Methods Of Immune Modulation

A method of modulating an immune response in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of:

• a) Formula I:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or S;
• R1 is C1-C9 straight or branched chain alkyl, optionally substituted with one or more —NH2 or —NH—C(═NH)NH2;
• Y is a bond or a carbonyl;
• Z is a bond or a carbonyl;
• R2 is hydrogen or C1-C9 straight or branched chain alkyl optionally substituted with one or more —NH2 or —NH—C(═NH)NH2;
• or R2 is —X—R1;
• R3 is methylene or
• wherein the methylene is substituted with C1-C9 straight or branched chain alkyl, wherein the C1-C9 straight or branched chain alkyl is optionally substituted with one or more —NH2 or —NH—C(═NH)NH2;
• n is 2-10;
• and
• m is 1 or 2;
• b) Formula II:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or S;
• Y is O or S;
• R1 is H or —C(═O)-A, where A is C1-C9 straight or branched alkyl optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R2 is C1-C9 straight or branched alkyl optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R3 is C1-C9 straight or branched alkyl optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• and
• R4 is H, —B, or —C(═O)—O—B, where B is C1-C9 straight or branched alkyl;
• c) Formula III:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each A is, independently, —C═O, —C═S, or CH2;
• each D is, independently, O or S;
• each R1 is, independently, hydrogen, C1-3alkyl, C1-3alkoxy, halo, or haloC1-3alkyl;
• each R2 is, independently, hydrogen, C1-3alkyl, C1-3alkoxy, halo, or halo C1-3alkyl;
• each R3 is, independently, hydrogen, C1-4alkyl, C1-4alkoxy, halo, or haloC1-4alkyl;
• and
• each R4 is, independently, hydrogen, C1-3alkyl, C1-3alkoxy, halo, or haloC1-3alkyl;
• d) Formula IV:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• n=1 to 10;
• X is O or S;
• Y is O or S;
• Z is a bond, C1-C9 straight or branched alkyl, or a 1,4-cyclohexyl;
• R1 is NH2 or NH-A, where A is C1-C9 straight or branched alkyl, where A is optionally substituted with —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R2 is C1-C9 straight or branched alkyl, where R2 is optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R3 is C1-C9 straight or branched alkyl, where R3 is optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R4 is H or
• e) Formula V:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• n is 2-8;
• X is a bond, O or —O—CH2—C(═O)—O—,
• R1 is -A or —O-A, where A is C1-C9 straight or branched alkyl;
• and
• R2 is C1-C9 straight or branched alkyl, where R2 is optionally substituted with one or more —NH2, —N(CH3)2, or —NH—C(═NH)NH2;
• f) Formula VI:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• n is 2 to 10;
• R1 is H or
• R2 is C1-C9 straight or branched alkyl, where R2 is optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R3 is C1-C9 straight or branched alkyl, where R2 is optionally substituted with one or more —NH2, —N(CH3)2 or —NH—C(═NH)NH2;
• R4 is OH, NH2 or
• where A is OH or NH2;
• g) Formula VII:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is C(R7)C(R8), C(═O), N(R9), O, S, S(═O), or S(═O)2;
• R7, R8, and R9 are, independently, H, C1-C8alkyl, C1-C8alkoxy, halo, OH, CF3, or aromatic group;
• R1 and R2 are, independently, H, C1-C8alkyl, C1-C8alkoxy, halo, OH, haloC1-C8alkyl, or CN;
• R3 and R4 are, independently, carbocycle(R5)(R6);
• each R5 and each R6 are, independently, H, C1-C8alkyl, C1-C8alkoxy, halo, OH, CF3, aromatic group, heterocycle, or the free base or salt form of —(CH2)n—NH2, or —(CH2)n—NH—(CH2)n—NH2, or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 8;
• or a pharmaceutically acceptable salt thereof;
• h) Formula VIII:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or S;
• each Y is, independently, O, S, or N;
• each R1 is, independently, H, 5- or 6-membered heterocycle, or the free base or salt form of —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• or each R1 is, independently, together with Y a 5- or 6-membered heterocycle;
• each R2 is, independently, H, CF3, C(CH3)3, halo, or OH;
• and
• each R3 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• or a pharmaceutically acceptable salt thereof;
• i) Formula IX:
• Q—X—Z—X-Q IX
• or a pharmaceutically acceptable salt thereof,
• wherein:
• Z is
• or phenyl;
• each Q is, independently,
• or —C(═O)—(CH2)b—NH—C(═NH)—NH2, where each b is, independently, 1 to 4;
• each X is, independently, O, S, or N;
• each R1 is, independently, H, CF3, C(CH3)3, halo, or OH;
• each R3 is, independently, H, —NH—R2, —(CH2)n—NH2, —NH2, —NH—(CH2)w—NH2, or
