COMPOSITIONS AND METHODS FOR THE TREATMENT OF BACTERIAL INFECTIONS

Background

The need for novel antibacterial treatments for bacterial infections is significant and especially critical in the medical field. Antibacterial resistance is a serious global healthcare threat. Polymyxins are a class of antibiotics that exhibit potent antibacterial activities against Gram-negative bacteria. However, the use of polymyxins as an antibiotic has been limited due to the associated toxicity and adverse effects (e.g., nephrotoxicity). Moreover, mcr- 1, a plasmid-borne gene conferring bacterial resistance to polymyxins, has a high potential for dissemination and further threatens the efficacy of this class of antibiotics.

Because of the shortcomings of existing antibacterial treatments, combined with the emergence of multidrug-resistant Gram-negative bacteria, there is a need in the art for improved antibacterial therapies having greater efficacy, bioavailability, and reduced toxicity.

Summary

The disclosure relates to compounds, compositions, and methods for inhibiting bacterial growth (e.g., Gram-negative bacterial growth) and for the treatment of bacterial infections (e.g., Gram-negative bacterial infections). In particular, such compounds contain dimers of cyclic heptapeptides. The dimers of the cyclic heptapeptides bind to lipopolysaccharides (LPS) in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization of the Gram-negtaive bacteria to other antibiotics.

In one aspect, the invention features a compound described by formula (I):

wherein L’ is a linker covalently attached to the linking nitrogen in each of M1 and M2; L is a remainder of L’; each of R ¹ , R ¹² , R’ ¹ , and R’ ¹² is, independently, a lipophilic moiety, a polar moiety, or H; each of R ^{1 1} , R ¹³ , R ¹⁴ , R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ is, independently, optionally substituted C1 -C5 alkamino, a polar moiety, a positively charged moiety, or H; each of R ¹⁵ and R’ ¹⁵ is, independently, a lipophilic moiety or a polar moiety; each of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R’ ² , R’ ³ , R’ ⁴ , R’ ⁵ , R’ ⁶ , R’ ⁷ , R’ ⁸ , R’ ⁹ , and R’ ¹⁰ is, independently a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or two R groups on the same or adjacent atoms join to form an optionally substituted 3-8 membered ring; each of R ¹⁷ and R ^'17 is, independently, H, C1 -C3 alkyl, or C2-C3 alkamino; each of a’, b’, c’, a, b, and c is, independently, 0 or 1 ; each of X ¹ , X ² , X ³ , X’ ¹ , X’ ² , and X’ ³ is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ , X ² , X ³ , X’ ¹ , X’ ² , and X’ ³ is a nitrogen atom, wherein if X ¹ is a nitrogen atom then R ³ is absent, if X’ ¹ is a nitrogen atom then R’ ³ is absent, if X ² is a nitrogen atom then R ⁵ is absent, if X’ ² is a nitrogen atom then R’ ⁵ is absent, if X ³ is a nitrogen atom then R ⁹ is absent, and if X’ ³ is a nitrogen atom then R’ ⁹ is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and X ¹ ; (ii) R ³ , R ⁴ , N ¹ , and X ¹ ; (iii) R ⁵ , R ⁶ , and X ² ; (iv) R ⁶ , R ⁷ , N ² , and X ² ; (v) R ⁸ , R ⁹ , and X ³ ; (vi) R ⁹ , R ¹⁰ , N ³ , and X ³ ; (vii) R’ ² , R’ ³ , and X’ ¹ ; (viii) R’ ³ , R’ ⁴ , N’ ¹ , and X’ ¹ ; (ix) R’ ⁵ , R’ ⁶ , and X’ ² ; (x) R’ ⁶ , R’ ⁷ , N’ ² , and X’ ² ; (xi) R’ ⁸ , R’ ⁹ , and X’ ³ ; or (xii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and X’ ³ .

In some embodiments, the compound is described by formula (1-1 ):

wherein each of b’, c’, b, and c is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ⁵ , R ⁶ , and C ² ; (ii) R ⁶ , R ⁷ , N ² , and C ² ; (iii) R ⁸ , R ⁹ , and C ³ ; (iv) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (v) R’ ⁵ , R’ ⁶ , and C’ ² ; (vi) R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² ; (vii) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (viii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ .

In some embodiments, the compound is described by formula (I-2):

wherein each of c’ and c is, independently, 0 or 1 ; each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ⁸ , R ⁹ , and C ³ ; (ii) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (iii) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (iv) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ .

In some embodiments, the compound is described by formula (1-3):

(1-3)

wherein each of c’ and c is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and C ¹ ; (ii) R ³ , R ⁴ , N ¹ , and C ¹ ; (iii) R ⁸ , R ⁹ , and C ³ ; (iv) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (v) R’ ² , R’ ³ , and C’ ¹ ; (vi) R’ ³ , R’ ⁴ , N’ ¹ , and C’ ¹ ; (vii) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (viii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ .

In some embodiments, the compound is described by formula (I-4):

(I-4)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and C ¹ ; (ii) R ³ , R ⁴ , N ¹ , and C ¹ ; (iii) R ⁵ , R ⁶ , and C ² ; (iv) R ⁶ , R ⁷ , N ² , and C ² ; (v) R’ ² , R’ ³ , and C’ ¹ ; (vi) R’ ³ , R’ ⁴ , N’ ¹ , and C’ ¹ ; (vii) R’ ⁵ , R’ ⁶ , and C’ ² ; or (viii) R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² . In some embodiments, the compound is described by formula (1-5):

(1-5)

wherein each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and C ¹ ; (ii) R ³ , R ⁴ , N ¹ , and C ¹ ; (iii) R’ ² , R’ ³ , and C’ ¹ ; or (iv) R’ ³ , R’ ⁴ , N’ ¹ , and C’ ¹ .

In some embodiments, each of R ¹⁷ and R ^'17 is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl.

In another aspect, the invention features a compound described by formula (II):

wherein L’ is a linker covalently attached to the linking nitrogen in each of M1 and M2; L is a remainder of L’; each of R ¹ , R ¹² , R’ ¹ , and R’ ¹² is, independently, a lipophilic moiety, a polar moiety, or H; each of R ^{1 1} , R ¹³ , R ¹⁴ , R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ is, independently, optionally substituted C1 -C5 alkamino, a polar moiety, a positively charged moiety, or H; each of R ¹⁵ and R’ ¹⁵ is, independently, a lipophilic moiety or a polar moiety; each of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R’ ² , R’ ³ , R’ ⁴ , R’ ⁵ , R’ ⁶ , R’ ⁷ , R’ ⁸ , R’ ⁹ , and R’ ¹⁰ is, independently a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or two R groups on the same or adjacent atoms join to form an optionally substituted 3-8 membered ring; each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; each of a’, b’, c’, a, b, and c is, independently, 0 or 1 ; and each of X ¹ , X ² , X ³ , X’ ¹ , X’ ² , and X’ ³ is, independently, a carbon atom or a nitrogen atom, wherein if X ¹ is a nitrogen atom then R ³ is absent, if X’ ¹ is a nitrogen atom then R’ ³ is absent, if X ² is a nitrogen atom then R ⁵ is absent, if X’ ² is a nitrogen atom then R’ ⁵ is absent, if X ³ is a nitrogen atom then R ⁹ is absent, and if X’ ³ is a nitrogen atom then R’ ⁹ is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and X ¹ ; (ii) R ³ , R ⁴ , N ¹ , and X ¹ ; (iii) R ⁵ , R ⁶ , and X ² ; (iv) R ⁶ , R ⁷ , N ² , and X ² ; (v) R ⁸ , R ⁹ , and X ³ ; (vi) R ⁹ , R ¹⁰ , N ³ , and X ³ ; (vii) R’ ² , R’ ³ , and X’ ¹ ; (viii) R’ ³ , R’ ⁴ , N’ ¹ , and X’ ¹ ; (ix) R’ ⁵ , R’ ⁶ , and X’ ² ; (x) R’ ⁶ , R’ ⁷ , N’ ² , and X’ ² ; (xi) R’ ⁸ , R’ ⁹ , and X’ ³ ; or (xii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and X’ ³ .

In some embodiments, the compound is described by formula (11-1 ):

(11-1 )

wherein each or R ¹⁷ and R’ ¹⁷ is, independently, C1 -C3 alkyl, or C2-C3 alkamino; and each of a’, b’, c’, a, b, and c is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and C ¹ ; (ii) R ³ , R ⁴ , N ¹ , and C ¹ ; (iii) R ⁵ , R ⁶ , and C ² ; (iv) R ⁶ , R ⁷ , N ² , and C ² ; (v) R ⁸ , R ⁹ , and C ³ ; (vi) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (vii) R’ ² , R’ ³ , and C’ ¹ ; (viii) R’ ³ , R’ ⁴ , N’ ¹ , and C’ ¹ ; (ix) R’ ⁵ , R’ ⁶ , and C’ ² ; (x) R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² ; (xi) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (xii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ . In some embodiments, the compound is described by formula (11-2):

(II-2)

wherein each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; wherein each or R ¹⁷ and R’ ¹⁷ is, independently, C1 -C3 alkyl, or C2-C3 alkamino; and each of c’ and c is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ⁵ , R ⁶ , and C ² ; (ii) R ⁶ , R ⁷ , N ² , and C ² ; (iii) R ⁸ , R ⁹ , and C ³ ; (iv) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (v) R’ ⁵ , R’ ⁶ , and C’ ² ; (vi) R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² ; (vii) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (viii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ .

In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl.

In another aspect, the invention features a compound described by formula (III):

wherein L’ is a linker covalently attached to the linking nitrogen in each of M1 and M2; L is a remainder of

L’; each of R ¹ , R ¹² , R’ ¹ , and R’ ¹² is, independently, a lipophilic moiety, a polar moiety, or H; each of R ^{1 1} ,

R ¹³ , R ¹⁴ , R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ is, independently, optionally substituted C1 -C5 alkamino, a polar moiety, a positively charged moiety, or H; each of R ¹⁵ and R’ ¹⁵ is, independently, a lipophilic moiety or a polar moiety; each of R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R’ ² , R’ ³ , R’ ⁴ , R’ ⁷ , R’ ⁸ , R’ ⁹ , and R’ ¹⁰ is, independently a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4- C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C1 5 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or two R groups on the same or adjacent atoms join to form an optionally substituted 3-8 membered ring; each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; each of R ¹⁷ and R ^’17 is, independently, H, C1 -C3 alkyl, or C2-C3 alkamino; each of c’ and c is, independently, 0 or 1 ; and each of X ¹ , X ³ , X’ ¹ , and X’ ³ is, independently, a carbon atom or a nitrogen atom, wherein if X ¹ is a nitrogen atom then R ³ is absent, if X’ ¹ is a nitrogen atom then R’ ³ is absent, if X ³ is a nitrogen atom then R ⁹ is absent, and if X’ ³ is a nitrogen atom then R’ ⁹ is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and X ¹ ; (ii) R ³ , R ⁴ , N ¹ , and X ¹ ; (iii) R ⁸ , R ⁹ , and X ³ ; (iv) R ⁹ , R ¹⁰ , N ³ , and X ³ ; (v) R’ ² , R’ ³ , and X’ ¹ ; (vi) R’ ³ , R’ ⁴ , N’ ¹ , and X’ ¹ ; (vii) R’ ⁸ , R’ ⁹ , and X’ ³ ; or (viii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and X’ ³ .

In some embodiments, the compound is described by formula (111-1 ):

(HI-1 )

wherein each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; each or R ¹⁷ and R’ ¹⁷ is, independently, H, C1 -C3 alkyl, or C2-C3 alkamino; and each of c’and c is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound includes at least one optionally substituted 3-8 membered ring formed by joining (i) R ² , R ³ , and C ¹ ; (ii) R ³ , R ⁴ , N ¹ , and C ¹ ; (iii) R ⁸ , R ⁹ , and C ³ ; (iv) R ⁹ , R ¹⁰ , N ³ , and C ³ ; (v) R’ ² , R’ ³ , and C’ ¹ ; (vi) R’ ³ , R’ ⁴ , N’ ¹ , and C’ ¹ ; (vii) R’ ⁸ , R’ ⁹ , and C’ ³ ; or (viii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and C’ ³ . In some embodiments, each of R ¹⁷ and R ¹⁷ is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl. In some embodiments, each of R ¹ , R ¹² , R’ ¹ , and R’ ¹² is a lipophilic moiety; each of R ^{1 1} , R ¹³ , R ¹⁴ ,

R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ is, independently, optionally substituted C1 -C5 alkamino, a polar moiety, or a positively charged moiety; and/or each of R ¹⁵ and R’ ¹⁵ is, independently, a polar moiety.

In some embodiments, each of R ¹ and R ¹² is a lipophilic moiety. In some embodiments, each of

R’ ¹ and R’ ¹² is a lipophilic moiety.

In some embodiments, each lipophilic moiety is, independently, optionally substituted C1 -C20 alkyl, optionally substituted C5-C15 aryl, optionally substituted C6-C35 alkaryl, or optionally C5-C10 substituted heteroaryl.

In some embodiments, each lipophilic moiety is, independently, C1 -C8 alkyl, methyl substituted C2-C4 alkyl, (C1 -C10)alkylene(C6)aryl, phenyl substituted (C1 -C10)alkylene(C6)aryl, or alkyl substituted C4-C9 heteroaryl.

In some embodiments, each lipophilic moiety is, independently, benzyl, isobutyl, sec-butyl, isopropyl, n-propyl, methyl, biphenylmethyl, n-octyl, or methyl substituted indolyl.

In some embodiments, each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH ₂ CH(CH ₃ ) ₂ , cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl. In some embodiments, each of R ¹ and R’ ¹ is, independently, benzyl or CH2CH(CH3)2.

In some embodiments, each of R ^{1 1} , R ¹³ , R ¹⁴ , R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ is independently optionally substituted C1 -C5 alkamino (e.g., CH2CH2NH2).

In some embodiments, each of R ¹⁵ and R’ ¹⁵ is a polar moiety. In some embodiments, each polar moiety includes a hydroxyl group, a carboxylic acid group, an ester group, or an amide group. In some embodiments, each polar moiety is hydroxyl substituted C1 -C4 alkyl (e.g., CHCH3OH).

In some embodiments, the compound is described by formula (IV):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2 _;

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (IV-1 ):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IV-2):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IV-3):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, each of R ² and R’ ² is independently H, C1 -C8 alkyl, or C2-C8 alkamino.

In some embodiments, the compound is described by formula (V):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2 _;

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R ⁶ and R’ ⁶ is independently H, C1 -C8 alkyl, or C2-C8 alkamino. In some embodiments, the compound is described by formula (VI):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2 _;

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (VI-1 ):

(VI-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2 _;

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (VI-2):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, each of R ⁸ and R’ ⁸ is independently H, C1 -C8 alkyl, or C2-C8 alkamino. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl. In some embodiments, each of R ¹ and R’ ¹ is, independently, benzyl or CH2CH(CH3)2. In some embodiments, the compound is described by formula (VII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (VI 1-1 ) :

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (VI 1-2) :

(VII-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl, and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (VII-3):

(VII-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4- C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C1 5 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl. In some embodiments, each of R ¹ and R’ ¹ is, independently, benzyl or CH2CH(CH3)2. In some embodiments, the compound is described by formula (VIII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl, each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl. In some embodiments, each of R ¹ and R’ ¹ is, independently, benzyl or CH2CH(CH3)2.

In some embodiments, the compound is described by formula (IX):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R’ ² , and R’ ⁶ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of X ¹ , X ² , X’ ¹ , and X’ ² is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ , X ² , X’ ¹ , and X’ ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-1 ):

(IX-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² , R ⁶ , R’ ² , and R’ ⁶ is,

independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-2):

(IX-2) wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-3):

(IX-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-4):

(IX-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² , R ⁶ , R’ ² , and R’ ⁶ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-5):

(IX-5)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (IX-6):

(IX-6)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (X):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R’ ² , and R’ ⁶ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (X-1 ):

(X-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (X-2):

(X-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (X-3):

(X-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (X-4):

(X-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (X-5):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XI):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-1 ) :

(XI-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-2):

(XI-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-3):

(XI-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-4):

(XI-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-5):

(XI-5)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XI-6):

(XI-6)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl.

In some embodiments, the compound is described by formula (XII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , R’ ⁶ , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of X ¹ , X ² , X ³ , X’ ¹ , X’ ² , and X’ ³ is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ , X ² , X ³ , X’ ¹ , X’ ² · and X’ ³ is a nitrogen atom, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XII-1 ):

(XII-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² , R ⁶ , R ⁸ , R’ ² , R’ ⁶ , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-2):

(XII-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ⁸ and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-3):

(XII-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-4):

(XII-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-5):

(XII-5)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ⁸ and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-6):

(XII-6) wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-7):

(XII-7)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl.

In some embodiments, the compound is described by formula (XII-8):

(XII-8)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² , R ⁶ , R ⁸ , R’ ² , R’ ⁶ , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII-9):

(XI 1-9)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl;or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XII-10):

(XII-10)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , R’ ⁶ , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XII 1-1 ) :

(XIII-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , R’ ⁶ , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIII-2):

(XIII-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XII 1-3) :

(XII 1-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIII-4):

(XIII-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII 1-5) :

(XII 1-5)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIII-6):

(XIII-6)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XII 1-7) :

(XII 1-7)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino,or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XII 1-8) :

(XII 1-8)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^’17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIII-9):

(XII 1-9)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl.

In some embodiments, the compound is described by formula (XIV):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁸ , R’ ² , and R’ ⁸ is, independently, H, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIV-1 ):

(XIV-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XIV-2):

(XIV-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIV-3):

(XIV-3)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIV-4):

(XIV-4)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R’ ¹⁶ and R ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5- C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl.

In some embodiments, the compound is described by formula (XV):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , and R’ ⁶ is,

independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of X ¹ , X ² , X ³ , X’ ¹ , and X’ ² is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ , X ² , X ³ , X’ ¹ , and X’ ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XV-1 ):

(XV-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ⁶ , R ⁸ , and R’ ⁶ is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XV-2):

(XV-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² , R ⁸ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVI):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , and R’ ⁶ is,

independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVI-1 ):

(XVI-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , R ⁸ , R’ ² , and R’ ⁶ is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4- C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁸ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVI 1-1 ) :

(XVI 1-1 ) wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁸ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, the compound is described by formula (XVIII):

(XVIII)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, and each of X ¹ , X ² , and X’ ¹ is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ , X ² , and X’ ¹ is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVIII-1 ):

(XVIII-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and R ⁶ is a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XVIII-2):

(XVIII-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XIX):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XIX-1 ):

(XIX-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² , R ⁶ , and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XX):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XX-1 ):

(XX-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁶ and R’ ¹⁶ is, independently, a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R’ ¹⁶ and R ¹⁶ is, independently, C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, the compound is described by formula (XXI):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXI-1 ):

(XXI-1 )

wherein each of R’ ¹ and R ¹ is, independently, benzyl or CH2CH(CH3)2; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XXII):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXIII):

(XXIII)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R ⁶ is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of X ¹ and X ² is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ and X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXII 1-1 )

(XXIII-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and R ⁶ is a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20

cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XXII 1-2) :

(XXIII-2)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; and R ² is a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXIV):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R ⁶ is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXIV-1 ):

(XXIV-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R ⁶ is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20

heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (XXV):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; R ² is a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20

cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and R ¹⁶ is a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4- C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXV-1 ):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; R ² is a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20

cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; and R ¹⁶ is a lipophilic moiety, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4- C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; or a pharmaceutically acceptable salt thereof.

In some embodiments, R ¹⁶ is C1 -C6 alkyl, benzyl, or phenethyl.

