, (xvii) C1-C12-alkyl substituted with substituted heterocycloaryl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl; or R13 and R14 are taken together with the atom to which they are attached form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (viii) C1-C3-alkoxy-C1-C3-alkyl; (j) â€”CO2R10 wherein R10 is as previously defined, (k) â€”C(O)R11R12 wherein R11 and R12 are as previously defined, (l) &boxH;Nâ€”Oâ€”R10 wherein R10 is as previously defined, (m) â€”CN, (n) â€”Oâ€”S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) â€”NHâ€”C(O)R10 wherein R10 is as previously defined, (y) â€”NHâ€”C(O)NR11R12 wherein R11 and R12 are as previously defined, (z) &boxH;Nâ€”NR13R14 wherein R13 and R14 are as previously defined, (aa) &boxH;Nâ€”R9 wherein R9 is as previously defined, (bb) &boxH;Nâ€”NHâ€”C(O)R10 wherein R10 is as previously defined, and (cc) &boxH;Nâ€”NHâ€”C(O)NR11R12 wherein R11 and R12 are as previously defined; (5) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) â€”CHO, (c) â€”CO2R10 wherein R10 is as previously defined, (d) â€”C(O)NR11R12 wherein R11 and R12 are as previously defined, (e) â€”C(O)R9 wherein R9 is as previously defined, (f) â€”CN, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C8-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl; (6) C4-C10-alkenyl; (7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) â€”CHO, (e) â€”CO2R10 wherein R10 is as previously defined, (f) â€”C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) NR13R14 wherein R13 and R14 are as previously defined, (h) &boxH;Nâ€”Oâ€”R10 wherein R10is as previously defined, (i) â€”CN, (j) â€”Oâ€”S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C8-cycloalkyl, (p) C1-C12-alkyl substituted with substituted heteroaryl, (q) â€”NHâ€”C(O)R10 wherein R10 is as previously defined, (r) â€”NHâ€”C(O)NR11R12 wherein R11 and R12 are as previously defined, (s) &boxH;Nâ€”NR13R14 wherein R13 and R14 are as previously defined, (t) &boxH;Nâ€”R9 wherein R9 is as previously defined, (u) &boxH;Nâ€”NHâ€”C(O)R10 wherein R10 is as previously defined, and (v) &boxH;Nâ€”NHâ€”C(O)NR11R12 wherein R11 and R12 are as previously defined; (8) C3-C10-alkynyl; (9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl; and (10) C(O)NR7R8 where R7 and R8 are previously defined; Ra is selected from a group consisting of (1) hydrogen; (2) C1 alkyl further substituted with a one or more substituents selected from a group consisting of (a) hydroxyl, (b) halogen, (c) thiol, which can be further substituted with an alkyl or substituted alkyl group, (d) C1-C12-alkyl which can be further substituted by halogen, hydroxyl alkoxy, or amino, (e) C1-C3-alkoxy, (f) C1-C3-thioalkoxy, (g) amino, (h) alkylamino, (i) dialkylamino, (j) nitrile, (k) nitro, (l) amido, (m) carboxylic acid, (n) ester, (o) azido, (p) &boxH;Nâ€”Oâ€”R10, wherein R10 is as previously defined, (q) &boxH;Nâ€”R9, wherein R9 is as previously defined, (r) &boxH;Nâ€”NR13R14, wherein R13 and R14 are as previously defined, (s) &boxH;Nâ€”NHâ€”C(O)R10, wherein R10 is as previously defined, and (t) &boxH;Nâ€”NHâ€”C(O)NR11R12, wherein R11 and R12 are as previously defined; (3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halo groups; (4) â€”C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halo groups; (5) aryl, which can be further substituted with C1-C12-alkyl and one or more halo groups; (6) CHO; (7) â€”CO2H; (8) â€”CN; (9) â€”CO2R10, wherein R10is as previously defined; (10) â€”C(O)NR11R12, wherein