• where each r is, independently, 1 or 2, each w is, independently, 1 to 3, and each y is, independently, 1 or 2;
• each R2 is, independently, H, or the free base or salt form of —(CH2)n—NH2 or (CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• each R4 is, independently, H, —NH—C(═O)—(CH2)p—NH—C(═NH)—NH2 or
• where each p is, independently, 1 to 6, and each q is, independently, 1 or 2;
• and
• each R5 is, independently, H or CF3;
• or a pharmaceutically acceptable salt thereof;
• j) Formula X:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• G is
• each X is, independently, O or S;
• each R1 is, independently,
• or the free base or salt form of —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• each R2 is, independently, H, C1-C8alkyl, or the free base or salt form of —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• each R3 is, independently, H, CF3, C(CH3)3, halo, or OH;
• and
• each R4 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• k) Formula XI:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each X is, independently, O, S, or S(═O)2;
• each R1 is, independently, —(CH2)n—NH2, —(CH2)n—NH—C(═NH)NH2, or —(CH2)n—NH—C(═O)—R4, where each n is, independently, 1 to 4, and each R4 is, independently, H, C1-C3alkyl, or —(CH2)p—NH2, where each p is, independently, 1 or 2;
• each R2 is, independently, H, halo, CF3, or C(CH3)3;
• and
• each V2 is H, and each V1 is, independently, —N—C(═O)—R3, where each R3 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• or each V1 is H and each V2 is, independently, —S—R5, where each R5 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• or a pharmaceutically acceptable salt thereof;
• l) Formula XII:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each Y is, independently, O, S, or NH;
• each R1 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• and
• each R2 is, independently, H, halo, CF3, or C(CH3)3;
• or a pharmaceutically acceptable salt thereof;
• m) Formula XIII:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each R1 is, independently, H, C1-C8alkyl, C1-C8alkoxy, halo, OH, CF3, or CN;
• each R2 is, independently, —(CH2)n—NH2 or —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4;
• or a pharmaceutically acceptable salt thereof;
• n) Formula XIV:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• D is
• each B is, independently, —(CH2)n—NH—C(═NH)NH2, where each n is, independently, 1 to 4
• and
• each X is, independently, O or S;
• or a pharmaceutically acceptable salt thereof;
• o) Formula XV:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is H or C1-10 alkyl;
• R2 is H or C1-10 alkyl;
• and
• m is 1 or 2;
• p) Formula XVI:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is H or C1-8 alkyl;
• and
• R2 is H or C1-8 alkyl;
• q) Formula XVII:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is H or C1-8 alkyl;
• and
• R2 is H or C1-8 alkyl;
• r) Formula XVIII:
• R1—[—X-A1-Y—X-A2-Y—]mR2 XVIII
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each X is, independently, NR8, —N(R8)N(R8)—, O, or S;
• each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, or —CRaRb—;
• Ra and Rb are each, independently, hydrogen, a PL group, or an NPL group;
• each R8 is, independently, hydrogen or alkyl;
• A1 and A2 are each, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or
• each A1 is, independently, optionally substituted arylene or optionally substituted heteroarylene, and each A2 is a C3 to C8 cycloalkyl or —(CH2)q—, wherein q is 1 to 7, wherein A1 and A2 are, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or
• each A2 is optionally substituted arylene or optionally substituted heteroarylene, and each A1 is a C3 to C8 cycloalkyl or —(CH2)q—, wherein q is 1 to 7, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• R1 is hydrogen, a PL group, or an NPL group, and R2 is —X-A1-Y—R11, wherein R11 is hydrogen, a PL group, or an NPL group;
• or
• R1 and R2 are each, independently, hydrogen, a PL group, or an NPL group;
• or
• R1 and R2 together are a single bond;
• or
• R1 is —Y-A2-X—R12, wherein R12 is hydrogen, a PL group, or an NPL group, and R2 is hydrogen, a PL group, or an NPL group;
• each NPL group is, independently, —B(OR4)2 or —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4 and R4′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more substitutents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
• each UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—NR3—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pNPL is, independently, an integer from 0 to 8;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL group is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q2PL—UPL-LKPL—(NR5″)q2PL—V, wherein:
• R5, R5′, and R5″ are each, independently, hydrogen, alkyl, or alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—NR5—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═NH)NH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkyl is substituted with one or more substitutents, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents, and wherein each of the substituents for the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each Rc is, independently, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substituted by one or more substitutents, wherein each substituent is, independently, OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• Rd and Re are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, C1-6 alkyl, C1-6haloalkyl, C1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• or Rd and Re together with the N atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;
• each LKPL is, independently, —(CH2)pPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pPL is, independently, an integer from 0-8;
• q1PL and q2PL are each, independently, 0, 1, or 2;
• and
• m is an integer from 1 to about 20;
• s) Formula XIX:
• R1—[—X-A1-X—Y-A2-Y-]mR2 XIX
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each X is, independently, NR8, O, S, —N(R8)N(R8)—, —N(R8)—(N═N)—, —(N═N)—N(R8)—, —C(R7R7′)NR8—, —C(R7R7′)O—, or —C(R7R7′)S—;
• each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, C(R6R6′)C═O, or C(R6R6′)C═S;
• each R8 is, independently, hydrogen or alkyl;
• each R7 and each R7′ are, independently, hydrogen or alkyl;
• or R7 and R7′ together form —(CH2)p—, wherein p is 4 to 8;
• each R6 and each R6′ are, independently, hydrogen or alkyl;
• or R6 and R6′ together form —(CH2)2NR12(CH2)2—, wherein R12 is hydrogen, —C(═N)CH3, or —C(═NH)—NH2;
• A1 and A2 are each, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or each A2 is, independently, optionally substituted arylene or optionally substituted heteroarylene, and each A1 is, independently, optionally substituted C3 to C8 cycloalkyl, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• R1 is hydrogen, a PL group, or an NPL group, and R2 is —X-A1-X—R1, wherein A1 is as defined above and is optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or
• R1 is hydrogen, a PL group, or an NPL group, and R2 is —X-A′-X—R1, wherein A′ is C3 to C8 cycloalkyl, aryl, or heteroaryl and is optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or
• R1 is —Y-A2-Y—R2, and each R2 is, independently, hydrogen, a PL group, or an NPL group;
• or
• R1 is —Y-A1 and R2 is —X-A′, wherein each A′ is, independently, C3 to C8 cycloalkyl, aryl, or heteroaryl and is optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• or
• R1 and R2 are, independently, a PL group or an NPL group;
• or
• R1 and R2 together form a single bond;
• each NPL is, independently, —B(OR4)2 or —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4 and R4′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more alkyl or halo groups;
• each UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—NR3—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— or C2-8 alkenylenyl, wherein each of the (CH2)pNPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pNPL is, independently, an integer from 0 to 8;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5′)q2PL—V, wherein:
• R5, R5′, and R5″ are each, independently, hydrogen, alkyl, and alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—NR5—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═NH)NH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkyl is substituted with one or more substitutents, wherein each of the heterocycloalkyl, and heteroaryl is optionally substituted with one or more substituents, and wherein each of the substituents for the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each LKPL is, independently, —(CH2)pPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pPL is, independently, an integer from 0 to 8;
• q1PL and q2PL are each, independently, 0, 1, or 2;
• and
• m is an integer from 1 to about 20;
• t) Formula XIXa:
• R1—X-A1-X—Y-A2-Y—X-A1-X—R2 XIXa
• or pharmaceutically acceptable salt thereof, wherein:
• each X is, independently, NR8, O, S, or —N(R8)N(R8)—;
• each Y is, independently, C═O, C═S, or O═S═O;
• each R8 is, independently, hydrogen or alkyl;
• A1 and A2 are each, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• R1 is a PL group or an NPL group;
• R2 is R1;