In some embodiments, the compound is described by formula (XXVI):

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; R ⁶ , R ⁷ , N ² , and C ² together form an optionally substituted 5-8 membered ring including optionally substituted C3- C7 heterocycloalkyl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted C2-C7 heteroaryl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S; R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² together form an optionally substituted 5-8 membered ring including optionally substituted C3-C7 heterocycloalkyl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted C2-C7 heteroaryl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S; and each of X ¹ and X’ ¹ is, independently, a carbon atom or a nitrogen atom, wherein at least one of X ¹ and X’ ¹ is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXVI-1 ):

(XXVI-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXVII):

(XXVII)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted thiophenylmethyl, or optionally substituted furanylmethyl; each of R ² and R’ ² is, independently, a positively charged moiety, a polar moiety, optionally substituted C1 -C5 alkamino, optionally substituted C1 -C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C15 aryl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C2-C15 heteroaryl, optionally substituted C6-C35 alkaryl, or optionally substituted C6-C35 heteroalkaryl; R ⁶ , R ⁷ , N ² , and C ² together form an optionally substituted 5-8 membered ring including optionally substituted C3- C7 heterocycloalkyl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted C2-C7 heteroaryl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S; R’ ⁶ , R’ ⁷ , N’ ² , and C’ ² together form an optionally substituted 5-8 membered ring including optionally substituted C3-C7 heterocycloalkyl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted C2-C7 heteroaryl including an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S; and each of R ¹⁷ and R ^'17 is, independently, C1 -C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXVII-1 ):

(XXVI 1-1 )

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (XXVIII):

(XXVIII)

wherein each of R ¹ and R’ ¹ is, independently, optionally substituted benzyl, CH2CH(CH3)2,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphtylmethyl, optionally substituted

thiophenylmethyl, or optionally substituted furanylmethyl; and each of R ¹⁷ and R ^'17 is, independently, C1 - C3 alkyl, or C2-C3 alkamino; or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), each of R ¹ and R’ ¹ is, independently, benzyl or CH2CH(CH3)2. In some embodiments, R ² is optionally substituted C1 -C5 alkamino (e.g., CH2NH2 or CH2CH2NH2). In some embodiments, R’ ² is optionally substituted C1 -C5 alkamino (e.g., CH2NH2 or CH2CH2NH2).

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ² is a polar moiety In some embodiments, R’ ² is a polar moiety. In some embodiments, the polar moiety includes a hydroxyl group, a carboxylic acid group, an ester group, or an amide group. In some embodiments, the polar moiety is hydroxyl substituted C1 -C4 alkyl (e.g.,

CHCH3OH or CH2OH).

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ² is H. In some embodiments, R’ ² is H. In some embodiments, R ⁶ is a polar moiety. In some embodiments, R’ ⁶ is a polar moiety. In some embodiments, the polar moiety includes a hydroxyl group, a carboxylic acid group, an ester group, or an amide group. In some embodiments, the polar moiety is hydroxyl substituted C1 -C4 alkyl (e.g., CHCH3OH or CH2OH).

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ⁶ is H. In some embodiments, R’ ⁶ is H. In some embodiments, R ⁸ is optionally substituted C1 -C5 alkamino (e.g., CH2NH2 or CH2CH2NH2). In some embodiments, R’ ⁸ is optionally substituted C1 -C5 alkamino (e.g., CH2NH2 or CH2CH2NH2).

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ⁸ is optionally substituted C5-C15 aryl. In some embodiments, R’ ⁸ is optionally substituted C5-C15 aryl. In some embodiments, the optionally substituted C5-C15 aryl is naphthyl.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ⁸ is H. In some embodiments, R’ ⁸ is H.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), R ¹⁶ is C1 -C6 alkyl, benzyl, or phenethyl. In some embodiments, R’ ¹⁶ is C1 - C6 alkyl, benzyl, or phenethyl.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), each of R ¹⁷ and R’ ¹⁷ is H. In some embodiments, each of R ¹⁷ and R’ ¹⁷ is methyl.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), L’, or L includes one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15

heteroarylene, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino, wherein R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), the backbone of L’ or L consists of one or more optionally substituted C1 - C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4- C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, optionally substituted C2-C15

heteroarylene, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino, wherein R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), L’ or L is oxo substituted. In some embodiments, the backbone of L’ or L includes no more than 250 atoms. In some embodiments, L’ or L is capable of forming an amide, a carbamate, a sulfonyl, or a urea linkage. In some embodiments, L’ or L is a bond.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), each L is described by formula (L-l):

|_ ^B - Q - |_ ^A

(L-l)

wherein L ^A is described by formula G ^A1 -(Z ^A1 )gi-(Y ^A1 )hi-(Z ^A2 )h-(Y ^A2 )ji -(Z ^A3 ) i -(Y ^A3 )ii -(Z ^A4 ) _mi -(Y ^A4 )ni-(Z ^A5 )oi- G ^A2 ; L ^B is described by formula G ^B1 -(Z ^B1 )g2-(Y ^B1 )h2-(Z ^B2 )i2-(Y ^B2 )j2-(Z ^B3 ) _k 2-(Y ^B3 )i2-(Z ^B4 )m2-(Y ^B4 )n2-(Z ^B5 )o2-G ^B2 ; G ^A1 is a bond attached to Q; G ^A2 is a bond attached to A1 or M1 if A1 is absent; G ^B1 is a bond attached to Q; G ^B2 is a bond attached to A2 or M2 if A2 is absent; each of Z ^A1 , Z ^A2 , Z ^A3 , Z ^A4 , Z ^A5 , Z ^B1 , Z ^B2 , Z ^B3 , Z ^B4 , and Z ^B5 is independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20

heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20

heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of Y ^A1 , Y ^A2 , Y ^A3 , Y ^A4 , Y ^B1 , Y ^B2 , Y ^B3 , and Y ^B4 is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, 12, m2, n2, and o2 is independently, 0 or 1 ; Q is a nitrogen atom, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4- C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene.

In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), L is

wherein each of R’ ¹⁸ and R ¹⁸ is, independently, H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C1 5 heteroaryl ; and wherein each q is, independently, an integer from 1 to 1 1 , inclusive. In some embodiments of any of the aspects described herein (e.g., in some embodiments of any one of formulas (l)-(XXVI II)), L is

In some embodiments, each of R’ ¹⁸ and R ¹⁸ is, independently, butyl, cyclohexyl, isopropyl, or isobutyl.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), or (VIII)), c’ and c are each 1 .

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), or (VIII)), if c’ and c are each 0, then L is

not -C(0)CH2NHCH ₂ C(0)-.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), or (VIII)), if c’ and c are each 0, and L

is -C(0)CH2NHCH ₂ C(0)-, then R ¹⁶ and R’ ¹⁶ are not both -(CH ₂ ) ₄ CH ₃ .

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), (VIII), (XI), (XI-4), (XI-5), (XI-6), (XVII), (XVII-1 ), (XX), (XX-1 ), (XXV), or (XXV-1 )), L is not -C(0)CH ₂ NHCH ₂ C(0)-.

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), (VIII), (XI), (XI-4), (XI-5), (XI-6), (XVII), (XVII-1 ), (XX), (XX-1 ), (XXV), or (XXV-1 )), if L is -C(0)CH ₂ NHCH ₂ C(0)-, then R ¹⁶ and R’ ¹⁶ are not -(CH ₂ ) ₄ CH ₃ .

In some embodiments of any of the aspects described herein (e.g., any one of formulas (I)- (XXVIII), such as any one of formulas (III), (111-1 ), (VIII), (XI), (XI-4), (XI-5), (XI-6), (XVII), (XVII-1 ), (XX), (XX-1 ), (XXV), or (XXV-1 )), if R ¹⁶ and R’ ¹⁶ are -(CH ₂ ) ₄ CH _3, then L is not -C(0)CH ₂ NHCH ₂ C(0)-. In some embodiments of any of the aspects described herein, if the compound is described by formula (XI-4) (e.g., the compound of any one of formulas any one of formulas (l)-(XXVIII) that is described by formula (XI-4)):

then the compound is not compound 51

Compound 51 .

In some embodiments of any of the aspects described herein, if the compound is described by formula (XI-4) (e.g., the compound of any one of formulas any one of formulas (l)-(XXVIII) that is described by formula (XI-4)), then L is not -C(0)CH2NHCH2C(0)-.

In some embodiments of any of the aspects described herein, if the compound is described by formula (XI-4) (e.g., the compound of any one of formulas any one of formulas (l)-(XXVIII) that is described by formula (XI-4)), and if R ¹⁶ and R’ ¹⁶ are each -(CH2)4CH3, then L is not - C(0)CH2NHCH ₂ C(0)-.

In some embodiments of any of the aspects described herein, if the compound is described by formula (XI-4) (e.g., the compound of any one of formulas any one of formulas (l)-(XXVIII) that is described by formula (XI-4)), then R ¹⁶ and R’ ¹⁶ are not -(CH2)4CH3.

In some embodiments of any of the aspects described herein, if the compound is described by formula (XI-4) (e.g., the compound of any one of formulas any one of formulas (l)-(XXVIII) that is described by formula (XI-4)), and if L not -C(0)CH2NHCH2C(0)-, then R ¹⁶ and R’ ¹⁶ are not -(CH2)4CH3. In another aspect, the invention features a compound of Table 1 , or a pharmaceutically acceptable salt thereof.

Table 1 .

In another aspect, the invention features a pharmaceutical composition including a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition further includes an antibacterial agent. In some embodiments, the antibacterial agent is selected from the group consisting of linezolid, tedizolid, posizolid, radezolid, retapamulin, valnemulin, tiamulin, azamulin, lefamulin, plazomicin, amikacin, gentamicin, gamithromycin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem,

imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, solithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin g, penicillin v, piperacillin, penicillin g, temocillin, ticarcillin, amoxicillin clavulanate, ampicillin/sulbactam,

piperacillin/tazobactam, ticarcillin/clavulanate, bacitracin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole (tmp-smx), sulfonamidochrysoidine, eravacycline, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol(bs), ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, thiamphenicol, tigecycline, tinidazole, and trimethoprim, prodrugs thereof, and pharmaceutically acceptable salts thereof. In some embodiments, a prodrug of tedizolid is tedizolid phosphate.

In some embodiments, the antibacterial agent is tedizolid, azithromycin, meropenem, amikacin, levofloxacin, rifampicin, linezolid, erythromycin, or solithromycin. In some embodiments, the antibacterial agent is tedizolid, azithromycin, meropenem, amikacin, or levofloxacin.

In another aspect, the invention features a method of protecting against or treating a bacterial infection in a subject including administering to said subject a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ).

In some embodiments, the method further includes administering to the subject an antibacterial agent.

In another aspect, the invention features a method of protecting against or treating a bacterial infection in a subject including administering to said subject (1 ) a compound of of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) and (2) an antibacterial agent.

In another aspect, the invention features a method of inducing immune cell activation of the immune response in a subject having a bacterial infection including administering to said subject a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (I)- (XXVIII) or a compound of Table 1 ).

In some embodiments, the method further includes administering to the subject an antibacterial agent.

In another aspect, the invention features a method of inducing immune cell activation of the immune response in a subject having a bacterial infection, said method including administering to said subject (1 ) a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) and (2) an antibacterial agent.

In some embodiments, the compound and the antibacterial agent are administered substantially simultaneously. In some embodiments, the compound and the antibacterial agent are administered separately. In some embodiments, the compound is administered first, followed by administering of the antibacterial agent alone. In other embodiments, the antibacterial agent is administered first, followed by administering of the compound alone. In some embodiments, the compound and the antibacterial agent are administered substantially simultaneously, followed by administering of the compound or the antibacterial agent alone. In some embodiments, the compound or the antibacterial agent is administered first, followed by administering of the compound and the antibacterial agent substantially simultaneously.

In some embodiments, administering the compound and the antibacterial agent together lowers the MIC of each of the compound and the antibacterial agent relative to the MIC of each of the compound and the antibacterial agent when each is used alone.

In some embodiments, the compound and/or the antibacterial agent is administered

intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, by inhalation, by injection, or by infusion.

In another aspect, the invention features a method of preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria, including contacting the bacteria or a site susceptible to bacterial growth with a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ).

In some embodiments, the method further includes contacting the bacteria or the site susceptible to bacterial growth with an antibacterial agent.

In another aspect, the invention features a method of preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria, including contacting the bacteria or a site susceptible to bacterial growth with (1 ) a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) and (2) an antibacterial agent.

In some embodiments, the antibacterial agent is selected from the group consisting of linezolid, tedizolid, posizolid, radezolid, retapamulin, valnemulin, tiamulin, azamulin, lefamulin, plazomicin, amikacin, gentamicin, gamithromycin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, solithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin g, penicillin v, piperacillin, penicillin g, temocillin, ticarcillin, amoxicillin clavulanate, ampicillin/sulbactam,

piperacillin/tazobactam, ticarcillin/clavulanate, bacitracin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole (tmp-smx), sulfonamidochrysoidine, eravacycline, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol(bs), ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, thiamphenicol, tigecycline, tinidazole, and trimethoprim, prodrugs thereof, and pharmaceutically acceptable salts thereof. In some embodiments, a prodrug of tedizolid is tedizolid phosphate.

In some embodiments, the antibacterial agent is tedizolid, azithromycin, meropenem, amikacin, levofloxacin, rifampicin, linezolid, erythromycin, or solithromycin. In some embodiments, the antibacterial agent is tedizolid, azithromycin, meropenem, amikacin, or levofloxacin.

In some embodiments, the bacterial infection is caused by Gram-negative bacteria.

In some embodiments, the bacterial infection is caused by a resistant strain of bacteria. In some embodiments, the resistant strain of bacteria possesses the mcr-1 gene, the mcr-2 gene, the mcr- 3 gene, the mcr- 4 gene, the mcr- 5 gene, the mcr- 6 gene, the mcr- 7 gene, the mcr- 8 gene, and/or a chromosomal mutation conferring polymyxin resistance. In some embodiments, the resistant strain of bacteria possesses the mcr-l gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 2 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 3 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 4 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 5 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 6 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 7 gene. In some embodiments, the resistant strain of bacteria possesses the mcr- 8 gene. In some embodiments, the resistant strain of bacteria possesses a chromosomal mutation conferring polymyxin resistance. In some embodiments, the resistant strain of bacteria is a resistant strain of E. coli.

In another aspect, the invention features a method of preventing lipopolysaccharides (LPS) in Gram-negative bacteria from activating an immune system in a subject, including administering to the subject a compound of any of any of the aspects described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ).

In some embodiments, the method prevents LPS from activating a macrophage. In some embodiments, the method prevents LPS-induced nitric oxide production from a macrophage.

Definitions

The term“cyclic heptapeptide” or“cycloheptapeptide,” as used herein, refers to certain compounds that bind to lipopolysaccharides (LPS) in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization to other antibiotics. Cyclic heptapeptides or cycloheptapeptides comprise seven natural or non-natural a-amino acid residues, such as D- or L-amino acid residues, in a closed ring. Generally, cyclic heptapeptides are formed by linking the a-carboxyl group of one amino acid to the a-amino group or the g-amino group of another amino acid and cyclizing. The cyclic heptapeptide comprises a heterocycle comprising carbon and nitrogen ring members, which may be substituted, for example, with amino acid side chains. One nitrogen from an a-amino group in the cyclic heptapeptide, however, is not a ring member and is branched from a ring member of the heterocycle. Thus, this nitrogen is directly attached to a ring member, such as a carbon atom (e.g., an a-carbon atom). This nitrogen atom serves as an attachment point for the cyclic heptapeptide to a linker and/or to a peptide (e.g., a peptide including 1 -5 amino acid residue(s)), and thus is referred to herein as a“linking nitrogen.” The linking nitrogen is directly attached to the ring of the cyclic heptapeptide and is not derived from a side chain, such as an ethylamine side chain. The linking nitrogens in a compound of, e.g., any one of formulas (l)-(XXVIII), are N ⁴ and N’ ⁴ .

In some embodiments, a peptide including one or more (e.g., 1 -5; 1 , 2, 3, 4, or 5) amino acid residues (e.g., natural and/or non-natural amino acid residues) may be covalently attached to a linking nitrogen (e.g., N ⁴ and/or N’ ⁴ , the nitrogen from an a-amino group) in the cyclic heptapeptide ring. Cyclic heptapeptides may be derived from polymyxins (e.g., naturally existing polymyxins and non-natural polymyxins) and/or octapeptins (e.g., naturally existing octapeptins and non-natural octapeptins).

Examples of naturally existing polymyxins include, but are not limited to, polymyxin Bi , polymyxin B2, polymyxin B3, polymyxin B4, polymyxin Bs, polymyxin Bb, polymyxin B1 -lie, polymyxin B2-lle, polymyxin Ci , polymyxin C2, polymyxin Si , polymyxin T 1, polymyxin T2, polymyxin A1 , polymyxin A2, polymyxin D1 , polymyxin D2, polymyxin E1 (colistin A), polymyxin E2 (colistin B), polymyxin E3, polymyxin E ₄ , polymyxin E7, polymyxin E1 -lie, polymyxin Ei-Val, polymyxin Ei-Nva, polymyxin E2-lle, polymyxin E2-Val, polymyxin E2-Nva, polymyxin Eb-lle, polymyxin Mi , and polymyxin M2. In other embodiments, a cyclic heptapeptide may be entirely synthetic and prepared by standard peptide methodology as known in the art.

The term“covalently attached” refers to two parts of a compound that are linked to each other by a covalent bond formed between two atoms in the two parts of the compound. For example, in the compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII)), when a’ is 0, L is covalently attached to N’ ⁴ , which means that when a’ is 0, an atom in L forms a covalent bond with N’ ⁴ in the compound. Similarly, when a’ is 1 and b’ is 0, L is covalently attached to N’ ¹ ; when b’ is 1 , and c’ is 0, L is covalently attached to N’ ² ; when c’ is 1 , L is covalently attached to N’ ³ ; when a is 0, L is covalently attached to N ⁴ ; when a is 1 and b is 0, L is covalently attached to N ¹ ; when b is 1 , and c is 0, L is covalently attached to N ² ; and when c is 1 , L is covalently attached to N ³ .

The terms“linker,”“L’,” and“L” as used herein, refer to a covalent linkage or connection between two or more components in a compound (e.g., between two cyclic heptapeptides in a compound described herein). In some embodiments, a compound described herein may contain a linker that has a bivalent structure (e.g., a bivalent linker). A bivalent linker has two arms, in which each arm is covalently linked to a component of the compound (e.g., a first arm conjugated to a first cyclic heptapeptide and a second arm conjugated to a second cyclic heptapeptide).

Molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and a maleimide group, a carboxylic acid group and an alkyne group, a carboxylic acid group and an amine group, a carboxylic acid group and a sulfonic acid group, an amine group and a maleimide group, an amine group and an alkyne group, or an amine group and a sulfonic acid group.

The first functional group may form a covalent linkage with a first component in the compound and the second functional group may form a covalent linkage with the second component in the compound. In some embodiments of a bivalent linker, the two arms of a linker may contain two dicarboxylic acids, in which the first carboxylic acid may form a covalent linkage with the first cyclic heptapeptide in the compound and the second carboxylic acid may form a covalent linkage with the second cyclic heptapeptide in the compound. Examples of dicarboxylic acids are described further herein. In some embodiments, a molecule containing one or more maleimide groups may be used as a linker, in which the maleimide group may form a carbon-sulfur linkage with a cysteine in a component in the compound. In some embodiments, a molecule containing one or more alkyne groups may be used as a linker, in which the alkyne group may form a 1 ,2,3-triazole linkage with an azide in a component in the compound. In some embodiments, a molecule containing one or more azide groups may be used as a linker, in which the azide group may form a 1 ,2,3-triazole linkage with an alkyne in a component in the compound. In some embodiments, a molecule containing one or more bis-sulfone groups may be used as a linker, in which the bis-sulfone group may form a linkage with an amine group a component in the compound. In some embodiments, a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the compound. In some embodiments, a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the compound. In some embodiments, a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the compound.

In some embodiments, a linker provides space, rigidity, and/or flexibility between the two or more components. In some embodiments, a linker may be a bond, e.g., a covalent bond. The term“bond” refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 250 atoms. In some embodiments, a linker includes no more than 250 non-hydrogen atoms. In some embodiments, the backbone of a linker includes no more than 250 atoms. The“backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of a compound to another part of the compound (e.g., the shortest path linking a first cyclic heptapeptide and a second cyclic heptapeptide). The atoms in the backbone of the linker are directly involved in linking one part of a compound to another part of the compound (e.g., linking a first cyclic heptapeptide and a second cyclic heptapeptide). For examples, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.

In some embodiments, a linker may comprise a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may comprise one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, a linker may be a residue of an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, 1 -2 amino acid, or 1 amino acid sequence). In some embodiments, a linker may comprise one or more, e.g., 1 -100, 1 -50, 1 -25, 1 -10, 1 -5, or 1 -3, optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted

heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine),

O, S, NR' (R' is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl, or optionally substituted heteroaryl),

P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino. For example, a linker may comprise one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20

heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2- C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.