R11 and R12 are as previously defined; (11) â€”C(O)R9 wherein R9 is as previously defined; and (12) thioester; with the proviso that in formula II, when Z is amino or substituted amino, then Ra can not be â€”CH2OH, â€”NR4R6, or â€”(CH2)n NR4R6, wherein R4 and R6 are selected from the group consisting of hydrogen, loweralkyl and aralkyl; Rb is hydrogen, halogen or C1-C12-alkyl which can be further substituted by one or more halo groups, or Rb can be taken together with V to form a double bond; Rc is hydrogen or a hydroxy protecting group; Rd is selected from the group consisting of (1) C1-C12-alkyl, (2) C1-C12-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, and (c) C1-C3-alkoxy, (3) C3-C7-cycloalkyl, (4) C2-C4-alkenyl, and (5) C2-C4-alkynyl; Re is hydroxyl, amino, or alkylamino, provided that when Ra is hydroxymethyl then Re is not hydroxy; or Re and Ra may be taken together to form an epoxide, a carbonyl, an olefin, or a substituted olefin; or Re and Ra when taken together with the atom to which they are attached form a spiro ring consisting of C3-C7-carbocyclic, carbonate or carbamate wherein the nitrogen atom can be unsubstituted or substituted with an alkyl group; or Re and T when taken together with the carbon atoms to which they are attached form a ring of the structure: â€ƒwherein L is methylene or carbonyl and P is â€”Oâ€”, â€”NHâ€” or â€”NR1â€” wherein R1 is as previously defined; provided that when L is methylene, T is â€”Oâ€” and P is â€”Oâ€”; Rg is hydrogen, R where R is as previously defined; or Rg may be taken together with Y, separated by a linker of the formula â€”C(&boxH;O)â€” or â€”C(CH3)2â€”, to form a cyclic moiety; Rh is selected from the group consisting of (1) hydrogen, (2) â€”ORj, where Rj is hydrogen or a hydroxy protecting group, (3) halogen, (4) OC(O)NHRi wherein Ri is selected from a group consisting of (a) C1-C4 alkyl, (b) C1-C4 aminoalkyl where the amino group is substituted with one or two groups selected from (i) C1-C4 alkyl, (ii) C1-C4 alkyl substituted with halogen, (iii) C1-C4 alkyl substituted with alkoxy, (iv) C1-C4 alkyl substituted with hydroxyl, (v) C1-C4 alkyl substituted with aryl, (vi) C1-C4 alkyl substituted with substituted aryl, (vii) C1-C4 alkyl substituted with heteroaryl, (viii) C1-C4 alkyl substituted with substituted heteroaryl, (ix) C3-C6 cycloalkyl; and A, B, D, and E are independently selected from the group consisting of: (1) hydrogen; (2) C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) heterocycloalkyl, (f) hydroxy, (g) C1-C6-alkoxy, (h) halogen selected from the group consisting of Br, Cl, F or I, and (i) NR7R8 where R7 and R8 are as previously defined; (3) C3-C7-cycloalkyl; (4) aryl; (5) substituted aryl; (6) heteroaryl; (7) substituted heteroaryl; (8) heterocycloalkyl; and (9) a group selected from option (2) above further substituted with â€”Mâ€”R9, wherein M and R9 are as previously defined; or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of â€”Oâ€”, â€”NHâ€”, â€”N(C1-C6-alkyl-)-, â€”N(aryl-C1-C6-alkyl-)-, â€”N(substituted-aryl-C1-C6-alkyl-)-, â€”N(heteroaryl-C1-C6-alkyl-)-, â€”N(substituted-heteroaryl-C1-C6-alkyl-)-, â€”Sâ€” or â€”S(O)nâ€”, wherein n is 1 or 2, â€”C(O)â€”NH, â€”C(O)â€”NR12, wherein R12 is as previously defined, â€”NHâ€”C(O)â€”, â€”NR12â€”C(O)â€”, wherein R12 is as previously defined, and â€”C(&boxH;NH)â€”NHâ€”; with the provision that at least two of A, B, D, and E are hydrogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.