• each NPL is, independently, —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4 and R4′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more alkyl or halo groups;
• UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— or C2-8 alkenylenyl, wherein the —(CH2)pNPL— is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, or alkyl;
• each pNPL is, independently, an integer from 0 to 8;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5′)q2PL—V, wherein:
• R5, R5′, and R5″ are each, independently, hydrogen, alkyl, or alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aryl, heterocycloalkyl, or heteroaryl, wherein the aryl is substituted with one or more substitutents, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents, and wherein each of each of the substituents for the aryl, heterocycloalkyl, and heteroaryl is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each LKPL is, independently, —(CH2)pPL— or C2-8 alkenylenyl, wherein the —(CH2)pNPL— is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, or alkyl;
• each pPL is, independently, an integer from 0 to 8;
• and
• q1PL and q2PL are each, independently, 0, 1, or 2;
• u) Formula XX:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each X is, independently, NR8;
• each Y is C═O;
• each R8 is, independently, hydrogen or alkyl;
• each A2 is optionally substituted arylene or optionally substituted heteroarylene, and each A1 is —(CH2)q—, wherein q is 1 to 7, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• R2 and R2a are each, independently, hydrogen, a PL group, an NPL group or —X-A1-Y—R11, wherein R11 is hydrogen, a PL group, or an NPL group;
• L1 is C1-10alkylene optionally substituted with one or more substitutents, wherein each substituent is, independently, alkyl, halo, haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH2)pPL—V, wherein pPL is an integer from 1 to 5;
• each NPL group is, independently, —B(OR4)2 or
• —(NR3′)q1NPL—UNPL-LKNPL—(NR3)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4 and R4′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more substitutents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
• each UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—NR3—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— and C2-8 alkenylenyl, wherein each of the —(CH2)pNPL and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pNPL is, independently, an integer from 0 to 8;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL group is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5″)q2PL—V, wherein:
• R5, R5′, and R5″ are each, independently, hydrogen, alkyl, or alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—NR5—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═NH)NH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkyl is substituted with one or more substitutents, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents, and wherein each of the substituents for the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each Rc is, independently, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substituted by one or more substitutents, wherein each substituent is, independently, OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• Rd and Re are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• or Rd and Re together with the N atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;
• each LKPL is, independently, —(CH2)pPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pPL is, independently, an integer from 0 to 8;
• q1PL and q2PL are each, independently, 0, 1, or 2;
• m11 is an integer from 1 to about 20;
• and
• m12 is an integer from 1 to about 20;
• v) Formula XXI:
• R1—[—X-A1-Y—X-A2-Y—]m13—X-L1-Y—[—X-A1-Y—X-A2-Y—]m14—R2 XXI
• or a pharmaceutically acceptable salt thereof,
• wherein:
• each X is, independently, NR8;
• each Y is C═O;
• each R8 is, independently, hydrogen or alkyl;
• each A2 is optionally substituted arylene or optionally substituted heteroarylene, and each A1 is —(CH2)q—, wherein q is 1 to 7, wherein A1 and A2 are each, independently, optionally substituted with one or more PL group(s), one or more NPL group(s), or a combination of one or more PL group(s) and one or more NPL group(s);
• R1 is hydrogen, a PL group, or an NPL group, and R2 is —X-A1-Y—R11, wherein R11 is hydrogen, a PL group, or an NPL group;
• or
• R1 and R2 are each, independently, hydrogen, a PL group, or an NPL group;
• or
• R1 and R2 together are a single bond;
• or
• R1 is —Y-A2-X—R12, wherein R12 is hydrogen, a PL group, or an NPL group, and R2 is hydrogen, a PL group, or an NPL group;