The term“lipophilic moiety,” as used herein, refers to a portion, substituent, or functional group of a compound that is, in general, hydrophobic and non-polar. A moiety is lipophilic if it has a hydrophobicity determined using a cLogP value of greater than 0, such as about 0.25 or greater, about 0.5 or greater, about 1 or greater, about 2 or greater, 0.25-5, 0.5-4 or 2-3. As used herein, the term“cLogP” refers to the calculated partition coefficient of a molecule or portion of a molecule. The partition coefficient is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium (e.g., octanol and water) and measures the hydrophobicity or hydrophilicity of a compound. A variety of methods are available in the art for determining cLogP. For example, in some embodiments, cLogP can be determined using quantitative structure-property relationship algorithims known in the art (e.g., using fragment based prediction methods that predict the logP of a compound by determining the sum of its non-overlapping molecular fragments). Several algorithims for calculating cLogP are known in the art including those used by molecular editing software such as CHEMDRAW® Pro, Version 12.0.2.1092 (Camrbridgesoft, Cambridge, MA) and MARVINSKETCH® (ChemAxon, Budapest, Hungary). A moiety is considered lipophilic if it has a cLogP value described above in at least one of the above methods. A lipophilic moiety having the stated cLogP value will be considered lipophilic, even though it may have a positive charge or a polar substituent.

In some embodiments, a lipophilic moiety contains entirely hydrocarbons. In some embodiments, a lipophilic moiety may contain one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms independently selected from N, O, and S (e.g., an indolyl), or one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo groups, which, due to the structure of the moiety and/or small differences in electronegativity between the heteroatoms or halo groups and the hydrocarbons, do not induce significant chemical polarity into the lipophilic moiety. Thus, in some embodiments, a lipophilic moiety having, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms and/or, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo atoms may still be considered non-polar. In some embodiments, a lipophilic moiety may be optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, wherein the optional substituents are also lipophilic (such as alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heteroaryl) or are not lipophilic but do not change the overall lipophilic character of the moiety, i.e. , the moiety has a cLogP value of greater than 0. For example, octanol contains a polar group, OH, but is still a lipophilic moiety. In some embodiments, a lipophilic moiety may be benzyl, isobutyl, sec-butyl, isopropyl, n-propyl, methyl, biphenylmethyl, n-octyl, or substituted indolyl (e.g., alkyl substituted indolyl). In some embodiments, a lipophilic moiety may be the side chain of a hydrophobic amino acid residue, e.g., leucine, isoleucine, alanine, phenylalanine, valine, and proline, or groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pyrrolidinyl. In some embodiments, lipophilic moieties of the compounds described herein may interact with the hydrophobic portions of lipid A (e.g., fatty acid side chains of lipid A) when the compounds bind to the membrane of bacterial cells (e.g., Gram-negative bacterial cells). Due to its position on the cyclic heptapeptide, one or more of R ¹ , R ¹² , R ¹⁵ , R’ ¹ , R’ ¹² , and R’ ¹⁵ may be a lipophilic moiety.

The term“positively charged moiety,” as used herein, refers to a portion, substituent, or functional group of a compound that contains at least one positive charge. In some embodiments, a positively charged moiety contains one or more (e.g., 1 -4, 1 -3, 1 , 2, 3, or 4) heteroatoms independently selected from N, O, and S, for example. In some embodiments, a positively charged moiety may possess a pH- dependent positive charge, e.g., the moiety becomes a positively charged moiety at physiological pH (e.g., pH 7), such as -NH ₃ ⁺ , -(CH ₂ )4NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₂ NH ₂ , -CH ₂ NH ₂ , -(CH ₂ ) ₄ N(CH ₃ ) ₂ ,

-(CH ₂ ) ₃ N(CH ₃ ) ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₃ ) _2, -(CH ₂ ) ₄ NH(CH ₃ ), -(CH ₂ ) ₃ NH(CH ₃ ),-(CH ₂ ) ₂ NH(CH ₃ ), and -CH ₂ NH(CH ₃ ). In some embodiments, a positively charged moiety may be optionally substituted alkamino, optionally substituted heteroalkyl (e.g., optionally substituted heteroalkyl containing 1 -3 nitrogens; -(CH ₂ ) ₄ -guanidinium, -(CH ₂ ) ₃ -guanidinium, -(CH ₂ ) ₂ -guanidinium, -CH ₂ -guanidinium), optionally substituted heterocycloalkyl (e.g., optionally substituted heterocycloalkyl containing 1 -3 nitrogens), or optionally substituted heteroaryl (e.g., optionally substituted heteroaryl containing 1 -3

nitrogens; -(CH ₂ ) ₄ -imidazole, -(CH ₂ ) ₃ -imidazole, -(CH ₂ ) ₂ -imidazole, -CH ₂ -imidazole). In some embodiments, a positively charged moiety may be pH independent such

as -CH ₂ N(CH ₃ )3 ⁺ , -(CH ₂ )2N(CH ₃ )3 ⁺ , -(CH ₂ ) ₃ N(CH ₃ ) ₃ ⁺ , or -(CH ₂ ) ₄ N(CH ₃ ) ₃ ⁺ . Thus, substituents may transform an otherwise lipophilic moiety such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, to a positively charged moiety with the addition of a substituent that imparts a positive charge or a pH dependent positive charge, such as guanidinyl, -NH ₃ ⁺ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , and/or -N(CH ₃ ) ₃ ⁺ . In some embodiments, a positively charged moiety may be the side chain of an amino acid residue (e.g., a natural or non-natural amino acid residue, such as a D- or L-amino acid residue, that is positively charged at physiological pH (e.g., pH 7), such as the side chain of a basic amino acid residue (e.g., arginine, lysine, histidine, ornithine, diaminobuteric acid, or diaminopropionic acid). In some embodiments, positively charged moieties of the compounds described herein interact with the negatively charged portions of lipid A (e.g., phosphates of lipid A) when the compounds bind to the membrane of bacterial cells (e.g., Gram-negative bacterial cells). Due to its position on the cyclic heptapeptide, one or more of R ^{1 1} , R ¹³ , R ¹⁴ , R’ ^{1 1} , R’ ¹³ , and R’ ¹⁴ may be a positively charged moiety.

The term“polar moiety,” as used herein, refers to a portion, substituent, or functional group of a compound that has a chemical polarity induced by atoms with different electronegativity. The polarity of a polar moiety is dependent on the electronegativity between atoms within the moiety and the asymmetry of the structure of the moiety. In some embodiments, a polar moiety contains one or more (e.g., 1 -4, 1 -3, 1 , 2, 3, or 4) heteroatoms independently selected from N, O, and S, which may induce chemical polarity in the moiety by having different electronegativity from carbon and hydrogen. In general, a polar moiety interacts with other polar or charged molecules. In some embodiments, a polar moiety may be optionally substituted alkamino, optionally substituted heteroalkyl (e.g., N- and/or O-containing

heteroalkyl; -(CH ₂ )4-carboxylic acid, -(CH ₂ ) ₃ -carboxylic acid, -(CH ₂ ) ₂ -carboxylic acid, -CH ₂ -carboxylic acid), optionally substituted heterocycloalkyl (e.g., N- and/or O-containing heterocycloalkyl), or optionally substituted heteroaryl (e.g., N- and/or O-containing heteroaryl). In some embodiments, a polar moiety may -CH(CH ₃₎ OH, -CH ₂ OH, -(CH ₂ ) ₂ CONH ₂ , -CH ₂ CONH ₂ , -CH ₂ COOH, or -(CH ₂ ) ₂ COOH. Thus, substituents may transform an otherwise lipophilic moiety such optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, to a polar moiety with the addition of a substituent that imparts polarity, such as -OH, -COOH, -COOR, or -CONR ₂ , in which R is H or C1 -C4 alkyl. In some embodiments, a polar moiety may be the side chain or a polar or charged amino acid residue (e.g., threonine, serine, glutamine, asparagine, arginine, lysine histidine, aspartic acid, and glutamic acid). In some embodiments, a polar moiety is the side chain of threonine. In some embodiments, polar moieties of the compounds described herein interact with the negatively charged portions of lipid A (e.g., phosphates of lipid A) when the compounds bind to the membrane of bacterial cells (e.g., Gram-negative bacterial cells). Due to its position on the cyclic heptapeptide, one or more of R ¹ , R ¹² , R ¹⁵ , R’ ¹ , R’ ¹² , and R’ ¹⁵ may be a polar moiety. The term“polymyxin core,” as used herein means a cyclic heptapeptide having the structure:

wherein Q ¹ , Q ² and Q ³ are as follows:

wherein“D-Nle” is D-norleucine,“L-Abu” is L-2-aminobutyric acid, and“ ' ^lllll ™'” refers to the point of attachment of the polymyxin core to the remainder of the compounds disclosed herein, including the second polymyxin core (e.g., via a linker) of the compounds disclosed herein.

The terms“alkyl,”“alkenyl,” and“alkynyl,” as used herein, include straight-chain and branched- chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. When the alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an“alkenyl” or“alkynyl” group respectively. The monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, the alkyl or heteroalkyl group may contain, e.g., 1 -20. 1 -18, 1 -16, 1 -14, 1 -12, 1 -10, 1 -8, 1 - 6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C16, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.

The term“cycloalkyl,” as used herein, represents a monovalent saturated or unsaturated non aromatic cyclic alkyl group. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a“cycloalkenyl” group. A cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4- C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl).

Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a“cycloalkynyl” group. A cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C1 1 , C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term“cycloalkyl” also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1 ]heptyl and adamantane. The term“cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro cyclic compounds.

The term“aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene. In some embodiments, a ring system contains 5-15 ring member atoms or 5-10 ring member atoms. An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term “heteroaryl” also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1 - 4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from O, S and N. A heteroaryl group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9. C2-C10, C2-C1 1 , C2-C12, C2-C13, C2-C14, or C2-C15 heteroaryl). The inclusion of a heteroatom permits inclusion of 5-membered rings to be considered aromatic as well as 6-membered rings. Thus, typical heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl. Because tautomers are possible, a group such as phthalimido is also considered heteroaryl.

In some embodiments, the aryl or heteroaryl group is a 5- or 6-membered aromatic rings system optionally containing 1 -2 nitrogen atoms. In some embodiments, the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.

The term“alkaryl,” refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl is attached to the compound. In some embodiments, an alkaryl is CO COS alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl. Examples of alkaryls include, but are not limited to, (C1 - C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl. In some embodiments, an alkaryl is benzyl or phenethyl. In a heteroalkaryl, one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group. In an optionally substituted alkaryl, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group.

The term“amino,” as used herein, represents -N(R ^X )2 or -N ⁺ (R ^X )3, where each R ^x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R ^x combine to form a

heterocycloalkyl. In some embodiment, the amino group is -NH2.

The term“alkamino,” as used herein, refers to an amino group, described herein, that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene group (e.g., C2- C5 alkenylene). In general, if a compound is attached to an alkamino group, the alkylene, alkenylene, or alkynylene portion of the alkamino is attached to the compound. The amino portion of an alkamino refers to -N(R ^x ) ₂ or -N ⁺ (R ^x ) ₃ , where each R ^x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R ^x combine to form a heterocycloalkyl. In some embodiment, the amino portion of an alkamino is -NH2. An example of an alkamino group is C1 -C5 alkamino, e.g., C2 alkamino (e.g., CH2CH2NH2 or CH2CH2N(CH3)2). In a heteroalkamino group, one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamino group. In some embodiments, an alkamino group may be optionally substituted. In a substituted alkamino group, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamino group and/or may be present on the amino portion of the alkamino group.

The term“alkamide,” as used herein, refers to an amide group that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkenylene) group. In general, if a compound is attached to an alkamide group, the alkylene, alkenylene, or alkynylene portion of the alkamide is attached to the compound. The amide portion of an alkamide refers to -C(0)-N(R ^X )2, where each R ^x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R ^x combine to form a heterocycloalkyl. In some embodiment, the amide portion of an alkamide is -C(0)NH2. An alkamide group may be -(CH2)2-C(0)NH2 or -CH2-C(0)NH2. In a heteroalkamide group, one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group. In some embodiments, an alkamide group may be optionally substituted. In a substituted alkamide group, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamide group and/or may be present on the amide portion of the alkamide group.

The terms“alkylene,”“alkenylene,” and“alkynylene,” as used herein, refer to divalent groups having a specified size. In some embodiments, an alkylene may contain, e.g., 1 -20, 1 -18, 1 -16, 1 -14, 1 - 12, 1 -10, 1 -8, 1 -6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C16, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2). In some embodiments, an alkenylene or alkynylene may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2- C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group. For example, two cyclic heptapeptides may be attached to each other by way of a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof. Each of the alkylene, alkenylene, and/or alkynylene groups in the linker is considered divalent with respect to the two attachments on either end of alkylene, alkenylene, and/or alkynylene group. For example, if a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene is considered divalent with respect to its attachments to the two alkylenes at the ends of the linker. The optional substituents on the alkenylene are not included in the divalency of the alkenylene. The divalent nature of an alkylene, alkenylene, or alkynylene group (e.g., an alkylene, alkenylene, or alkynylene group in a linker) refers to both of the ends of the group and does not include optional substituents that may be present in an alkylene, alkenylene, or alkynylene group. Because they are divalent, they can link together multiple (e.g., two) parts of a compound, e.g., a first cyclic

heptapeptide and a second cyclic heptapeptide. Alkylene, alkenylene, and/or alkynylene groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. For example, C=0 is a C1 alkylene that is substituted by an oxo (=0). For

example, -FICR-CºC- may be considered as an optionally substituted alkynylene and is considered a divalent group even though it has an optional substituent, R. Fleteroalkylene, heteroalkenylene, and/or heteroalkynylene groups refer to alkylene, alkenylene, and/or alkynylene groups including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. For example, a polyethylene glycol (PEG) polymer or a PEG unit -(CFl2)2O- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms.

The term“cycloalkylene,” as used herein, refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound. A cycloalkylene group may include saturated or unsaturated non-aromatic cyclic groups. A cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene). When the cycloalkylene group includes at least one carbon-carbon double bond, the cycloalkylene group can be referred to as a“cycloalkenylene” group. A cycloalkenylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkenylene (e.g., a C4-C7, C4-C8, C4-C9. C4-C10, C4-C1 1 , C4- C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene). When the cycloalkylene group includes at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a“cycloalkynylene” group. A cycloalkynylene may have, e.g., four to twenty carbons in the cyclic portion of the

cycloalkynylene (e.g., a C4-C7, C4-C8, C4-C9. C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C8-C20 cycloalkynylene). A cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene. A tetrahydrofuran may be considered as a heterocycloalkylene.

The term“arylene,” as used herein, refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound. An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9. C5-C10, C5-C1 1 , C5-C12, C5-C13, C5- C14, or C5-C15 arylene). An arylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heteroarylene refers to an aromatic group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. A heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2- C9. C2-C10, C2-C1 1 , C2-C12, C2-C13, C2-C14, or C2-C15 heteroarylene).

The term“optionally substituted,” as used herein, refers to having 0, 1 , or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above. Substituents include, but are not limited to, F, Cl, methyl, phenyl, benzyl, OR, NR ₂ , SR, SOR, S0 ₂ R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, S1R3, and NO2, wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or two of the optional substituents on the same atom can be joined to form an optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.

An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent. For example, an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH. As another example, a substituent on a heteroalkyl or its divalent counterpart, heteroalkylene, may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. For example, the hydrogen atom in the

group -R-NH-R- may be substituted with an alkamide substituent, e.g., -R-N[(CH2C(0)N(CH3)2]-R.

Generally, an optional substituent is a noninterfering substituent. A“noninterfering substituent” refers to a substituent that leaves the ability of the compounds described herein (e.g., compounds of any one of formulas (l)-(XXVIII)) to either bind to lipopolysaccharides (LPS) or to kill or inhibit the growth of Gram negative bacteria qualitatively intact. Thus, in some embodiments, the substituent may alter the degree of such activity. However, as long as the compound retains the ability to bind to LPS and/or to kill or inhibit the growth of Gram-negative bacteria, the substituent will be classified as“noninterfering.” In some aspects, a noninterfering substituent leaves the ability of a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II)) to kill or inhibit the growth of Gram-negative bacteria qualitatively intact as determined by measuring the minimum inhibitory concentration (MIC) against at least one Gram negative bacteria as known in the art, wherein the MIC is 128 pg/mL or less (e.g., 1 10 pg/mL or less, 100 pg/mL or less, 90 pg/mL or less, 80 pg/mL or less, 70 pg/mL or less, 60 pg/mL or less, 50 pg/mL or less, 40 pg/mL or less, 30 pg/mL or less, 20 pg/mL or less, or 10 pg/mL or less). In some aspects, a noninterfering substituent leaves the ability of a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II)) to bind to lipopolysaccharides (LPS) from the cell membrane of Gram-negative bacteria qualitatively intact, as determined by an LPS binding assay, wherein the compound shows a value of about 10% or greater displacement of a fluorogenic substrate at 250 pM of the compound.

The term“hetero,” when used to describe a chemical group or moiety, refers to having at least one heteroatom that is not a carbon or a hydrogen, e.g., N, O, and S. Any one of the groups or moieties described above may be referred to as hetero if it contains at least one heteroatom. For example, a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group that has one or more heteroatoms independently selected from, e.g., N, O, and S. An example of a heterocycloalkenyl group is a maleimido. For example, a heteroaryl group refers to an aromatic group that has one or more heteroatoms independently selected from, e.g., N, O, and S. One or more heteroatoms may also be included in a substituent that replaced a hydrogen atom in a group or moiety as described herein. For example, in an optionally substituted heteroaryl group, if one of the hydrogen atoms in the heteroaryl group is replaced with a substituent (e.g., methyl), the substituent may also contain one or more heteroatoms (e.g., methanol).

O

The term“acyl,” as used herein, refers to a group having the structure: ^A _R , wherein R ^z is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,

heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkamino.

The term“halo” or“halogen,” as used herein, refers to any halogen atom, e.g., F, Cl, Br, or I. Any one of the groups or moieties described herein may be referred to as a“halo moiety” if it contains at least one halogen atom, such as haloalkyl.

The term“hydroxyl,” as used herein, represents an -OH group.

The term“oxo,” as used herein, refers to a substituent having the structure =0, where there is a double bond between an atom and an oxygen atom.

0

The term“carbonyl,” as used herein, refers to a group having the structure:

S

The term“thiocarbonyl,” as used herein, refers to a group having the structure: O

The term“phosphate,” as used herein, represents the group having the structure: Cr

O

I I <,

-p-o-1

The term“phosphoryl,” as used herein, represents the group having the structure: OR or

The term“sulfonyl,” as used herein, represents the group having the structure:

NR

The term“imino,” as used herein, represents the group having the structure ,:. YV , wherein R is an optional substituent.

The term“/V-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 5th Edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference. /V-protecting groups include, e.g., acyl, aryloyl, and carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acid residues such as alanine, leucine, phenylalanine;

sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl ; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3.4.5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-

3.5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl (BOC),

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; alkaryl groups such as benzyl, triphenylmethyl, and benzyloxymethyl ; and silyl groups such as trimethylsilyl.

The term“amino acid,” as used herein, means naturally occurring amino acids and non-naturally occurring amino acids.

The term“naturally occurring amino acids,” as used herein, means amino acids including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. The term“non-naturally occurring amino acid,” as used herein, means an alpha amino acid that is not naturally produced or found in a mammal. Examples of non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N-methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine;

diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxy piperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutanoic acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids are a-aminobutyric acid, a-amino-a- methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L- cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L- N-methylphenylalanine, L-N-methylproline, L-N-methylserine, L-N-methyltryptophan, D-ornithine, L-N- methylethylglycine, L-norleucine, a-methyl-aminoisobutyrate, a-methylcyclohexylalanine, D-a- methylalanine, D-a-methylarginine, D-a-methylasparagine, D-a-methylaspartate, D-a-methylcysteine, D- a-methylglutamine, D-a-methylhistidine, D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine, D-a- methylmethionine, D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline, D-a-methylserine, D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D- N-methylalanine, D-N-methylarginine, D-N-methylasparagine, D-N-methylaspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate, D-N-methylhistidine, D-N-methylisoleucine, D-N- methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N- methylaminoisobutyrate, N-(1 -methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D- N-methyltyrosine, D-N-methylvaline, g-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L- homophenylalanine, L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine, L-a-methylhistidine, L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine, L-a-methylnorvaline, L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan, L-a-methylvaline, N-(N-(2,2- diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl-ethylamino) cyclopropane, 4- hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L- citrulline, a-cyclohexylglycine, L-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4- carboxylic acid, L-homotyrosine, L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O- methyl-L-tyrosine, O-glycan-serine, meta-tyrosine, nor-tyrosine, L-N,N',N"-trimethyllysine, homolysine, norlysine, N-glycan asparagine, 7-hydroxy-1 ,2,3,4-tetrahydro-4-fluorophenylalanine, 4- methylphenylalanine, bis-(2-picolyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2- aminobenzoic acid, 3-amino-2-naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1 - carboxylic acid, D-tetrahydroisoquinoline-1 -carboxylic acid, 1 -amino-cyclohexane acetic acid, D/L- allylglycine, 4-aminobenzoic acid, 1 -amino-cyclobutane carboxylic acid, 2 or 3 or 4-aminocyclohexane carboxylic acid, 1 -amino-1 -cyclopentane carboxylic acid, 1 -aminoindane-1 -carboxylic acid, 4-amino- pyrrolidine-2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, azetidine-3-carboxylic acid, 4-benzyl- pyrolidine-2-carboxylic acid, tert-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropyl alanine, 5,5- dimethyl-1 ,3-thiazolidine-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy-pyrrolidine-2- carboxylic acid, (2R,5S)and(2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1 -benzoyl- pyrrolidine-2-carboxylic acid, t-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, 1 - aminomethyl-cyclohexane-acetic acid, 3,5-bis-(2-amino)ethoxy-benzoic acid, 3,5-diamino-benzoic acid, 2- methylamino-benzoic acid, N-methylanthranylic acid, L-N-methylalanine, L-N-methylarginine, L-N- methylasparagine, L-N-methylaspartic acid, L-N-methylcysteine, L-N-methylglutamine, L-N- methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine, L-N-methyllysine, L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine, L-N-methyltyrosine, L-N-methylvaline, L-N-methyl-t- butylglycine, L-norvaline, a-methyl-y-aminobutyrate, 4,4'-biphenylalanine, a-methylcylcopentylalanine, a- methyl-a-napthylalanine, a-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3- aminopropyl)glycine, N-amino-a-methylbutyrate, a-napthylalanine, N-benzylglycine, N-(2- carbamylethyl)glycine, N-(carbamylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cylcododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cycloundecylglycine, N-(2,2- diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine, N-(1 - hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine, N-(3-indolylyethyl)glycine, N- methyl-y-aminobutyrate, D-N-methylmethionine, N-methylcyclopentylalanine, D-N-methylphenylalanine, D-N-methylproline, D-N-methylthreonine, N-(1 -methylethyl)glycine, N-methyl-napthylalanine, N- methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-a-methylalanine, L-a-methylasparagine, L-a-methyl-t-butylglycine, L-methylethylglycine, L-a-methylglutamate, L-a- methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a- methylornithine, L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl- homophenylalanine, N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid, D- pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, a-carboxyglutamate, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine (dimethyl), L-2-naphthylalanine, L- dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N- cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-p-homolysine, O-glycan-threoine, Ortho-tyrosine, L-N.N'-dimethyllysine, L-homoarginine, neotryptophan, 3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4- chlorophenylalanine, L-1 ,2,3,4-tetrahydronorharman-3-carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1 ,2,3,4-tetrahydronorharman-3-carboxylic acid, 3- aminobenzoic acid, 3-amino-1 -carboxymethyl-pyridin-2-one, 1 -amino-1 -cyclohexane carboxylic acid, 2- aminocyclopentane carboxylic acid, 1 -amino-1 -cyclopropane carboxylic acid, 2-aminoindane-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4-carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)- alanine, neopentylglycine, 2-carboxymethyl piperidine, b-cyclobutyl alanine, allylglycine, diaminopropionic acid, homo-cyclohexyl alanine, (2S,4R)- 4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2- carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, nipecotic acid, (2S,4R)and (2S,4S)-4-(4-phenylbenzyl) pyrrolidine-2-carboxylic acid, (3S)-1 -pyrrolidine-3-carboxylic acid, (2S,4S)-4-tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, t-butylglycine, N,N- bis(3-aminopropyl)glycine, 1 -amino-cyclohexane-1 -carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.

It is specifically contemplated that in some embodiments, a terminal amino group in the amino acid may be an amido group or a carbamate group.

The term“antibacterial agent,” as used herein, refers to an agent that is used in addition to one or more of the compounds described herein (e.g., compounds of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) in methods of treating a bacterial infection (e.g., Gram-negative bacterial infection) and/or preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria. An antibacterial agent may be an agent that prevents the entrance of a bacteria (e.g., a Gram-negative bacteria) into a subject’s cells, tissues, or organs, inhibits the growth of a bacteria (e.g., a Gram-negative bacteria) in a subject’s cells, tissues, or organs, and/or kills a bacteria (e.g., a Gram-negative bacteria) that is inside a subject’s cells, tissues, or organs. Examples of antibacterial agents are described in detail further herein. In some embodiments, an antibacterial agent used in addition to a compound described herein is linezolid or tedizolid (e.g., tedizolid phosphate).

The term“bacterial infection,” as used herein, refers to the invasion of a subject’s cells, tissues, and/or organs by bacteria (e.g., Gram-negative bacteria), thus, causing an infection. In some

embodiments, the bacteria may grow, multiply, and/or produce toxins in the subject’s cells, tissues, and/or organs. In some embodiments, a bacterial infection can be any situation in which the presence of a bacterial population(s) is latent within or damaging to a host body. Thus, a subject is“suffering” from a bacterial infection when a latent bacterial population is detectable in or on the subject’s body, an excessive amount of a bacterial population is present in or on the subject’s body, or when the presence of a bacterial population(s) is damaging the cells, tissues, and/or organs of the subject.

The term“protecting against,” as used herein, refers to preventing a subject from developing a bacterial infection (e.g., a Gram-negative bacterial infection) or decreasing the risk that a subject may develop a bacterial infection (e.g., a Gram-negative bacterial infection). Prophylactic drugs used in methods of protecting against a bacterial infection in a subject are often administered to the subject prior to any detection of the bacterial infection. In some embodiments of methods of protecting against a bacterial infection, a subject (e.g., a subject at risk of developing a bacterial infection) may be

administered a compound described herein (e.g., a compound having any one of formulas (l)-(XXVI II) or a compound of Table 1 ) to prevent the bacterial infection development or decrease the risk of the bacterial infection development.

The term“treating” or“to treat,” as used herein, refers to a therapeutic treatment of a bacterial infection (e.g., a Gram-negative bacterial infection) in a subject. In some embodiments, a therapeutic treatment may slow the progression of the bacterial infection, improve the subject’s outcome, and/or eliminate the infection. In some embodiments, a therapeutic treatment of a bacterial infection (e.g., a Gram-negative bacterial infection) in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the bacterial infection, diminish the extent of the bacterial infection, stabilize (i.e. , not worsening) the state of the bacterial infection, prevent the spread of the bacterial infection, and/or delay or slow the progress of the bacterial infection, as compare the state and/or the condition of the bacterial infection in the absence of the therapeutic treatment.

The phrase“LPS-induced nitric oxide (NO) production from a macrophage,” as used herein, refers to the ability of the lipopolysaccharides (LPS) in Gram-negative bacteria to activate a macrophage and induce NO production from the macrophage. NO production from a macrophage in response to LPS is a signal of macrophage activation, which may lead to sepsis in a subject, e.g., a Gram-negative bacteria infected subject. The disclosure features compounds (e.g., compounds of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) that are able to bind to LPS in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, thus neutralizing an immune response to LPS.

NO production from a macrophage may be measured using available techniques in the art, e.g., a Griess assay.

The term“resistant strain of bacteria,” as used herein, refers to a strain of bacteria (e.g., Gram negative or Gram-positive bacteria) that is refractory to treatment with an antibiotic, such as an antibiotic described in the Detailed Description. Antibiotics to which a strain of bacteria is resistant do not include the compounds described herein (e.g., compounds of any one of formulas (l)-(XXVIII) or a compound of Table 1 ). Resistance may arise through natural resistance in certain types of bacteria, spontaneous random genetic mutations, and/or by inter- or intra-species horizontal transfer of resistance genes. In some embodiments, a resistant strain of bacteria contains an mcr-1 gene, an mcr-2 gene, an mcr- 3 gene, an mcr- 4 gene, an mcr- 5 gene, an mcr- 6 gene, an mcr- 7 gene, and/or an mcr- 8 gene. In some embodiments, a resistant strain of bacteria contains a chromosomal mutation conferring polymyxin resistance. In some embodiments, a resistant strain of bacteria contains an mcr-1 gene, an mcr-2 gene, an mcr- 3 gene, an mcr- 4 gene, an mcr- 5 gene, an mcr- 6 gene, an mcr- 7 gene, and/or an mcr- 8 gene in combination with other antibiotic resistance genes. In some embodiments, a resistant strain of bacteria is a resistant strain of E. coli (e.g., E. coli BAA-2469).

The term“subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.

The term“substantially simultaneously,” as used herein, refers to two or more events that occur at the same time or within a narrow time frame of each other. As disclosed herein, a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 )) and an antibacterial agent (e.g., linezolid or tedizolid) may be administered substantially simultaneously, which means that the compound and the antibacterial agent are administered together (e.g., in one

pharmaceutical composition) or separately but within a narrow time frame of each other, e.g., within 10 minutes, e.g., 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute, or 45, 30, 15, or 10 seconds of each other.

The term“therapeutically effective amount,” as used herein, refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a bacterial infection (e.g., a Gram-negative bacterial infection)). It is also to be understood herein that a“therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route, and/or taken alone or in combination with other therapeutic agents (e.g., an antibacterial agent described herein). For example, in the context of administering a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) that is used for the treatment of a bacterial infection, an effective amount of a compound is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the bacterial infection as compared to the response obtained without administration of the compound.

As used herein, the term“pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains at least one active ingredient (e.g., a compound of any one of formulas (I)- (XXVIII) or a compound of Table 1 ) as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ).

As used herein, the term“pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active compound (e.g., a compound of any one of formulas (I)- (XXVIII) or a compound of Table 1 ). The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a compound described herein. The nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, and/or a buffered solution) is generally used.

The term“pharmaceutically acceptable salt,” as used herein, represents salts of the compounds described herein (e.g., compounds of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCFI, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

The term“about,” as used herein, indicates a deviation of ±5%. For example, about 1 0% refers to from 9.5% to 10.5%. Definitions of abbreviations used in the disclosure are provided in Table 2 below:

Table 2

Other features and advantages of the compounds described herein will be apparent from the following Detailed Description and the claims.

Description of the Drawings

FIG. 1 is a graph showing KIM-1 protein levels in rats after subcutaneous administration of 50 mg/kg/day of colistin and Compound 80.

FIG. 2 is a graph showing the activity of selected compounds in a thigh model of infection with

COL ^R E. coli (mcr- 1 ). Compound 80 demonstrated improved efficacy versus colistin when administered either subcutaneously (SC) or intraperitoneally (IP).

Detailed Description

The disclosure features compounds, compositions, and methods for the treatment of bacterial infections (e.g., Gram-negative bacterial infections). The compounds disclosed herein include dimers of cyclic heptapeptides (e.g., two polymyxin cores). The dimers of cyclic heptapeptides are linked to each other through a linker and/or one or two peptides (e.g., a peptide including a 1 -5 amino acid residue(s)). The dimers of cyclic heptapeptides in the compounds described herein bind to lipopolysaccharides (LPS) in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization of the Gram-negtaive bacteria to other antibiotics. I. Bacterial Infections

Pathogenic bacteria cause bacterial infections and diseases such as tuberculosis, pneumonia, and foodborne illnesses. Bacteria may be categorized into two major types: Gram-positive bacteria and Gram-negative bacteria. Gram-positive bacteria possess a thick cell wall containing multiple layers of peptidoglycan and teichoic acids, while Gram-negative bacteria have a relatively thin cell wall containing fewer layers of peptidoglycan that are surrounded by a second lipid membrane containing

lipopolysaccharides (LPS) and lipoproteins. LPS, also called endotoxins, are composed of

polysaccharides and lipid A. These differences in bacterial cell wall structure can produce differences in antibiotic susceptibility. Examples of Gram-positive bacteria include, but are not limited to, bacteria in the genus Streptococcus (e.g., Streptococcus pyogenes), bacteria in the genus Staphylococcus (e.g., Staphylococcus cohnii ), bacteria in the genus Corynebacterium (e.g., Corynebacterium auris), bacteria in the genus Listeria (e.g., Listeria grayi), bacteria in the genus Bacillus (e.g., Bacillus aerius), and bacteria in the genus Clostridium (e.g., Clostridium acetium). Examples of Gram-negative bacteria include, but are not limited to, bacteria in the genus Escherichia (e.g., Escherichia coli), bacteria in the genus Klebsiella (e.g., Klebsiella granulomatis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella terrigena, and Klebsiella variicola), bacteria in the genus Acinetobacter (e. g., Acinetobacter baumannii,

Acinetobacter calcoaceticus, Acinetobacter kookii, and Acinetobacter junii), bacteria in the genus Pseudomonas (e.g., Pseudomonas aeruginosa), bacteria in the genus Neisseria (e.g., Neisseria gonorrhoeae), bacteria in the genus Yersinia (e.g., Yersinia pestis), bacteria in the genus Vibrio (e.g., Vibrio cholerae), bacteria in the genus Campylobacter (e.g., Campylobacter jejuni), and bacteria in the genus Salmonella (e.g., Salmonella enterica).

Bacteria may evolve to become more or fully resistant to antibiotics. Resistance may arise through natural resistance in certain types of bacteria, spontaneous random genetic mutations, and/or by inter- or intra-species horizontal transfer of resistance genes. Resistant bacteria are increasingly difficult to treat, requiring alternative medications or higher doses, which may be more costly or more toxic. Bacteria resistant to multiple antibiotics are referred to as multidrug resistant (MDR) bacteria. For example, the mcr-1 gene encodes a phosphoethanolamine transferase (MCR-1 ) which confers resistance to colistin, a natural polymyxin, through modification of LPS. This is the first known horizontally- transferable resistance determinant for the polymyxin class of antibiotics. The mcr-1 gene has also been found in bacterial strains which already possess resistance to other classes of antibiotics, such as in carbapenem-resistant Enterobacteriaceae (CRE). An mcr-1 resistance plasmid refers to a bacterial plasmid that carries mcr-1 alone or in combination with other antibiotic resistance genes. A mcr-1 resistance plasmid refers to a bacterial plasmid that carries one or more antibiotic resistance genes. Examples of mcr-1 resistance plasmids include, but are not limited to, pHNSHP45, pMR0516mcr, pESTMCR, pAF48, pAF23, pmcr1 -lncX4, pmcr1 -lncl2, pA31 -12, pVT553, plCBEC72Hmcr, pE15004, pE15015, and pE15017.

In another example, the mcr-2 gene also confers resistance to colistin. The mcr-2 gene was identified in porcine and bovine colistin-resistance E.coli that did not contain mcr-1 (Xavier et al., Euro Surveill 21 (27), 2016). The mcr-2 gene is a 1 ,617 bp phspoethanolamine transferase harbored on an lncX4 plasmid. The mcr-2 gene has 76.7% nucleotide identity to mcr-1. Analysis of mcr-2 harboring plasmids from E.coli isolates shows that the mobile element harboring mcr-2 is an IS element of the IS1595 superfamily, which are distinguished by the presence of an ISXCMike transposase domain (Xavier et al. , supra). The MCR-2 protein was predicted to have two domains, with domain 1 (1 -229 residues) as a transporter and domain 2 (230-538 residues) as a transferase domain. An mcr-2 resistance plasmid refers to a bacterial plasmid that carries mcr-2 alone or in combination with other antibiotic resistance genes. A mcr-2 resistance plasmid refers to a bacterial plasmid that carries one or more antibiotic resistance genes. Mcr-2 resistance plasmids include, but are not limited to, pKP37-BE and pmcr2-lncX4. In another example, the mcr- 3, mcr- 4, mcr- 5, mcr- 6, mcr- 7, and mcr- 8 genes also confer resistance to colistin, described in Wang et al., Emerging Microbes & Infections 7:122 (2018), which is herein incorporated by reference in its entirety.

Furthermore, resistant strain E. coli BAA-2469 possesses the New Delhi metallo-p-lactamase (NDM-1 ) enzyme, which makes bacteria resistant to a broad range of b-lactam antibiotics. Additionally,

E. coli BAA-2469 is also known to be resistatnt to penicillins (e.g., ticarcillin, ticarcillin/clavulanic acid, piperacillin, ampicillin, and ampicillin/sulbactam), cephalosporins (e.g., cefalotin, cefuroxime, cefuroxime, cefotetan, cefpodoxime, cefotaxime, ceftizoxime, cefazolin, cefoxitin, ceftazidime, ceftriaxone, and cefepime), carbapenems (e.g., doripenem, meropenem, ertapenem, imipenem), quinolones (e.g., nalidixic acid, moxifloxacin, norfloxacin, ciprofloxacin, and levofloxacin), aminoglycosides (e.g., amikacin, gentamicin, and tobramycin), and other antibiotics (e.g., tetracycline, tigecycline, nitrofurantoin, aztreonam, trimethoprim/sulfamethoxazole).

In some embodiments, a resistant strain of bacteria possesses the mcr-1 gene, the mcr-2 gene, the mcr-3 gene, the mcr- 4 gene, the mcr- 5 gene, the mcr- 6 gene, the mcr- 7 gene, the mcr- 8 gene, and/or a chromosomal mutation conferring polymyxin resistance. In some embodiments, a resistant strain of bacteria is a resistant strain of E. coli (e.g., E. coli BAA-2469).

II. Compounds of the Disclosure

Provided herein are synthetic compounds useful in the treatment of bacterial infections (e.g., Gram-negative bacterial infections). The compounds disclosed herein include dimers of two cyclic heptapeptides. The dimers of two cyclic heptapeptides include a first cyclic heptapeptide (e.g., a first polymyxin core) and a second cyclic heptapeptide (e.g., a second polymyxin core). The first and second cyclic heptapeptides are linked to each other by way of a linker and/or one or two peptides (e.g., each peptide including a 1 -5 amino acid residue(s)).

Without being bound by theory, in some aspects, compounds described herein bind to the cell membrane of Gram-negative bacteria (e.g., bind to LPS in the cell membrane of Gram-negative bacteria) through the interactions between the cyclic heptapeptides in the compounds and the cell membrane of Gram-negative bacteria. The binding of the compounds to the cell membrane of Gram-negative bacteria disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization of the Gram negative bacteria to other antibiotics. In some embodiments, the initial association of the compounds with the bacterial cell membrane occurs through electrostatic interactions between the cyclic heptapepdies in the compounds and the anionic LPS in the outer membrane of Gram-negative bacteria, disrupting the arrangement of the cell membrane. Specifically, compounds described herein may bind to lipid A in the LPS. More specifically, the cyclic heptapeptides in the compounds described herein may bind to one or both phosphate groups in lipid A. In some embodiments, antibiotic-resistant bacteria (e.g., antibiotic- resistant, Gram-negative bacteria) has one phosphate group in lipid A. In some embodiments, compounds described herein may bind to multiple Gram-negative bacterial cells at the same time. The binding of the compounds described herein to the LPS may also displace Mg ²⁺ and Ca ²⁺ cations that bridge adjacent LPS molecules, causing, e.g., membrane permeabilization, leakage of cellular molecules, inhibition of cellular respiration, and/or cell death.

Compounds provided herein are described by any one of formulas (l)-(XXVIII) or provided in Table 1 . In some embodiments, the compounds described herein include dimers of cyclic heptapeptides (e.g., dimer of cyclic heptapeptides joined by a linker). Compounds described herein may be synthesized using available chemical synthesis techniques in the art. In some embodiments, available functional groups in the cyclic heptapeptides and the linker, e.g., amines, carboxylic acids, maleimides, bis-sulfones, azides, alkynes, and/or hydroxyl groups, may be used in making the compounds described herein. For example, the linking nitrogen (described further herein) in a cyclic heptapeptide may form an amide bond with the carbon in a carboxylic acid group in the linker. A peptide including one or more (e.g., 1 -3; 1 , 2, or 3) amino acid residues (e.g., natural and/or non-natural amino acid residues) may be also be covalently attached to the linking nitrogen of the cyclic heptapeptide through forming an amide bond between the carbon in a carboxylic acid group in the peptide and the linking nitrogen. In cases where a functional group is not available for conjugation, a molecule may be derivatized using conventional chemical synthesis techniques that are well known in the art. In some embodiments, the compounds described herein contain one or more chiral centers. The compounds include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.