• L1 is C1-10alkylene optionally substituted with one or more substitutents, wherein each substituent is, independently, alkyl, halo, haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH2)pPL—V wherein pPL is an integer from 1 to 5;
• each V is, independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNH2 wherein p is 1 to 5, C(═O)NH(CH2)pNHC(═NH)NH2 wherein p is 1 to 5, —C(═O)NH(CH2)pNHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl, —N(CH2CH2NH2)2, guanidino, amidino, ureido, carbamoyl, —C(═O)OH, —C(═O)ORc, —C(═O)NH—OH, —O—NH—C(═NH)NH2, —NH—S(═O)2OH, S(═O)2OH, NRdRe, a substituted aryl group, heterocycloalkyl, or heteroaryl, wherein each of the heterocycloalkyl and heteroaryl is optionally substituted with one more substituents, wherein each substituent is, independently, amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• and wherein the substituted aryl group is substituted with one more substituents, wherein each substituent is, independently, amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 5, —N(CH2CH2NH2)2, amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• each NPL group is, independently, —B(OR4)2 or
• —(NR3′)q1NPL—UNPL-LKNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are each, independently, hydrogen, alkyl, or alkoxy;
• R4 and R4′ are each, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more substitutents, wherein each substituent is, independently, alkyl, halo, or haloalkyl;
• each UNPL is, independently, absent or O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—NR3—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• each LKNPL is, independently, —(CH2)pNPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pNPL is, independently, an integer from 0 to 8;
• q1NPL and q2NPL are each, independently, 0, 1, or 2;
• each PL group is, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or —(NR5′)q1PL—UPL-LKPL—(NR5″)q2PL—V, wherein:
• R5, R5′, and R5″ are each, independently, hydrogen, alkyl, or alkoxy;
• each UPL is, independently, absent or O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—NR5—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt either of the two possible orientations;
• each Rc is, independently, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substituted by one or more substitutents, wherein each substituent is, independently, OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
• Rd and Re are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
• or Rd and Re together with the N atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;
• each LKPL is, independently, —(CH2)pPL— or C2-8 alkenylenyl, wherein each of the —(CH2)pNPL— and C2-8 alkenylenyl is optionally substituted with one or more substituents, wherein each substituent is, independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;
• each pPL is, independently, an integer from 0 to 8;
• q1PL and q2PL are each, independently, 0, 1, or 2;
• m13 is an integer from 1 to about 10;
• and
• m14 is an integer from 1 to about 10;
• w) Formula XXII:
• R1—[—X-A1-X—Z—Y-A2-Y—Z]m—R2 XXII
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is NR8, —NR8NR8—, C═O, or O;
• Y is NR8, —NR8NR8—, C═O, S, or O;
• R8 is hydrogen or alkyl;
• Z is C═O, C═S, O═S═O, —NR8NR8—, or —C(═O)C(═O)—;
• A1 and A2 are, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are, independently, optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• R1 is
• (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is —X-A1-X—R1, wherein A1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is —X-A1-X—Z—Y-A2-Y—R1, wherein A1 and A2 are as defined above, and each of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (iii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is —X-A′-X—R1, wherein A′ is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (iv) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is —X-A1-X—Z—Y-A′-Y—R1, wherein A1 is as defined above, A′ is aryl or heteroaryl, and each of A1 and A′ is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (v) —Z—Y-A1 and R2 is hydrogen, a polar group (PL), or a non-polar group (NPL), wherein A′ is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (vi) —Z—Y-A′, and R2 is —X-A″, wherein A′ and A″ are, independently, aryl or heteroaryl, and each of A and A″ is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (vii) R1 and R2 are, independently, a polar group (PL) or a non-polar group (NPL);
• or
• (viii) R1 and R2 together form a single bond;
• NPL is a nonpolar group independently selected from —B(OR4)2 and
• —(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• R4 and R4′ are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N—, and —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)pNPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pNPL is 0 to 8;