Cyclic heptapeptide or polymyxin core

In some aspects, a cyclic heptapeptide or polymyxin core, as used herein, refers to certain compounds that bind to lipopolysaccharides (LPS) in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization to other antibiotics. In some aspects, cyclic heptapeptide, as used herein, refers to certain compounds that kill or inhibit the growth of Gram-negative bacteria as determined by measuring the minimum inhibitory concentration (MIC) against at least one Gram-negative bacteria as known in the art, for example, wherein the MIC is 128 pg/mL or less (e.g., 1 10 pg/mL or less, 100 pg/mL or less, 90 pg/mL or less, 80 pg/mL or less, 70 gg/mL or less, 60 pg/mL or less, 50 pg/mL or less, 40 pg/mL or less, 30 pg/mL or less, 20 pg/mL or less, or 10 pg/mL or less).

Cyclic heptapeptides are composed of, at least, amino acid residues, each of which may, independently, may have a D- or L- configuration, assembled as a cyclic heptapeptide ring. A cyclic heptapeptide includes seven natural or non-natural amino acid residues attached to each other in a closed ring. The ring contains six bonds formed by linking the carbon in the a-carboxyl group of one amino acid residue to the nitrogen in the a-amino group of the adjacent amino acid residue and one bond formed by linking the carbon in the a-carboxyl group of one amino acid residue to the nitrogen in the y- amino group in the side chain of the adjacent amino acid residue. For the amino acid residue whose nitrogen in the g-amino group in the side chain participates in forming the ring, the nitrogen in the a-amino group of this amino acid residue does not participate directly in forming the ring and serves as the linking nitrogen (thus, referred to as the“linking nitrogen” herein) that links one cyclic heptapeptide or polymyxin core to an second cyclic heptapeptide or polymyxin by way of a linker and/or one or two peptides (e.g., a peptide including a 1 -5 amino acid residue(s)).

In some embodiments, a peptide including one or more (e.g., 1 -5; 1 , 2, 3, 4, or 5) amino acid residues (e.g., natural and/or non-natural amino acid residues) may be covalently attached to the linking nitrogen of the cyclic heptapeptide or the polymyxin core.

Cyclic heptapeptides or polymyxin cores may be derived from polymyxins (e.g., naturally existing polymyxins and non-natural polymyxins) and/or octapeptins (e.g., naturally existing octapeptins and non natural octapeptins). In some embodiments, cyclic heptapeptides may be compounds described in Gallardo-Godoy et al., J. Med. Chem. 59:1068, 201 6 (e.g., compounds 1 1 -41 in Table 1 of Gallardo- Godoy et al.), which is incorporated herein by reference in its entirety. Examples of naturally existing polymyxins and their structures are shown in Table 3A. Examples of non-natural polymyxins and their structures are shown in Table 3B.

Table 3A. Natural polymyxins and their structures

Table 3B. Non-natural polymyxins and their structures

(Dab: diaminobutyric acid; Dap: diaminopropionic acid; Orn: ornithine;

Abu: 2-aminobutyric acid; Nle: norleucine)

Dimers of cyclic heptapeptides

The compounds described herein include dimers of cyclic heptapeptides. The dimers of two cyclic heptapeptides include a first cyclic heptapeptide (e.g., a first polymyxin core) and a second cyclic heptapeptide (e.g., a second polymyxin core). The first and second cyclic heptapeptides are linked to each other by way of a linker and/or one or two peptides (e.g., each peptide including a 1 -5 amino acid residue(s)). In some embodiments of the dimers of cyclic heptapeptides, the first and second cyclic heptapeptides are the same. In some embodiments, the first and second cyclic heptapeptides are different. The disclosure provides a compound, or a pharmaceutically acceptable salt thereof, described by any one of formulas (l)-(XXVI II) :

(1-3)

(IX-1)

(IX-4)

(X-3)

(XI-3)

(XI-6)

(XII-2)

(XII-5)

(XII-8)

(XIII-3)

(XIII-6)

(XIII-9)

(XIV-2)

(XVI 1-1)

(XXIII-1)

(XXIV-1)

(XXVI 1-1)

(XXVIII).

In some embodiments, when a is 1 , e.g., in the compound of any one of formulas (l)-(XXVI II), (i) each of R ² , R ³ , and R ⁴ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety,

H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R ² , R ³ , and X ¹ together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R ⁴ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R ³ , R ⁴ , N ¹ , and X ¹ together form a ring (e.g., an optionally substituted 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, and R ² is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

In some embodiments, when b is 1 , e.g., in the compound of any one of formulas (l)-(XXVI II), (i) each of R ⁵ , R ⁶ , and R ⁷ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R ⁵ , R ⁶ , and X ² together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R ⁷ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R ⁶ , R ⁷ , N ² , and X ² together form a ring (e.g., an optionally substituted 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, and R ⁵ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

In some embodiments, when c is 1 , e.g., in the compound of any one of formulas (l)-(XXVI II), (i) each of R ⁸ , R ⁹ , and R ¹⁰ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R ⁸ , R ⁹ , and X ³ together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R ¹⁰ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R ⁹ , R ¹⁰ , N ³ , and X ³ together form a ring (e.g., an optionally substituted 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, and R ⁸ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

In some embodiments, when a’ is 1 , e.g., in the compound of any one of formulas (l)-(XXVIII), (i) each of R’ ² , R’ ³ , and R’ ⁴ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R’ ² , R’ ³ , and X’ ¹ together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R’ ⁴ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R’ ³ , R’ ⁴ , N’ ¹ , and X’ ¹ together form a ring (e.g., an optionally substituted 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, and R’ ² is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

In some embodiments, when b’ is 1 , e.g., in the compound of any one of formulas (l)-(XXVIII), (i) each of R’ ⁵ , R’ ⁶ , and R’ ⁷ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R’ ⁵ , R’ ⁶ , and X’ ² together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R’ ⁷ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R’ ⁶ , R’ ⁷ , N’ ² , and X’ ² together form a ring (e.g., an optionally substituted 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, and R’ ⁵ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted

heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

In some embodiments, when c’ is 1 , e.g., in the compound of any one of formulas (l)-(XXVI II), (i) each of R’ ⁸ , R’ ⁹ , and R’ ¹⁰ is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (ii) R’ ⁸ , R’ ⁹ , and X’ ³ together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted cycloalkyl, optionally substituted heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from N, O, and S, and R’ ¹⁰ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted

cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl; or (iii) R’ ⁹ , R’ ¹⁰ , N’ ³ , and X’ ³ together form a ring (e.g., an optionally substituted 3-8 or 5-8 membered ring) comprising optionally substituted heterocycloalkyl comprising an N heteroatom and additional 0-2 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl comprising an N heteroatom and additional 0-2 heteroatoms

independently selected from N, O, and S, and R’ ⁸ is a lipophilic moiety, a positively charged moiety, a polar moiety, H, optionally substituted alkamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenylene, optionally substituted cycloalkynylene, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenylene, optionally substituted heterocycloalkynylene, optionally substituted heteroaryl, optionally substituted alkaryl, or optionally substituted heteroalkaryl.

As described further herein, a linker in a compound described herein (e.g., L’ or L) may be a branched structure. As described further herein, a linker in a compound described herein (e.g., L’ or L) may be a multivalent structure, e.g., a divalent or trivalent structure having two or thee arms, respectively.

In some embodiments, the linker includes alkyl or alkamino substitution of the nitrogen atom of a backbone amide (e.g., alkyl or alkamino substitution of the linking nitrogen, N ⁴ and/or N’ ⁴ ). Alkyl or alkamino substitution (e.g., C1 -C3 alkyl, or C2-C3 alkamino substitution) may increase stability (e.g., proteolytic stability) and/or activity of the compound (e.g., relative to the same compound where N ⁴ and/or N’ ⁴ is H). In some embodiments, alkyl or alkamino substitution of the nitrogen atom of a backbone amide increases stability (e.g., proteolytic stability) of the compound by 5%, 10%, 1 5%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound where N ⁴ and/or N’ ⁴ is H). In some embodiments, alkyl or alkamino substitution of the nitrogen atom of a backbone amide increases activity (e.g., as measured by a reduction in minimum inhibitory concentration) of the compound by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound where N ⁴ and/or N’ ⁴ is H). In some embodiments, alkyl or alkamino substitution of the nitrogen atom of a backbone amide decreases the minimum inhibitory concentration of the compound by 5%, 1 0%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1 50%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound where N ⁴ and/or N’ ⁴ is H).

In some embodiments, the linker includes an aza bond in place of a backbone amide bond (e.g., at least one of X ¹ , X ² , X ³ , X’ ¹ , X’ ² , and X’ ³ of, for example in any one of formulas (l)-(XXVIII), is a nitrogen atom). The replacement of a backbone amide bond with an aza bond may increase stability (e.g., proteolytic stability) and/or activity of the compound (e.g., relative to the same compound having a standard amide bond in the linker). In some embodiments, replacement of a backbone amide bond with an aza bond increases stability (e.g., proteolytic stability) of the compound by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1 50%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound having a standard amide bond in the linker). In some embodiments, replacement of a backbone amide bond with an aza bond increases activity (e.g., as measured by a reduction in minimum inhibitory concentration) of the compound by 5%, 10%, 15%, 20%, 30%, 40%,

50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound having a standard amide bond in the linker). In some embodiments, replacement of a backbone amide bond with an aza bond decreases the minimum inhibitory concentration of the compound by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or 1000% or more (e.g., relative to the same compound having a standard amide bond in the linker). III. Linkers

A linker refers to a linkage or connection between two or more components in a compound described herein (e.g., between two cyclic heptapeptides in a compound described herein).

Linkers in compounds having a dimer of cyclic heptapeptides

In a compound containing a dimer of cyclic heptapeptides as described herein, a linker in the compound (e.g., L’ or L) may be a branched structure. As described further herein, a linker in a compound described herein (e.g., L’ or L) may be a multivalent structure, e.g., a divalent or trivalent structure having two or thee arms, respectively. In some embodiments when the linker has two arms, one arm may be attached to a first cyclic heptapeptide or polymyxin core and the other arm may be attached to a second cyclic heptapeptide or polymyxin core.

In some embodiments, the linker L’ in the compound described by any one of formulas (I)- (XXVIII) is described by formula (L’):

^-A2— L— A1— \

(L’)

in which L is a remainder of L’; A1 is a 1 -5 amino acid peptide (e.g., a 1 -4, 1 -3, or 1 -2 amino acid peptide) covalently attached to the linking nitrogen in each M1 or is absent; and A2 is a 1 -5 amino acid peptide (e.g., a 1 -4, 1 -3, or 1 -2 amino acid peptide) covalently attached to the linking nitrogen in each M2 or is absent.

In some embodiments, a linker in a compound having a first cyclic heptapeptide linked to a second cyclic heptapeptidenis described by formula (L-l):

L ^B - Q - L ^A

(L-l)

wherein L ^A is described by formula G ^A1 -(Z ^A1 )gi-(Y ^A1 )hi-(Z ^A2 )h-(Y ^A2 )ji -(Z ^A3 ) i -(Y ^A3 )ii -(Z ^A4 ) _mi -(Y ^A4 )ni-(Z ^A5 )oi- G ^A2 ; L ^B is described by formula G ^B1 -(Z ^B1 ) _g 2-(Y ^B1 )h2-(Z ^B2 )i2-(Y ^B2 )j2-(Z ^B3 ) _k 2-(Y ^B3 )i2-(Z ^B4 )m2-(Y ^B4 )n2-(Z ^B5 )o2-G ^B2 ; G ^A1 is a bond attached to Q; G ^A2 is a bond attached to A1 or M1 if A1 is absent; G ^B1 is a bond attached to Q; G ^B2 is a bond attached to A2 or M2 if A2 is absent; each of Z ^A1 , Z ^A2 , Z ^A3 , Z ^A4 , Z ^A5 , Z ^B1 , Z ^B2 , Z ^B3 , Z ^B4 , and Z ^B5 is independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20

heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20

heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20

heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of Y ^A1 , Y ^A2 , Y ^A3 , Y ^A4 , Y ^B1 , Y ^B2 , Y ^B3 , and Y ^B4 is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, I2, m2, n2, and o2 is independently, 0 or 1 ; Q is a nitrogen atom, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4- C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene.

Linkers of formula (L-l) that may be used in compounds described herein include, but are not limited to,

wherein each of R’ ¹⁸ and R ¹⁸ is, independently, H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and wherein each q is, independently, an integer from 1 to 1 1 , inclusive. In some embodiments, each of R’ ¹⁸ and R ¹⁸ is, independently, butyl, cyclohexyl, isopropyl, or isobutyl.

In some embodiments, a linker in a compound having a first cyclic heptapeptide linked to a second cyclic heptapeptidenis described by formula (L-ll):

J ¹ -(S ¹ )g-CT )h-(S ² )i-(T ² ) _j -(S ⁸ ) _k -(T ⁸ ),-(S ⁴ ) _m -(T ⁴ ) _n -(S ⁸ )o-J ²

(L-ll)

wherein J ¹ is a bond attached to A1 or M1 if A1 is absent; J ² is a bond attached to A2 or M2 if A2 is absent; each of S ¹ , S ² , S ³ , S ⁴ , and S ⁵ is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2- C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of T ¹ , T ² , T ³ , T ⁴ is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 - C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and each of g, h, i, j, k, I, m, n, and o is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.

Linkers of formula (L-ll) that may be used in compounds described herein include, but are not

wherein each of d and e is, independently, an integer from 1 to 26; or a pharmaceutically acceptable salt thereof.

In some embodiments, a linker provides space, rigidity, and/or flexibility between two cyclic heptapeptides in the compounds described herein. In some embodiments, a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker (U or L as shown in any one of formulas (l)-( XXXVI)) includes no more than 250 atoms (e.g., 1 -2, 1 -4, 1 -6, 1 -8, 1-10, 1 -12, 1 -14, 1 -16, 1-18, 1 -20, 1 -25, 1 -30, 1 -35, 1 -40, 1 -45, 1 -50, 1 -55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1- 180, 1 -190, 1 -200, 1 -210, 1 -220, 1 -230, 1 -240, or 1 -250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). In some embodiments, a linker (L’ or L) includes no more than 250 non-hydrogen atoms (e.g., 1 -2, 1 -4, 1 -6, 1 -8, 1-10, 1 -12, 1-14, 1 -16, 1-18, 1 - 20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95,

90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3,

2, or 1 non-hydrogen atom(s)). In some embodiments, the backbone of a linker (L’ or L) includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1- 50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30,

28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). The“backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of the compound to another part of the compound. The atoms in the backbone of the linker are directly involved in linking one part of the compound to another part of the compound. For examples, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.

Molecules that may be used to make linkers (L’ or L) include at least two functional groups, e.g., two carboxylic acid groups. In some embodiments of a bivalent linker, two arms of a linker may contain two dicarboxylic acids, in which the first carboxylic acid may form a covalent linkage with the first cyclic heptapeptide in the compound and the second carboxylic acid may form a covalent linkage with the second cyclic heptapeptide in the compound. In some embodiments of a divalent linker, the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a first cyclic heptapeptide) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., a second cyclic heptapeptide) in the compound. In some embodiments, when the cyclic heptapeptide is attached to a peptide (e.g., a peptide including a 1 -5 amino acid residue(s)) at the linking nitrogen, the linker may form a covalent linkage with the peptide.

In some embodiments, dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker). For example, in a compound containing a dimers of cyclic heptapeptides, the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with the linking nitrogen of the first cyclic heptapeptide and the second carboxylic acid may form a covalent linkage with the linking nitrogen of the second cyclic heptapeptide.

In some embodiments, when the first and/or second cyclic heptapeptide is attached to a peptide (e.g., a peptide including a 1 -5 amino acid residue(s)) at the linking nitrogen, the first carboxylic acid in a dicarboxylic acid linker may form a covalent linkage with the terminal amine group at the end of the peptide that is attached to the first cyclic heptapeptide and the second carboxylic acid in the dicarboxylic acid linker may form a covalent linkage with the terminal amine group at the end of the peptide that is attached to the second cyclic heptapeptide.

Examples of dicarboxylic acids molecules that may be used to form linkers include, but are not limited to,

Other examples of dicarboxylic acids molecules that may be used to form linkers include, but are not limited to,

In some embodiments, dicarboxylic acid molecules, such as the ones described herein, may be further functionalized to contain one or more additional functional groups.

In some embodiments, when the cyclic heptapeptide is attached to a peptide (e.g., a peptide including a 1 -5 amino acid residue(s)) at the linking nitrogen, the linking group may comprise a moiety comprising a carboxylic acid moiety and an amino moiety that are spaced by from 1 to 25 atoms. Examples of such linking groups include, but are not limited to,

In some embodiments, a molecule containing an azide group may be used to form a linker, in which the azide group may undergo cycloaddition with an alkyne to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing an alkyne group may be used to form a linker, in which the alkyne group may undergo cycloaddition with an azide to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing a maleimide group may be used to form a linker, in which the maleimide group may react with a cysteine to form a C-S linkage. In some embodiments, a molecule containing one or more sulfonic acid groups may be used to form a linker, in which the sulfonic acid group may form a sulfonamide linkage with the linking nitrogen in a cyclic heptapeptide. In some embodiments, a molecule containing one or more isocyanate groups may be used to form a linker, in which the isocyanate group may form a urea linkage with the linking nitrogen in a cyclic heptapeptide. In some embodiments, a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a cyclic heptapeptide.

In some embodiments, a linker (U or L) may comprise a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may comprise one or more amino acid residues. In some embodiments, a linker may be an amino acid sequence (e.g., a 1 -25 amino acid, 1 -1 0 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, 1 -2 amino acid, or 1 amino acid sequence).

In some embodiments, a linker (L’ or L) may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C2-C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2- C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino. Covalent conjugation of two or more components in a compound using a linker may be accomplished using well-known organic chemical synthesis techniques and methods. Complementary functional groups on two components may react with each other to form a covalent bond. Examples of complementary reactive functional groups include, but are not limited to, e.g., maleimide and cysteine, amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine.

Other examples of functional groups capable of reacting with amino groups include, e.g., alkylating and acylating agents. Representative alkylating agents include: (i) an a-haloacetyl group, e.g., XCH2CO- (where X=Br, Cl, or I); (ii) a N-maleimide group, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group; (iii) an aryl halide, e.g., a nitrohaloaromatic group; (iv) an alkyl halide; (v) an aldehyde or ketone capable of Schiff’s base formation with amino groups; (vi) an epoxide, e.g., an epichlorohydrin and a bisoxirane, which may react with amino, sulfhydryl, or phenolic hydroxyl groups; (vii) a chlorine-containing of s-triazine, which is reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups; (viii) an aziridine, which is reactive towards nucleophiles such as amino groups by ring opening; (ix) a squaric acid diethyl ester; and (x) an a-haloalkyl ether.

Examples of amino-reactive acylating groups include, e.g., (i) an isocyanate and an

isothiocyanate; (ii) a sulfonyl chloride; (iii) an acid halide; (iv) an active ester, e.g., a nitrophenylester or N- hydroxysuccinimidyl ester; (v) an acid anhydride, e.g., a mixed, symmetrical, or N-carboxyanhydride; (vi) an acylazide; and (vii) an imidoester. Aldehydes and ketones may be reacted with amines to form Schiff’s bases, which may be stabilized through reductive amination.

It will be appreciated that certain functional groups may be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S- acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives;

conversion of thiols to carboxyls using reagents such as a -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.

Compounds decribed herein (e.g., a compound described by any one of formulas (l)-(XXVII)) may be synthesized by standard methods know to those of skill in the art, for example, as described herein or as described, for example, in International Patent Publication No. WO2017/218922, which is hereby incorporated by reference in its entirety.

IV. Antibacterial Agents

In some embodiments, one or more antibacterial agents may be administered in combination (e.g., administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or administered separately at different times) with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ).

Antibacterial agents may be grouped into several classes, e.g., quinolones, carbapenems, macrolides, DHFR inhibitors, aminoglycosides, ansamycins (e.g., geldanamycin, herimycin, and rifaximin), carbacephem (e.g., loracarbef), cephalosporins (e.g., cefadroxil, cefaolin, cefalotin, cefalothin, cephalexin, e.g., cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefdinir, cefditoren,

cefoperazone, cefotaxime, cefpodoxime, ceftazidime, and ceftobiprole), glycopeptides (e.g., teicoplanin, vancomycin, telavancin, dalbavancin, and oritavancin), lincosamides (e.g., clindamycin and lincomycin), lipopeptides (e.g., daptomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), oxazolidinones, pleuromutilins, penicillins , sulfonamides, and tetracyclines (e.g., eravacycline, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline). Quinolones include, but are not limited to, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin. Carbapenems include, but are not limited to, ertapenem, doripenem,

imipenem/cilastatin, and meropenem. Macrolides include, but are not limited to, solithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spiramycin. In some embodiments, a macrolide is solithromycin. DHFR inhibitors include, but are not limited to, diaminoquinazoline, diaminopyrroloquinazoline, diaminopyrimidine, diaminopteridine, and diaminotriazines. Aminoglycosides include, but are not limited to, plazomicin, amikacin, gentamicin, gamithromycin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, and spectinomycin. Oxazolidinones include, but are not limited to, linezolid, tedizolid, posizolid, radezolid, and furazolidone. Pleuromutilins include, but are not limited to, retapamulin, valnemulin, tiamulin, azamulin, and lefamulin. Penicillins include, but are not limited to, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, penicillin G, temocillin, and ticarcillin. Sulfonamides include, but are not limited to, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX), and sulfonamidochrysoidine.

In some embodiments, the antibacterial agent used in combination with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) is selected from the group consisting of linezolid, tedizolid, posizolid, radezolid, retapamulin, valnemulin, tiamulin, azamulin, lefamulin, plazomicin, amikacin, gentamicin, gamithromycin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, solithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin g, penicillin v, piperacillin, penicillin g, temocillin, ticarcillin, amoxicillin clavulanate,

ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate, bacitracin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole (tmp-smx), sulfonamidochrysoidine, eravacycline, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol(bs), ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, thiamphenicol, tigecycline, tinidazole, and

trimethoprim, prodrugs thereof, and pharmaceutically acceptable salts thereof.

In some embodiments, the antibacterial agent used in combination with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) is tedizolid, azithromycin, meropenem, amikacin, levofloxacin, rifampicin, linezolid, erythromycin, or solithromycin. In some embodiments, the antibacterial agent used in combination with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) is tedizolid, azithromycin, meropenem, amikacin, or levofloxacin. In some embodiments, the antibacterial agent used in combination with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) is tiamulin. In some embodiments, the antibacterial agent used in combination with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) is solithromycin.

V. Methods

Methods described herein include, e.g., methods of protecting against or treating a bacterial infection (e.g., a Gram-negative bacterial infection) in a subject and methods of preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria (e.g., Gram-negative bacteria). A method of treating a bacterial infection (e.g., a Gram-negative bacterial infection) in a subject includes administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) or a pharmaceutical composition thereof. In some embodiments, the bacterial infection is caused by Gram-negative bacteria. In some embodiments, the bacterial infection is caused by a resistant strain of bacteria. In some embodiments, the resistant strain of bacteria is a resistant strain of E. coli. A method of preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria (e.g., Gram-negative bacteria) includes contacting the bacteria (e.g., Gram-negative bacteria) or a site susceptible to bacterial growth (e.g., Gram-negative bacterial growth) with a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) or a pharmaceutical composition thereof. In some embodiments, the bacterial infection is caused by Gram-negative bacteria. In some embodiments, the bacterial infection is caused by a resistant strain of bacteria. In some embodiments, the resistant strain of bacteria is a resistant strain of E. coli. In some embodiments, a compound used in any methods described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) may bind to LPS in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization to other antibiotics.

Moreover, methods described herein also include methods of protecting against or treating sepsis in a subject by administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ). In some embodiments, the method further includes administering to the subject an antibacterial agent. Methods described herein also include methods of preventing lipopolysaccharides (LPS) in Gram-negative bacteria (e.g., a resistant strain of Gram-negative bacteria or a resistant strain of E. coli (e. g., E. coli BAA-2469)) from activating a immune system in a subject by administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ). In some embodiments of the method, the method prevents LPS from activating a macrophage. In some embodiments, the method further includes administering to the subject an antibacterial agent. In some embodiments, a compound used in any methods described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) may bind to LPS in the cell membrane of Gram-negative bacteria to disrupt and permeabilize the cell membrane, leading to cell death and/or sensitization to other antibiotics.

In some embodiments, the methods described herein may further include administering to the subject an antibacterial agent in addition to a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ). Methods described herein also include methods of protecting against or treating a bacterial infection in a subject by administering to said subject (1 ) a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) and (2) an antibacterial agent. Methods described herein also include methods of preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria, by contacting the bacteria or a site susceptible to bacterial growth with (1 ) a compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) and (2) an antibacterial agent.

In some embodiments, the compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) is administered first, followed by administering of the antibacterial agent alone. In some embodiments, the antibacterial agent is administered first, followed by

administering of the compound described herein alone. In some embodiments, the compound described herein and the antibacterial agent are administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, the compound described herein or the antibacterial agent is administered first, followed by administering of the compound described herein and the antibacterial agent substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, the compound described herein and the antibacterial agent are administered first substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions), followed by administering of the compound described herein or the antibacterial agent alone. In some embodiments, when a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) and an antibacterial agent are administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), the MIC of each of the compound and the antibacterial agent may be lower than the MIC of each of the compound and the antibacterial agent when each is used alone in a treatment regimen.

VI. Pharmaceutical Compositions and Preparations

A compound described herein may be formulated in a pharmaceutical composition for use in the methods described herein. In some embodiments, a compound described herein may be formulated in a pharmaceutical composition alone. In some embodiments, a compound described herein may be formulated in combination with an antibacterial agent in a pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a compound described herein (e.g., a compound described by any one of formulas (l)-(XXVIII) or a compound of Table 1 ) and pharmaceutically acceptable carriers and excipients.

Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.

Examples of other excipients include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,

methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The compounds herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds herein be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,

camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

Depending on the route of administration and the dosage, a compound herein or a

pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery. A compound (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) or a pharmaceutical composition thereof may be formulated to be administered intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions). Depending on the route of administration, a compound herein or a pharmaceutical composition thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.

A compound described herein may be formulated in a variety of ways that are known in the art. For use as treatment of human and animal subjects, a compound described herein can be formulated as pharmaceutical or veterinary compositions. Depending on the subject (e.g., a human) to be treated, the mode of administration, and the type of treatment desired, e.g., prophylaxis or therapy, a compound described herein is formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams &

Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is incorporated herein by reference.

Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives. The compounds can be administered also in liposomal compositions or as microemulsions. Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds herein. Suitable forms include syrups, capsules, and tablets, as is understood in the art.

The pharmaceutical compositions can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium). Such injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate. Formulation methods are known in the art, see e.g., Pharmaceutical Preformulation and Formulation, 2nd Edition, M. Gibson, Taylor & Francis Group, CRC Press (2009).

The pharmaceutical compositions can be prepared in the form of an oral formulation.

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium,

methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Other pharmaceutically acceptable excipients for oral formulations include, but are not limited to, colorants, flavoring agents, plasticizers, humectants, and buffering agents. Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Dissolution or diffusion controlled release of a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) or a pharmaceutical composition thereof can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of the compound, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated

methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

The pharmaceutical composition may be formed in a unit dose form as needed. The amount of active component, e.g., a compound described herein (e.g., a compound of any one of formulas (I)- (XXVIII) or a compound of Table 1 ), included in the pharmaceutical compositions are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.01 -100 mg/kg of body weight).

VII. Routes of Administration and Dosages

In any of the methods described herein, compounds herein may be administered by any appropriate route for treating or protecting against a bacterial infection (e.g., a Gram-negative bacterial infection), or for preventing, stabilizing, or inhibiting the growth of bacteria, or killing bacteria (e.g., Gram negative bacteria). Compounds described herein may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient. In some embodiments, administering comprises administration of any of the compounds described herein (e.g., compounds of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) or compositions

intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions). In some embodiments, if an antibacterial agent is also administered in addition to a compound described herein, the antibacterial agent or a pharmaceutical composition thereof may also be administered in any of the routes of administration described herein.

The dosage of a compound described herein (e.g., a compound of any one of formulas (I)- (XXVIII) or a compound of Table 1 ) or pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated (e.g., the extent and/or condition of the bacterial infection), and physical characteristics, e.g., age, weight, general health, of the subject. Typically, the amount of the compound or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the bacterial infection without inducing significant toxicity. A pharmaceutical composition may include a dosage of a compound described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific embodiment, about 0.1 to about 30 mg/kg and, in a more specific embodiment, about 1 to about 30 mg/kg. In some embodiments, when a compound described herein (e.g., a compound of any one of formulas (l)-(XXVI II) or a compound of Table 1 ) and an antibacterial agent are administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), the dosage needed of the compound described herein may be lower than the dosage needed of the compound if the compound was used alone in a treatment regimen.

A compound described herein (e.g., a compound of any one of formulas (l)-(XXVIII) or a compound of Table 1 ) or a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1 -10 times or more; 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The dosage and frequency of administration may be adapted by the physician in accordance with conventional factors such as the extent of the infection and different parameters of the subject.

EXAMPLES

Example 1 - Synthesis of Intermediate 1 (lnt-1): Degradation of polymyxin B to tri-Boc polymyxin B cycloheptapeptide

lnt-1 Polymyxin B (100 g, 72.2 mmol) was dissolved in acetonitrile (1 000 mL) and water (500 mL) and stirred at room temperature for 10 mins. TEA (58.5 g, 8.0 eq) was added and the mixture stirred for a further 10 mins. B0C2O (94.6 g, 6.0 eq) was subsequently added in one portion and the mixture stirred for 6 hrs at 20 °C. Savinase ^® (300 mL) was then added. The pH of the resulting mixture was adjusted to 9.0 with aq 4M sodium hydroxide solution (10 mL) and the reaction mixture stirred at 25°C. Additional Savinase ^® (100 mL) was added after 17 hrs, and another quantity of Savinase ^® (100 mL x2) was added after 26 hrs. After an overall reaction time of 80 hrs, the mixture was diluted with ethyl acetate (2000 mL). After separation of the layers, the organic phase was washed with 0.1 M NaOH solution (1000 mL x2,

10V x2), then water (1000 mL, 10V). The organic layer was dried over anhydrous Na2SC>4, filtered and the solvent evaporated at reduced pressure. The residue was purified by silica gel chromatography eluting with 80% (EtOAc : MeOH : H2q·NH3 = 40:1 0:1 ) in ethyl acetate to give the title compound (49.8 g,

65.0%). LCMS: m/z (M + H) ⁺ calcd for q5oH ₈₃ Ni iOΐ4:1061 .61 ; found:1062.5

Example 2 - Synthesis of lnt-2 (Tripeptide (Dab-Thr-Dab))

Step a.

NH2-Dab(Boc)-OMe (HCI salt) (5.000 g, 1 eq.), Z-NH-Thr-OH (5.049 g, 1 05eq.), EDCI (5.350 g,

1 .5eq.), HOBt (3.733 g, 1 .5eq.) and NaHC03 (3.095 g, 2eq.) were weighed into a 100- ml_ round bottom flask. 24 ml_ of DCM/DMF (4:1 ) was added into the flask. The mixture was stirred at room temperature for less than 3 hrs. (TLC or LC/MS monitoring). After completion, EtOAc (200 mL) was added to dilute the reaction mixture and washed with 1 N aq. HCI, saturated NaHC03 and brine. Dried with Na2S04 and condensed. The residue was purified with normal phase silica (2~7% MeOH/DCM) to give 8.24 g pure desired product (>95%).

Step b.

Starting material (SM) (8.24 g) was dissolved in 100 ml_ of MeOH/EtOAc. And 5%Pd/C (3.75 g, 0.1 eq.) was added. Under H2 balloon, the reaction mixture was stirred for 2h. Checked LC/MS. Celite filtration and MeOH wash. Dried to give 5.87 g of free amine (>99%). The material was used in the next step without purification. Step C.

NH ₂ -Thr-Dab(Boc)-OMe (1 .46 g, 1 eq.), Z-NH-Dab(Boc)-OH(DCHA salt) (2.463, 1 .05eq.), EDCI (1 .260 g, 1 .5eq.), HOBt (0.888 g, 1 .5eq.) and NaHC03 (0.738, 2 eq.) were weighed into a 100- mL round bottom flask. 20 mL of DCM/DMF (4:1 ) was added into the flask. The mixture was stirred at room temperature for less than 3 hrs with TLC or LC/MS monitoring. After the completion, EtOAc (100 mL) was added to dilute the reaction mixture and washed with 1 N aq. HCI, saturated NaHC03 and brine. Dried with Na2S04 and condensed. The residue was purified with normal phase silica (2~7% MeOH/DCM) to give 2.78 g pure desired product (>95% isolated yield). (The reaction was repeated at 4.4 g scale and gave the similar result.)

Step d.

A solution of the Cbz-tripeptide (1 .55 g, 2.32 mmol) in methanol (10 mL) was charged with 5% Pd/C (0.300 g) and flushed with hydrogen from a balloon. After stirring overnight under hydrogen atmosphere, LCMS showed complete conversion. Pd/C was removed by filtration through Celite. The filtrate was concentrated and used in the next Step without further purification.

Example 3 - Synthesis of lnt-3 (Tripeptide acid)

A solution of the Cbz-tripeptide-OMe (7.85 g, 1 1 .76 mmol, described in Step 3 of lnt-2 synthesis), dissolved in THF (30 ml_), and water (30 ml_), was treated with powdered LiOH (0.338 g, 14.1 mmol) and stirred at room temperature. After 15 minutes LCMS showed consumption of starting material. The reaction was made slightly acidic by adding concentrated HCI (aq), then extracted into ethyl acetate, dried over sodium sulfate, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% methanol and water, using no modifier. Yield 7.2 g, 94%. lon(s) found by LCMS: (M+H)+ = 654.2.

Example 4 - Synthesis of Compound 1

Step a.

A stirring solution of methyl (2S)-2-[(N-{(2S)-2-amino-4-[(tert-butoxycarbonyl)amino]butan oyl}-L- threonyl)amino]-4-[(tert-butoxycarbonyl)amino]butanoate (0.399 g, 0.748 mmol), 2,2'-

{[(benzyloxy)carbonyl]azanediyl}diacetic acid (0.100, 0.374 mmol), and DIEA (0.261 ml_, 1 .50 mmol), in DMF (1 ml_), were treated with a solution of HATU (0.285 g, 0.748 mmol), dropwise over 30 minutes, at room temperature. The desired product was isolated by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield 0.200 g, 41 %. lon(s) found by LCMS: (M+H)+ = 1298.7.

Step b.

A solution of dimethyl (2S,5S,8S,16S,19S,22S)-12-[(benzyloxy)carbonyl]-2,8,16,22-te trakis{2-

[(tert-butoxycarbonyl)amino]ethyl}-5,19-bis[(1 Ft)-1 -hydroxyethyl]-4,7,10,14,17,20-hexaoxo- 3,6,9,12,15,18,21 -heptaazatricosane-1 ,23-dioate (0.380 g, 0.242 mmol), in methanol(1 mL) was treated with a solution of lithium hydroxide(0.028 g, 1 .171 mmol), in water(1 mL), then stirred at room

temperature for 30 minutes. The reaction was made slightly acidic(pH=5) with concentrated HCI (several drops). The desired product was isolated directly by RPLC using an Isco CombiFlash liquid

chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield 0.164 g, 44%. lon(s) found by LCMS: [(M-2Boc)/2]+H+ = 535.8, [(M-3Boc)/2]+H+ =485.8

Step c.

A solution of (2S,5S,8S,16S,19S,22S)-12-[(benzyloxy)carbonyl]-2,8,16,22-te trakis{2-[(tert- butoxycarbonyl)amino]ethyl}-5,19-bis[(1 R)-1 -hydroxyethyl]-4,7,10,14,17,20-hexaoxo-3,6,9,12,15,18,21 - heptaazatricosane-1 ,23-dioic acid (0.164 g, 0.129 mmol), tri-Boc polymyxin heptapeptide (0.329 g, 0.310 mmol, lnt-1 ), DIEA (0.146 ml_, 0.839 mmol), and DMF (1 ml_), was treated with a solution of HATU (0.175 g, 0.460 mmol) in DMF (1 ml_), dropwise over 30 minutes. The crude reaction mixture was taken on to the next Step without purification lon(s) found by LCMS: [(M-2Boc)/3]+H+ = 1053.3, [(M-3Boc)/3]+H+ = 1019.9, [(M-4Boc)/3]+H+ = 986.6.

Step d.

Crude Cbz deca Boc intermediate from step c (DMF solution) was diluted with methanol (10 ml_), charged with 5%Pd/C (0.150 g), and hydrogen from a balloon. The reaction was monitored by LCMS. After 2hr the mixture was filtered through celite, concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield 0.252 g, 61 % (two steps) lon(s) found by LCMS: [M/3J+H+ = 1075.3. Step e.

Deca-Boc-product from the previous step (0.030 g, 0.0093 mmol), was suspended in DCM (1 ml_) and treated with TFA (1 ml_), while stirring at room temperature. After 5 minutes the reaction was concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using formic acid(0.1 %) as the modifier. Yield 0.022 g, 86%. lon(s) found by LCMS: (M+3FI)/3 = 741 .8, (M+4FI)/4 =556.6.

Example 5 - Synthesis of Compound 2

HATU (1 .56 g, 4.1 1 mmol) in DMF (1 .5 ml_) was added, dropwise, to a solution of 2,2'- {[(benzyloxy)carbonyl]azanediyl}diacetic acid (0.5 g, 1 .87 mmol), norleu-OMe hydrochloride salt (0.71 g, 3.93 mmol), and triethylamine (1 .13 g, 1 1 .23 mmol) in DMF (5 ml_) over a period of 30 minutes. The mixture was stirred for an additional 20 minutes then applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford the CBZ-protected di-ester as a clear oil, ion found by LC/MS [M+H]+ = 522.6. The di-ester intermediate was stirred in a 1/1/2 mixture (10 ml_) of

THF/methanol/water containing LiOH (0.18 g, 7.48 mmol) for 20 minutes. The mixture was applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford (2S,2'S)-2,2'- ({[(benzyloxy)carbonyl]azanediyl}bis[(1 -oxoethane-2,1 -diyl)azanediyl])dihexanoic acid as a white solid. Yield: 43%, 2 Steps. Ion found by LC/MS [m-H]- = 492.3.

Step b. Synthesis of lnt-4b

EDC (0.38 g, 2.0 mmol) was added to a solution of lnt-1 (2.0 g, 1 .88 mmol), Cbz-D-Ser-OH (0.48 g, 2.0 mmol), and HOBt (0.31 g, 2.0 mmol) in a 5/1 mixture of DCM/DMF (15 mL). The mixture was stirred for an additional 2 hours and applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford the CBZ-protected intermediate a white solid. Ion found by LC/MS [m/2+H]+ = 542.4 (loss of 1 Boc group). The CBZ-protected intermediate was stirred in methanol (50 mL) containing 1 g of 5% Pd/C under 1 atmosphere of hydrogen for 6 hours. The mixture was filtered and concentrated to afford the lnt-4b (free amine) as a white solid. Yield: 73%, 2 Steps. Ion found by LC/MS [m/2+H]+ = 525.6 (loss of 1 Boc group). Step c. Synthesis of lnt-4c

HATU (370 mg, 0.97 mmol) in DMF (2 ml_) was added, dropwise over 30 minutes, to a stirring solution of lnt-4b (1 .10 g, 0.95 mmol), CBZ-Thr-OH (253 mg, 1 .0 mmol), and triethylamine (300 mg, 2.97 mmol) in DMF (6 ml_). The reaction was stirred for 30 minutes and then applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford 1 .1 g of the CBZ-protected intermediate a white solid. LC/MS [m/2+H] ⁺ = 593.0 (loss of 2 Boc groups). The CBZ-protected intermediate was stirred in methanol (50 mL) containing 0.30 g of 5% Pd/C under 1 atmosphere of hydrogen for 6 hours. The mixture was filtered and concentrated to afford the lnt-4c (free amine) as a white solid. Yield: 66%, 2 Steps. Ion found by LC/MS [m/2+H] ⁺ = 525.8 (loss of 2 Boc groups).