• q1NPL and q2NPL are, independently, 0, 1, or 2;
• PL is a polar group selected from halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR5′)q1PL—UPL—(CH2)pPL—NR5′)q2PL—V, wherein:
• R5, R5′, and R5″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, and —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)pPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pPL is 0 to 8;
• q1PL and q2PL are, independently, 0, 1, or 2;
• and
• m is 1 to about 20;
• x) Formula XXIIa, Formula XXIIb, or Formula XXIIc:
• R1—X-A1-X—Z—Y-A2-Y—R2 XXIIa
• R1—X-A1-X—Z—Y-A2-Y—Z—X-A1-X—R2 XXIIb
• R1—X-A1-X—Z—Y-A2-Y—Z—X-A1-X—Z—Y-A2-Y—R2 XXIIc
• wherein:
• X is NR8, —NR8NR8—, C═O, or O;
• Y is NR8, —NR8NR8—, C═O, S, or O;
• R8 is hydrogen or alkyl;
• Z is C═O, C═S, O═S═O, —NR8NR8—, or —C(═O)C(═O)—;
• A1 and A2 are, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are, independently, optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• R1 is hydrogen, a polar group (PL), or a non-polar group (NPL);
• R2 is R1;
• NPL is a nonpolar group —(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• R4 and R4′ are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N—, and —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)pNPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pNPL is 0 to 8;
• q1NPL and q2NPL are, independently, 0, 1, or 2;
• PL is a polar group selected from halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V,
• wherein:
• R5, R5′, and R5″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, and —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)pPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pPL is 0 to 8;
• and
• q1PL and q2PL are, independently, 0, 1, or 2;
• y) Formula XXIII:
• R1-[-A1-W-A2-W—]mR2 XXIII
• or a pharmaceutically acceptable salt thereof,
• wherein:
• A1 and A2 are, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein:
• (i) A1 and A2 are, independently, optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (ii) one of A1 or A2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• and the other of A1 or
• A2 is the group —C≡C(CH2)pC≡C—, wherein p is 0 to 8, and the —(CH2)p— alkylene chain is optionally substituted with one or more amino or hydroxyl groups;
• W is absent, or represents —CH2—, —CH2—CH2—, —CH═CH—, or —C≡C—;
• R1 is
• (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -A1-R1, wherein A1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -A1-W-A2-R1, wherein each of A1 and A2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (iii) A′-W— and R2 is -A1-W-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (iv) A′-W— and R2 is -A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) groups(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (iv) R1 and R2 together form a single bond;
• NPL is a nonpolar group independently selected from —B(OR4)2 or
• —(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4, wherein:
• R3, R3′, and R3″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from O, S, S(═O), S(═O)2, NR3, —(C═O)O—, —(C═O)—N═N—NR3—, —(C═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N— and —(C═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)pNPL— alkylene chain is optionally substituted with one or more alkyl, amino or hydroxyl groups, or the alkylene chain is unsaturated;
• pNPL is 0 to 8;
• q1NPL and q2NPL are, independently, 0 to 2;
• PL is a polar group selected from halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V,
• wherein:
• R5, R5′, and R5″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from O, S, S(═O), S(═O)2, NR5, —(C═O)O—, —(C═O)—N═N—NR5—, —(C═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, and —(C═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH2)pNH2, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)pPL— alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;
• pPL is 0 to 8;
• q1PL and q2PL are, independently, 0 to 2;
• and
• m is 1 to about 25;
• z) Formula XXIIIa:
• R1-A1-W-A2-W-A1-R2 XXIIIa
• wherein:
• A1 and A2 are, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein:
• (i) A1 and A2 are, independently, optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• or
• (ii) one of A1 or A2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• and the other of A1 or A2 is the group —C≡C(CH2)pC≡C—, wherein p is 0 to 8, and the —(CH2)p— alkylene chain is optionally substituted with one or more amino or hydroxyl groups;
• W is —C≡C—;