Step d. Synthesis of lnt-4d

The title compound was prepared from lnt-4c and Z-(yBoc)-Dab-OH in an analogous manner as described in step c. Yield: 78%. Ion found by LC/MS [M/2+H] ⁺ 676.2 (loss of 1 Boc group). Step e. Synthesis of lnt-4e

FIATU (0.1 1 g, 0.30 mmol) in DMF (0.5 ml_) was added, dropwise, to a stirring mixture of lnt-4d (0.44 g, 0.30 mmol), and INT-A1 (0.70 g, 0.14 mmol) in DMF (1 .5 ml_) over a period of 20 minutes. The mixture was applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 30% to 95% methanol and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford the CBZ-protected intermediate, LC/MS [m/3+H] ⁺ 1020.0 (loss of 3 Boc groups). The CBZ- intermediate was stirred in methanol (10 mL) in the presence of 5% Pd/C (100 mg) under 1 atmosphere of hydrogen for 2 hours. The mixture was filtered and concentrated then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 30% to 95% acetonitrile and water using no modifier. The pure fractions were pooled and lyophilized to afford the title compound as a white solid. Yield: 51 %, 2 Steps. Ion found by LC/MS [m/2+H] ⁺ = 1562.6 (loss of 2 Boc groups).

Step f. Synthesis of Compound 2

The product from step e is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 0% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier. Example 6 - Synthesis of lnt-5

Step a. Synthesis of lnt-5a (benzyloxycarbonyl -3,4-bis{[(2S)-1-methoxy-1-oxooctan-2- yl]carbamoyl}pyrrolidine)

A solution of racemic 1 -[(benzyloxy)carbonyl]pyrrolidine-3,4-dicarboxylic acid (3.69 g, 12.6 mmol), methyl (2S)-2-aminooctanoate (4.58 g, 26.4 mmol), and DIEA (13.8 ml_, 79.3 mmol), in DMF (20 ml_) was treated with HATU (10.0 g, 26.4 mmol) at room temperature for 30 minutes. The crude product was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% methanol and water, using no modifier. Two diastereomers where observed and were separable. The desired more polar isomer (lnt-5a) had the shorter retention time and was taken on to Step b. Yield 1 .44 g, 19%. Step b. Synthesis of lnt-5

A solution of benzyloxycarbonyl -3,4-bis{[(2S)-1 -methoxy-1 -oxooctan-2-yl]carbamoyl}pyrrolidine (1 .44 g, 2.38 mmol, more polar isomer from Step A, lnt-5a) in THF (10 ml_) and water (10 ml_) was treated with powdered lithium hydroxide (0.143 g, 5.96 mmol) at room temperature. LCMS after 10 minutes showed complete conversion. The reaction was made slightly acidic by adding concentrated HCI, and concentrated to an oil. The oil was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% acetonitrile and water, using TFA as the modifier. Yield 1 .14 g, 83% yield.

Example 7 - Synthesis of aminooctanoyl penta Boc polymyxin B decapeptide (lnt-7)

Step a. Synthesis of penta Boc polymyxin B decapeptide (lnt-6)

Tri-Boc polymyxin B heptapeptide (0.464, 0.437 mmol, lnt-1 ), and tripeptide acid (0.316, 0.398 mmol, lnt-3), were dissolved in DMF (1 ml_), DIEA (0.229 ml_, 1 .31 mmol), then treated with HATU (0.166 g, 0.437 mmol). After stirring for 30 min LCMS showed complete conversion. The crude Cbz-product was diluted with methanol (4 mL), and charged with 5%Pd/C (0.250 g) and placed under a hydrogen atmosphere. After 2 hr the mixture was filtered through Celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield of lnt-6 was 0.640 g, 94% (two steps) lon(s) found by LCMS: [(M-1 Boc)/2]+H+ = 1054.6, [(M-2Boc)/2]+H+ = 1004.6. Step b. Synthesis of aminooctanoyl penta Boc polymyxin B decapeptide (lnt-7)

A solution of lnt-6 (3.00 g, 1 .918 mmol), Cbz-aminooctanoic acid (0.591 g, 2.01 mmol), and DIEA (1 .05 mL, 6.04 mmol), in DMF (10 ml_), was treated with a solution of HATU (0.766 g, 2.01 mmol) dissolved in DMF (3 mL), dropwise over 60 minutes. After 2h, LCMS showed complete consumption of starting material. The crude mixture was treated with 5% Pd/C (1 .7 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2hr or until complete by LCMS. The crude reaction was filtered through Celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid

chromatograph eluted with 20% to 100% methanol and water, using no modifier. Yield of lnt-7 was 2.59 g, 79% (two steps) lon(s) found by LCMS: [M/2]+H+ = 853.4.

Example 8 - Synthesis of Compound 3

Step a. Synthesis of lnt-8

A solution of lnt-5 (0.401 g, 0.70 mmol), lnt-6 (2.18 g, 1 .39 mmol), and DIEA (0.76 ml_, 4.39 mmol) in DMF, was treated with a solution of HATU (0.557 g, 1 .46 mmol) in DMF (5 ml_), dropwise over 1 h. After stirring for an additional 30 minutes the reaction was charged with 5% Pd/C (1 .5 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture was filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid

chromatograph eluted with 30% to 100% methanol and water, using no modifier. Yield 1 .39 g, 56% yield.

Step b. Synthesis of Compound 3

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 0% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier.

Example 9 - Synthesis of Compound 4

Step a. Synthesis of amino Peg 8 penta Boc polymyxin B undecapeptide (lnt-9a)

Boc Boc Boc

HN HN HN

Boo

A solution of lnt-7 (0.600 g, 0.352 mmol), Cbz-amino Peg 8 acid (0.223 g, 0.387 mmol), and DIEA (0.202 ml_, 1 .161 mmol), in DMF (3 ml_) was treated with a solution of HATU (0.147 g, 0.387 mmol), in DMF (1 ml_), dropwise over 1 hr. After stirring for an additional 30 minutes, the reaction was charged with 5% Pd/C (0.400 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere until complete by LCMS (2h). The resulting mixture was filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier. Yield 0.450 g, 64%. lon(s) found by LCMS: [M/2]+H+ = 1064.6, [M-1 (Boc)/2]+H+ = 1014.6.

Step b. Synthesis of deca Boc PEG8 polymyxin B dimer (lnt-9b)

A solution of amino PEG8 penta Boc polymyxin B undecapeptide (0.746 g, 0.350 mmol), Cbz iminodiacetic acid(0.046 g, 0.171 mmol), and DIEA(0.197 ml_, 1 .13 mmol), in DMF (5 ml_), was treated with a solution of HATU (0.133 g, 0.350 mmol) in DMF (2 ml_), dropwise over 1 h. After stirring an additional 30 minutes, the reaction was charged with 5% Pd/C (0.350 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere until complete by LCMS. The crude reaction was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier. Yield 0.465 g, 62% (two steps) lon(s) found by LCMS: [M-3(Boc)/4]+H+ = 897.3, [M- 4(Boc)/4]+H+ = 872.3.

Step c. Synthesis of Compound 4

The product from step b is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% methanol and water, using trifluoroacetic acid as the modifier. Example 10 - Synthesis of Compound 5

Compound 5

Step a. Synthesis of deca Boc amino PEG 8 dimer (lnt-10)

A solution of lnt-7 (0.500 g, 0.291 mmol), Cbz-amino PEG 8 diacid (0.089 g, 0.138 mmol), and DIEA (0.167 ml_, 0.960 mmol), in DMF (4 ml_), was treated with a solution of HATU (0.122 g, 0.320 mmol), in DMF (1 ml_), dropwise over 1 h. After stirring an additional 30 minutes, the reaction was charged with 5% Pd/C (0.5 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere until complete by LCMS. The crude mixture was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier. Yield 0.212 g, 37% (two steps) lon(s) found by LCMS: [M-3(Boc)/4]+H+ = 897.3, [M-4(Boc)/4]+H+ = 872.3. Step b. Synthesis of Compound 5

Compound 5

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 10% to 100% methanol and water, using trifluoroacetic acid as the modifier.

Example 11 - Synthesis of Compound 6

Step a. Synthesis of lnt-11

A solution of Cbz-iminodiacetic acid (0.149 g, 0.557 mmol), lnt-7 (2.00 g, 1 .173 mmol, described in Example 9.), and DIEA (0.644 ml_, 3.69 mmol) in DMF, was treated with a solution of FIATU (0.468 g,

1 .231 mmol) in DMF (5 ml_), dropwise over 1 h. After stirring for an additional 30 minutes the reaction was charged with 5% Pd/C (1 .0 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture was filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier. Yield 1 .0 g, 48% yield (two steps).

Step b. Synthesis of Compound 6

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 10% to 100% methanol and water, using trifluoroacetic acid as the modifier.

Example 12 - Synthesis of lnt-12 (azido-peg4-hexyl pyrolidine-3, 4-dicarboxamide)

Step a. Synthesis of benzyloxycarbonyl -3,4-bis{[(2S)-1-methoxy-1-oxohexan-2- yl]carbamoyl}pyrrolidone

HATU in DMF is added, dropwise, to a solution of racemic 1 -[(benzyloxy)carbonyl]pyrrolidine-3,4- dicarboxylic acid, H-Norleu-OMe-hydrochloride, and triethylamine over a period of 20 minutes. The reaction mixture is stirred at room temperature and then applied directly to RPLC using an Isco

Combiflash liquid chromatograph eluting with 5% to 100% methanol and water, using no modifier. Two diastereomers are observed. The desired isomer (lnt-12a) is used in the next step (step b).

Step b. Synthesis of lnt-12

A solution of the product from step a is dissolved in THF and water. Powdered lithium hydroxide is added and the reaction is stirred at room temperature. After complete conversion, the reaction is made slightly acidic by adding concentrated HCI and then concentrated. The crude material is purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% acetonitrile and water, using TFA as the modifier. Example 13 - Synthesis of Compound 7

Step a. Synthesis of lnt-13 A solution of lnt-12, lnt-6, and DIEA in DMF is treated with a solution of FIATU in DMF, dropwise over 1 h. After stirring for an additional 30 minutes the reaction is charged with 5% Pd/C, vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture is filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier.

Step b. Synthesis of Compound 7

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier.

Example 14 -Synthesis of Compound 8

Step a. Synthesis of lnt-1-Gly Conjugate

NHBoc

lnt-14a NHBoc

To a mixture of lnt-1 (4.24 g, 4 mmol) and Z-Gly-OH (1 g, 4.8 mmol) in anhydrous DMF (8 ml_) was added HATU (1 .87 g, 4.9 mmol) in portions over 20 minutes, followed by DIPEA (936 mg, 7.2 mmol). After the reaction mixture was stirred for 15 minutes, it was poured into water (100 ml_). The white solid product was collected by filtration and washed with water. The material was re-dissolved in MeOH (50 ml_) and treated with Pd/C (1 g). The mixture was stirred under hydrogen overnight. Pd/C was then filtered off, and the filtrate was concentrated and purified through RPLC (150 g, 15 to 75 % MeOH and water). Yield 4.02 g, 89.8 %. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 510.4, [(M - 3Boc + 2H)/2] ⁺ = 410.2

Step b.

NHBoc

-

NHBoc

To a mixture of the step a product (4.02 g, 3.592 mmol) and Z-Thr-OH (980.3 mg, 3.87 mmol) in anhydrous DMF (5 ml_) was added HATU (1 .47 g, 3.87 mmol) in portions over 10 minutes, followed by DIPEA (755 mg, 5.8 mmol). After the addition, the reaction was stirred for 20 minutes and then poured into water (100 ml_). The white solid product was collected by filtration and washed with water. The material was re-dissolved in MeOH (50 ml_) and added with Pd/C (1 g). The mixture was stirred under hydrogen overnight. Pd/C was then filtered, and the filtrate was concentrated and purified through RPLC (150 g, 15 to 80 % MeOH and water). Yield 3.68 g, 83.9 %. Ions found by LCMS: [(M - 2Boc + 2H)/2] ⁺ =

51 1 . Step C.

A mixture of the step b product (1 .2 g, 0.984 mmol) and Z-Dab(Boc)-OH.DCHA (605 mg, 1 .13 mmol) was dissolved in anhydrous NMP (3 ml_). It was added with HATU (430 mg, 1 .13 mmol) in portions over 5 minutes, followed by DIPEA (150 mg, 1 .13 mmol). The reaction was stirred for 30 minutes and then directly purified through RPLC (100 g, 40 to 100 % MeOH and water). The collected fractions were concentrated by rotary evaporation to a white solid (Ion found by LCMS: [M - 2Boc + 2H)/2] ⁺ = 678). The material was re-dissolved in MeOH (30 ml_) and treated with Pd/C. The mixture was stirred under hydrogen overnight. Pd/C was filtered, and the filtrate was concentrated by rotary evaporation and further dried under high vacuum. Yield 1 .07 g, 76.6%. Ion found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 61 1 .

Step d. Synthesis of lnt-14d

A solution of the step c product, lnt-12, and DIEA in DMF is treated with a solution of HATU in DMF, dropwise. After stirring for an additional 30 minutes the reaction is charged with 5% Pd/C, vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture is filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier. Step e. Synthesis of Compound 8

The step d product is dissolved in TFA/DCM (1 :1 , 1 ml_), and the solution is stirred for 30 minutes. It is directly purified by RPLC (50 g, 5 to 30 % acetonitrile and water, using 0.1 % TFA as modifier).

Example 15 - Synthesis of Compound 9

NH ₂ NH ₂ Step a.

A solution of racemic trans-cyclopentanone-3, 4-dicarboxylic acid (0.500 g, 2.90 mmol), L- norleucine methylester HCI (1 .16 g, 6.39 mmol), DIEA (3.03 ml_, 17.4 mmol), and HATU (2.43 g, 6.39 mmol) in DMF (5 ml_) was stirred at room temperature for 1 hr. The diastereomeric products were separated by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. The diastereomer with the shorter retention time was collected and taken on in the sequence. Yield of desired diastereomer 0.419 g, 34% yield lon(s) found by LCMS: did not ionize.

Step b.

A solution of product from the previous step, Boc-piperazine, acetic acid, and dichloromethane is stirred for 30 min at room temperature, and then treated with sodium triacetoxyborohydride in two equal portions 60 minutes apart. The reaction is stirred overnight, then purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier.

Step c.

A solution of product from the previous step dissolved in THF is treated with a solution of lithium hydroxide dissolved in water. After complete conversion, the reaction is made slightly acidic with concentrated HCI, then purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using no modifier.

Step d

A solution of the di-acid product from the previous step, lnt-6, and DIEA dissolved in DMF is treated with a solution of HATU in DMF, dropwise, over 60 minutes. Product is isolated by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using 0.1 % TFA as the modifier.

Step e.

A solution of the Boc-protected product from the previous step is stirred in TFA for five minutes, and then stripped of TFA using a rotary evaporator. Product is isolated by RPLC using an Isco

CombiFlash liquid chromatograph eluted with 5% to 100% methanol and water, using 0.1 % TFA as the modifier. Example 16 - Synthesis of Compound 10

Step a.

In a sealed tube, a stirring mixture of methyl 3-bromo-5-(bromomethyl)benzoate (3.08 g, 10.00 mmol) and sodium azide (0.715 g, 1 1 .00 mmol) in DMF (10 ml_) was heated at 80 °C for 1 h, when HPLC analysis showed full conversion of the bromide. All the volatiles were evaporated. The residue was taken up in DCM (40 ml_) and water (40 ml_). The water layer was washed with additional DCM (2 x 30 ml_).

The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated, affording 2.73 g of the crude azide derivative in high purity, as confirmed per ¹ H-NMR and LC-MS analysis. ¹ H NMR (DMSO-afe) d: 8.03 (t, J = 1 .6 Hz, 1 H), 7.98 - 7.93 (m, 1 H), 7.90 (t, J = 1 .5 Hz, 1 H), 4.60 (s, 2H), 3.88 (s, 3H). This azide (2.73 g) was dissolved under stirring in THF (30 ml_) and water (2 ml_), and triphenylphosphine (3.148 g, 12.00 mmol) was added. The reaction was stirred at room temperature overnight, allowing gas evolution through a bubbler. All the volatiles were evaporated per vacuum techniques. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 20% hexanes and ethylacetate. From the desired fractions, the desired compound was obtained still contaminated with triphenylphenylphosphine oxide. This material was therefore dissolved in DCM (50 ml_) and extracted an acidic solution (12 ml_ of 1 .0 M H2SO4 and 30 ml_ of water). The water layer was added dropwise to a vigorously stirring solution of saturated sodium bicarbonate (60 ml_) and stirring was continued overnight. The obtained mixture was extracted with DCM (3 x 30 ml_). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated per vacuum techniques, affording 1 .31 g, 54% of 3-(aminomethyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ = 244.0; 246.0.

Step b.

A solution of methyl 3-(aminomethyl)-5-bromobenzoate (1 .306 g, 5.350 mmol) and methyl 3- bromo-5-formylbenzoate (1 .238 g, 5.096 mmol) in DCM (10 ml_) was evaporated and left over high vacuum overnight. The residue was taken up in THF (30 ml_) and treated under vigorous stirring with sodium triacetoxyborohydride (3.240 g, 1 5.29 mmol). This mixture was quenched after 18 h by the addition of a saturated aqueous solution of ammonium chloride (50 ml_). The obtained mixture was extracted with DCM (3 x 30 ml_). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 50% hexanes and ethylacetate. Yield 1 .61 1 g, 67% of 3-((N-(1 '-(3'-carboxymethyl-5- bromo)phenylene)methylene)methyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ = 470.0, 472.1 , 474.0.

Step C.

To a 0 ^° C stirring solution of methyl 3-((N-(1 '-(3'-carboxymethyl-5- bromo)phenylene)methylene)methyl)-5-bromobenzoate (1 .61 1 g, 3.419 mmol) and DIPEA (0.953 ml_, 5.471 mmol) in THF (20 ml_) it was added Cbz-CI (0.732 ml_, 5.129 mmol) dropwise. The temperature was raised to ambient temperature after 10 minutes and stirring was continued until complete

disappearance of the starting amine by LC-MS analysis. All the volatiles were removed by rotatory evaporation. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 20% hexanes and ethylacetate. Yield 2.070 g, quantitative yield of N-Cbz protected methyl 3-((N-(1 '-(3'-carboxymethyl-5- bromo)phenylene)methylene)methyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ = 603.0, 605.0, 607.0.

Step d.

Under nitrogen, in a capped microwave reaction vessel stirring mixture of N-Cbz protected methyl 3-((N-(1 '-(3'-carboxymethyl-5-bromo)phenylene)methylene)methyl)-5-br omobenzoate (0.299 g, 0.494 mmol), potassium phenyltrifluoroborate (0.200 g, 1 .087 mmol), sodium carbonate (0.209 g, 1 .976 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.035 g, 0.049 mmol) in MeCN (4 ml_) and water (4 ml_) were irradiated with microwaves for 10 mim at 130 °C. Upon cooling, the reaction was treated under stirring with SiliaMetS® (0.200 g, 0.240 mmol) for 1 h, and TFA was added (0.380 ml_, 5.0 mmol). Upon filtration, all the volatiles were evaporated per vacuum techniques. The desired product was isolated as a dodeca-TFA salt by RPLC using an Isco CombiFlash liquid chromatograph eluted with 0% to 100% methanol and water, using TFA as the modifier. Yield 0.072 g, 25% yield of N-Cbz protected 3-((N-(1 '-(3'- carboxy-5-phenyl)phenylene)methylene)methyl)-5-phenylbenzoic acid. ¹ H NMR (0.500 ml_ Chloroform-c/ + 0.050 ml_ TFA) d: 8.18 (d, J = 5.5 Hz, 2H), 7.82 (d, J = 16.6 Hz, 2H), 7.60 (d, J = 33.5 Hz, 2H), 7.52 - 7.27 (m, 15H), 5.32 (s, 2H), 4.70 (d, J = 19.9 Hz, 4H). Step e.