• R1 is hydrogen, a polar group (PL), a non-polar group (NPL), or —W-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• R2 is R1;
• NPL is a nonpolar group —(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4;
• R3, R3′, and R3″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from O, S, S(═O), S(═O)2, NR3, —(C═O)O—, —(C═O)—N═N—NR3—, —(C═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R3—O—, —R3—S—, —S—C═N—, and —(C═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the alkylene chain —(CH2)pNPL— is optionally substituted with one or more alkyl, amino or hydroxyl groups, or the alkylene chain is unsaturated;
• pNPL is 0 to 8;
• q1NPL and q2NPL are, independently, 0 to 2;
• PL is a polar group selected from halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V,
• wherein:
• R5, R5′, and R5″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from O, S, S(═O), S(═O)2, NR5, —(C═O)O—, —(C═O)—N═N—NR5—, —(C═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, and —(C═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH2)pNH2, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• the alkylene chain —(CH2)pPL— is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;
• pPL is 0 to 8;
• and
• q1PL and q2PL are, independently, 0 to 2;
• aa) Formula XXIV:
• R1—X-A1-X—Y-A2-Y—X-A1-X—R2 XXIV
• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is NR8, O, S, or —N(R8)N(R8)—;
• Y is C═O, C═S, or O═S═O;
• R8 is hydrogen or alkyl;
• A1 and A2 are, independently, optionally substituted arylene or optionally substituted heteroarylene, wherein A1 and A2 are, independently, optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);
• R1 is a polar group (PL) or a non-polar group (NPL);
• R2 is R1;
• NPL is a nonpolar group independently selected from —B(OR4)2 and —(NR3′)q1NPL—UNPL—(CH2)pNPL—(NR3″)q2NPL—R4′, wherein:
• R3, R3′, and R3″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• R4 and R4′ are, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;
• UNPL is absent or selected from O, S, S(═O), S(═O)2, NR3, —C(═O)—, —C(═O)—N═N—NR3—, —C(═O)—NR3—N═N—, —N═N—NR3—, —C(═N—N(R3)2)—, —C(═NR3)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R30—, —R3S—, —S—C═N—, and —C(═O)—NR3—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• the —(CH2)pNPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pNPL is 0 to 8;
• q1NPL and q2NPL are, independently, 0, 1, or 2;
• PL is a polar group selected from halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR5′)q1PL—UPL—(CH2)pPL—(NR5′)q2PL—V,
• wherein:
• R5, R5′, and R5″ are, independently, selected from hydrogen, alkyl, and alkoxy;
• UPL is absent or selected from O, S, S(═O), S(═O)2, NR5, —C(═O)—, —C(═O)—N═N—NR5—, —C(═O)—NR5—N═N—, —N═N—NR5—, —C(═N—N(R5)2)—, —C(═NR5)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)2O—, —R5O—, —R5S—, —S—C═N—, and —C(═O)—NR5—O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;
• V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH2)pNH2 wherein p is 1 to 4, —N(CH2CH2NH2)2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl;
• the —(CH2)pPL— alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated;
• pPL is 0 to 8;
• and
• q1PL and q2PL are, independently, 0, 1, or 2;
• or
• bb) Formula XXV:
• A-(B)n1-(D)m1-H XXV
• or a pharmaceutically acceptable salt thereof,
• wherein:
• A is the residue of a chain transfer agent;
• B is —[CH2—C(R11)(B11)], wherein B11 is —X11—Y11—Z11, wherein X11 is carbonyl (—C(═O)—) or optionally substituted C1-6 alkylene;
• or X11 is absent;
• Y11 is O, NH, or optionally substituted C1-6 alkylene;
• or Y11 is absent;
• Z11 is —Z11A—Z11B, wherein Z11A is alkylene, arylene, or heteroarylene, any of which is optionally substituted;
• or Z11A is absent;
• and Z11B is -guanidino, -amidino, —N(R3)(R4), or —N+(R3)(R4)(R5), wherein R3, R4, and R5 are, independently, hydrogen, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclic, or aralkyl;
• or
• Z11 is pyridinium
• or phosphonium
• wherein R81, R911, R921, and R931 are, independently, hydrogen or alkyl;
• R11 is hydrogen or C1-4 alkyl;
• D is —[CH2—C(R21)(D21)]-, wherein D21 is —X21—Y21—Z21, wherein
• X21 is carbonyl (—C(═O)—) or optionally substituted C1-6 alkylene;
• or X21 is absent;
• Y21 is O, NH, or optionally substituted C1-6 alkylene, or Y21 is absent;
• Z21 is alkyl, cycloalkyl, alkoxy, aryl, or aralkyl, any of which is optionally substituted;
• R21 is hydrogen or C1-4 alkyl;
• m1, the mole fraction of D, is about 0.1 to about 0.9;
• and
• n1, the mole fraction of B, is 1−m1;
• wherein the compound is a random copolymer of B and D, and
• wherein the copolymer has a degree of polymerization of about 5 to about 50.