To a 0 °C stirring solution of N-Cbz protected 3-((N-(1 '-(3'-carboxy-5- phenyl)phenylene)methylene)methyl)-5-phenylbenzoic acid (0.075 g, 0.131 mmol), lnt-6 (0.466 g, 0.262 mmol, described in Example 7, step a), and DIEA (0.137 ml_, 0.787 mmol) in DMF (5.0 ml_), was treated with a solution of HATU (0.102 g, 0.269 mmol) in DMF (1 .5 ml_), dropwise. Temperature was slowly allowed to reach ambient temperature after 15 min. Upon completion, all the volatiles were evaporated. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to

100% water and methanol, using no modifier. Yield 0.451 g, 94% yield. ¹ H NMR for the diagnostic peaks ¹ H NMR (Methanol-cfc) d: 8.12 - 7.09 (m, 31 H), 5.25 (s, 2H), 1 .41 (br d, J = 10.2 Hz, 90H), 1 .24 - 1 .04 (m, 12H), 0.69 (br d, J = 18.7 Hz, 12H).

Step f.

Product from step e was dissolved in methanol (25 ml_) and suspended with SiliaCatPd(O)® (0.123 g, 0.025 mmol) under hydrogen atmosphere (~1 atm). When all the starting material was consumed by HPLC analysis, the mixture was filtered over a short Celite pad, and all the volatiles were evaporated per vacuum techniques. HPLC analysis for the residues revealed one component in high purity, so it was used in the next step without further purification. Yield 0.431 g, 99% yield. ¹ H NMR for the diagnostic peaks ¹ H NMR (Methanol-dt) d: 8.07 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 4H), 7.74 - 7.70 (m, 4H), 7.55 - 7.1 1 (m, 18H), 1 .42 (d, J = 1 1 .1 Hz, 90H), 1 .20 (br t, J = 6.7 Hz, 12H), 0.69 (br d, J = 17.9 Hz, 12H)

Step g.

Product from step f is treated with dichloromethane, 2-methyl-2-butene, and TFA until gas evolution ceased (bubbler monitoring), then concentrated to an oil. The product is purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% water and methanol, using 0.1 % TFA as the modifier. Example 17 - Synthesis of Extended Threonines

The general method for the preparation of the extended threonines is described in Aiker et al. , Tetrahedron 54 6089-6098 (1998).

Propionaldehyde (7.4 g, 127 mmol, 3 eq.) was added to a solution of the 5-phenyl-morpholin-2- one (7.5 g, 42 mmol, 1 eq.) in 100 mL toluene along with 15 grams of activated 4A sieves and a condenser. The reaction mixture was heated to reflux for 24 hours under nitrogen. The reaction was filtered and concentrated to give the crude product as an oil, which was used in the next step without any purification lon(s) found by LCMS: (M+H) ⁺ = 276.2.

Step b.

To the crude material from step a in methanol (50 mL) was added 2 M HCI (10 mL). The reaction mixture was heated to reflux under nitrogen until LCMS indicated the absence of starting material and the presence of a new compound (1 -2h). The solvent was removed in vacuo to yield a yellow oil, which was then purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of the product as yellow oil: 5.6 g, 42% yield in two steps lon(s) found by LCMS: (M+H)+ = 267.2.

Step c.

The compound from step b (1 .3 g, 5 mmol) was dissolved into 30 ml_ methanol, Pearlman's catalyst (1 .3 g) and ammonium formate (3.1 g, 10 eq.) were added to the reaction vessel and the solution degassed and heated to reflux for 4 hours. The solution was cooled and filtered to remove the catalyst. Solvent was removed in vacuo and the crude mixture was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of product as yellow oil as TFA salt, 1 .30 g, 100% yield lon(s) found by LCMS: (M+H) ⁺ = 147.1 .

Step d.

Lithium hydroxide (120 mg, 5 mmol) in 2 mL water was added into a solution of the amino acid ester from the previous step (0.3 g, 2 mmol) in 2 mL water, 2 mL methanol and 2 mL THF. The reaction was monitored by LCMS. After completion, the solution was treated with Amberlite® IRN-77, ion exchange resin to adjust to pH 1 , then filtered, concentrated, and used in next step without further purification.

Step e.

The amino acid from the previous step (0.3 g, 2 mmol) was dissolved in 5 ml_ methanol and 5 ml_ Sat. NaHC03 solution, followed added CbzCI (510 mg, 3 mmol, 1 .5 eq.), the solution was stirred for 1 hour then neutralized by 1 N HCI. The solution was extracted with ethyl acetate and dried over Na2SC>4. The solution was concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of the product as a yellow oil, 450 mg, 92% yield lon(s) found by LCMS: (M+H)+ = 268.1 .

Example 18 - Synthesis of lnt-16c

General method for the preparation of a decapeptide containing an extended L-threonine

Step a.

To a solution of lnt-1 (2.1 g, 2 mmol, Example 1 ) and (2S)-2-{[(benzyloxy) carbonyl]-amino}-4- [(tert-butoxycarbonyl)amino]butanoic acid (740 mg, 2 mmol) in DMF (30 ml_) was added EDC (0.6 g, 3 mmol), HOBT (0.45 g, 3 mmol), and DIEA (0.7 ml_, 5 mmol) at room temperature. The solution was stirred overnight. The resulting solution was concentrated and re-dissolved into 5 ml_ methanol, then added drop-wise to 200 ml_ vigorously stirred water, this heterogeneous solution was stirred for 1 hour, then filtered with Buchner funnel with Filter paper. The collected crude product was re-dissolved into 20 ml_ methanol, then 1 g of 5% Pd/C was added to the above solution, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Palladium was removed by filtration after the reaction was complete as determined by LCMS. The filtrate was concentrated and used next step without further purification lon(s) found by LCMS: [M/2]+H+= 631 .9, [M/3J+H+ = 421 .6.

Step b.

To a solution of product from the previous step and (3R)-N-[(benzyloxy)carbonyl]-3-hydroxy-L- norvaline (540 mg, 2 mmol) in DMF (20 mL) was added EDC (0.6 g, 3 mmol), HOBT (0.45 g, 3 mmol), DIEA (0.56 mL, 4 mmol) at room temperature. The solution was stirred overnight. The resulting solution was concentrated and re-dissolved into 5 mL methanol and added dropwise into 100 mL vigorously stirred water, this heterogeneous solution was stirred for 1 hour, then filtered with Buchner funnel with filter paper. The collected crude product was re-dissolved in 20 mL methanol, then treated with 1 g of 5% Pd/C. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The palladium charcoal was removed by filtration. The filtrate was concentrated and used next step without further purification lon(s) found by LCMS: [M/2]+H+= 689.4, [M/3]+H+ = 459.9. Step c.

To a solution of PMB nonapeptide-NH2 from the previous and (2S)-2-{[(benzyloxy) carbonyl]- amino}-4-[(tert-butoxycarbonyl)amino]butanoic acid (720 mg, 2 mmol) in DMF (20 ml_) was added EDC (0.6 g, 3 mmol), HOBT (0.45 g, 3 mmol), DIEA (0.56 ml_, 4 mmol) at room temperature. The solution was stirred overnight. The resulting solution was concentrated and re-dissolved into 5 ml_ methanol, then added drop-wise into 100 ml_ vigorously stirred water. This heterogeneous solution was stirred for 1 hour, then filtered with Buchner funnel with filter paper. The collected crude product was dissolved in 20 ml_ methanol, then treated withl g of 5% Pd/C. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The palladium charcoal was removed by filtration. The filtrate was concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of product as a TFA salt: 2.3 g, 73% yield lon(s) found by LCMS: [M/2]+FI+= 789.5, [M/3J+H+ = 526,7, [M/4J+H+ = 395.3.

Example 19 - Synthesis of Compound 11

General method for the preparation of the corresponding PMB dimer

Step a.

To lnt-4a and lnt-16c in DMF is added EDC, HOBT, and DIEA at room temperature. The solution is stirred overnight. The resulting solution is concentrated and re-dissolved into methanol. The resulting solution is added dropwise into vigorously stirred water, and this heterogeneous solution is stirred for 1 hour and then filtered with Buchner funnel with filter paper.

Step b.

The compound from the previous step is dissolved in methanol and 5% Pd/C is added to the solution. The mixture is stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture is filtered and concentrated. Step c. Deprotection to give Compound 11

H ₂ N

Product from the previous step is dissolved in DCM and and treated with TFA at room temperature. The solution is stirred 10 min, then concentrated and purified by RPLC using an Isco

CombiFlash liquid chromatograph eluted with 0% to 1 00% acetonitrile and water, using formic acid as the modifier.

Example 20 - Synthesis of Compound 12

The title compound Compound 12 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with butyraldehyde in step a of Example 17. Example 21 - Synthesis of Compound 13

The title compound Compound 13 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with heptanal in step a of Example 17.

Example 22 - Synthesis of Compound 14

The title compound Compound 14 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with 3-phenylpropionaldehyde in step a of Example 17. Example 23 - Synthesis of Compound 15

The title compound Compound 15 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with butyraldehyde in step a of Example 17, and where lnt-4a is substituted with lnt-12 in step a of Example 19.

Example 24 - Synthesis of Compound 16

The title compound Compound 16 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with heptanal in step a of Example 17, and where Int- 4a is substituted with lnt-12 in step a of Example 19.

Example 25 - Synthesis of Compound 17

The title compound Compound 17 is prepared analogously to Example 17, Example 1 8, and Example 19, where lnt-16c is substituted with the lnt-6.

Example 26 - Synthesis of Compound 18

The title compound Compound 18 is prepared analogously to Example 17, Example 1 8, and

Example 19, where propionaldehyde is substituted with heptanal in step a of Example 17. Example 27 - Synthesis of Compound 19

The title compound Compound 19 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with butyraldehyde in step a of Example 17, and where lnt-4a is substituted with lnt-12 in step a of Example 19.

Example 28 - Synthesis of Compound 20

Step a.

Benzyl Bromo-acetate is added into a solution of Boc-aminoethylpiperazine and DIPEA in DMF. The resulting solution is stirred at room temperature for overnight. The reaction solution is concentrated and purified by flash chromatography to provide products.

Step b.

Boc

Lithium hydroxide in water is added into a solution of the amino acid ester from step a in methanol and THF. After completion, the solution is adjusted to pH 1 with Amberlite® IRN-77. The resulting solution is filtered and concentrated.

Step c.

To a solution of intermediate from the previous step and L-norleucine methylester HCI in DMF is added EDC, HOBT, and DIEA at room temperature. The solution is stirred overnight. The resulting solution is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Step d.

Lithium hydroxide in water is added into a solution of the amino acid ester from step c in methanol and THF. After completion, the solution is adjusted to pH 1 with Amberlite® IRN-77, then the resulting solution is filtered and concentrated.

Step e.

To a mixture of the compound from step d and penta-Boc-polymyxin B decapeptide in DMF (5 ml_) is added EDC, HOBT, and DIEA at room temperature. The solution is stirred overnight then concentrated and redissolved into methanol. This solution is added dropwise to vigorously stirred water. This heterogeneous solution is stirred for 1 hour, then filtered with a Buchner funnel with filter paper.

Step f.

Intermediate from step e is treated with DCM and TFA at room temperature. The solution is stirred 10 min, then concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 0% to 100% acetonitrile and water, using formic acid as the modifier.

Example 29 - Synthesis of Compound 21

A flask is charged with (S)-Methyl 2-amino-5-methylhexanoate, 2,2'- {[(benzyloxy)carbonyl]azanediyl}diacetic acid, and DIEA in anhydrous DMF. To this reaction mixture is added a solution of HATU in DMF (1 ml_) at a rate of 2.5 ml_/h. After the addition, the reaction mixture is stirred for an addition hour then is purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5% to 95% acetonitrile and water, using 0.1 % TFA as modifier.

Step b.

A solution of bis-ester product from the previous step dissolved in MeOFLTHFiFbO (1 :1 :2) is treated with lithium hydroxide solid. The reaction mixture is stirred overnight. After the reaction is completed by monitoring with LCMS, the reaction is quenched with glacial acetic acid to pH 4, stripped of methanol and tetrahydrofuran then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 55% acetonitrile and water, using 0.1 % TFA as modifier.

Step c.

A flask is charged with di-acid product from the previous step, HOAt, EDC, and lnt-6 in DMF. The reaction mixture is stirred at room temperature for 10 minutes followed by addition of DIEA and then stirred overnight. The deca-Boc-protected intermediate is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 25% then 100% methanol and water, using 0.1 % TFA as modifier. Pure fractions are combined and concentrated to yield deca-boc-protected intermediate.

A solution of deca-Boc-protected intermediate is stirred in TFA/CH2CI2 (1 :1 ) at ambient temperature for 1 hour then stripped of TFA and CH2CI2 using the rotary evaporator. The product is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 30% acetonitrile and water, using 0.1 % TFA as modifier. Step d.

The product from the previous step is dissolved in methanol and 5% Pd/C is added to the solution. The mixture is stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture is filtered and concentrated.

Example 30 - Synthesis of Compound 22

The title compound Compound 22 is prepared analogously to Example 29, where lnt-6 is substituted with lnt-1 6c in step c of Example 29.

Example 31

Synthesis of Compound 23

Polar peak

lnt-19a Less Polar peak

Polar peak (R.R)

Less Polar peak A flask was charged with L-valine methyl ester HCI (0.970 g, 5.786 mmol), racemic-trans-(ferf- butoxycarbonyl)pyrrolidine-3,4-dicarboxylic acid (0.500 g, 1 .929 mmol), DIEA (2.0 ml_, 1 1 .57 mmol) in anhydrous DMF (8 ml_). To this reaction mixture was added a solution of HATU (2.2 g, 5.86 mmol) in DMF (8 ml_) at a rate of 4 mL/h. After stirring overnight solvent was stripped to half of the volume then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 45% acetonitrile and water, using 0.1 % TFA as modifier. Yield of 0.0845 g polar diastereomer 9% (used in the next step). Yield of less polar isomer 0.18 g, 14% yield (discarded) lon(s) found by LCMS: (M-Boc)+ = 386.2

Step b.

Boc

lnt-19b

A solution of bis-ester from the previous step, dissolved in Me0H:THF:H20 (1 :1 :2), is treated with lithium hydroxide solid. The reaction mixture is stirred overnight. After the reaction is completed by monitoring with LCMS, the reaction is quenched with glacial acetic acid to pH 4, stripped of methanol and tetrahydrofuran then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 45% acetonitrile and water, using 0.1 % TFA as modifier.

Step c.

H

A 4 ml_ scintillation vial is charged with lnt-19b, HOAt, EDC, and PMB-decapeptide-D-Ser (lnt-4d) in DMF. The reaction mixture is stirred at room temperature for 10 minutes followed by addition of DIEA, then continued to stir overnight. Crude product is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 25% then 100% methanol and water, using 0.1 % TFA as modifier. Pure fractions are combined and concentrated to yield Boc-protected intermediate.

A solution of Boc-protected intermediate is stirred in TFA/CH2CI2 (1 :1 , 6 ml_) at ambient temperature for 1 hour then stripped of TFA and CPI2CI2 using a rotary evaporator. The product is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 30% acetonitrile and water, using 0.1 % TFA as modifier.

Example 32 - Synthesis of Compound 24

H ₂ N

The title compound Compound 24 is prepared analogously to Example 31 , where lnt-4d is substituted with lnt-6 in step c of Example 31 .

Example 33 - Synthesis of Compound 25

Step a.

A flask was charged with tri-Boc-PMBH-(NH2) (2.00 g, 1 .883 mmol, Example 1 , lnt-1 ), 1 -Cbz- aminocyclopropane carboxylic acid (0.542 g, 2.259 mmol) and DIEA (0.98 ml_, 5.65 mmol) in DMF (19 ml_). To this solution was added a solution of HATU (0.877 g, 2.259 mmol) in DMF (3.5 ml_) via a syringe pump at rate of 2.5 mL/hr. The reaction was stirred overnight at ambient temperature. The reaction mixture concentrated to half of its volume using the rotary evaporator then purified by RPLC using an Isco CombiFlash eluting with 5% to 25% to 90% methanol and water, using 0.1 % TFA as modifier. Yield 2.159 g, 90%. lon(s) found by LCMS [(M-2Boc+2H)/2]+ = 540.5.

Step b.

A solution of the product from the previous step (2.08 g, 1 .62 mmol) in methanol (15 ml_) was charged with Pd/SiC>2 (0.405 g, 0.081 mmol) and hydrogen gas balloon. The reaction mixture was stirred at ambient temperature overnight. It was filtered through a pad of Celite® and washed with methanol, then concentrated to the title compound as white solid. Yield 1 .94 g, 104%. lon(s) was found by LCMS: : [(M-2Boc+2H)/2]+ = 473.4, [(M-3Boc+2H)/2]+ = 423.3 Step C.

A flask was charged with product from the previous step (0.979 g, 0.855 mmol), N-Cbz-L- threonine (0.227 g, 0.898 mmol), HOAt (0.175 g, 1 .282 mmol) and EDC (0.246 g, 1 .28 mmol) in DMF (2.6 ml_) then stirred for 10 minutes following by addition of DIEA (0.45 ml_, 2.56 mmol). The reaction mixture was stirred at ambient temperature overnight. It was purified by RPLC using an Isco CombiFlash eluting with 5% to 25% then 100% acetonitrile and water, using 0.1 %TFA as modifier. Yield 0.84 g, 71 %. lon(s) found by LCMS: [(M-2Boc+2H)/2]+ = 590.8 Step d.

The title compound was prepared from the product of the previous step using the procedure described in Step b of this example. Yield 0.725 g, 96%. lon(s) found by LCMS: [M-2Boc+2H)/2]+ = 523.6

Step e.

The title compound was prepared from the product of the previous (0.725 g, 0.581 mmol) and Z- dab(D Boc)-OH DOHA salt (0.341 g, 0.639 mmol) as described in procedure from Step c. Yield 0.626 g, 68%. lon(s) found by LCMS: [(M-2Boc+2H)/2]+ = 690.4

Step f.

The title compound was prepared from the product of the previous step (0.626 g, 0.396 mmol) and Pd/SiC>2 (0.099 g, 0.02 mmol) as described in step b of this example. Yield 0.575 g. 100%. lon(s) found by LCMS: (M+Na)+ = 646.0

Step g.

H ₂ N

The title compound Compound 25 is prepared analogously to Example 31 , where lnt-4d is substituted with lnt-20f in step c of Example 31 .

Example 34 - Synthesis of Compound 26

The diester was prepared from methyl (2S)-2-amino-5-methylhexanoate HCI salt (0.557 g, 2.85 mmol) and racemic-trans-1 -(ferf-butoxycarbonyl)pyrrolidine-3,4-dicarboxylic acid (0.352 g, 1 .36 mmol) as described in Example 31 , step a. Yield 0.303 g of the polar diastereomer 41 %,. lon(s) found by LCMS: [M-Boc +H]+ = 442.2.

Step b.

A solution of bis-ester from the previous step, dissolved in MeOH:THF:H20 (1 :1 :2), is treated with lithium hydroxide solid. The reaction mixture is stirred overnight. After the reaction is completed by monitoring with LCMS, the reaction is quenched with glacial acetic acid to pH 4, stripped of methanol and tetrahydrofuran then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 45% acetonitrile and water, using 0.1 % TFA as modifier.

Step c.

The title compound Compound 26 is prepared from lnt-21 b and lnt-4d using the procedure described in Example 31 , step c. Yield 0.135 g as TFA salt, 41 %, 2 steps lon(s) found by LCMS:

[(M+5H)/5]+ = 544.9, [(M+6H)/6]+ = 454.3 Example 35 - Synthesis of Compound 27

The title compound Compound 27 is prepared analogously to Example 34, where lnt-4d is substituted with lnt-6 in step c of Example 31 .

wo 2020/014469

The title compound was prepared from methyl (2S,3R)-2-amino-3-methylpentanoate (0.242 g,

1 .66 mmol) and racemic-trans1 -(ferf-butoxycarbonyl)pyrrolidine-3,4-dicarboxylic acid (0.210 g, 0.81 1 mmol) prepared analogously to Example 35, step a. Yield 0.121 g of polar isomer, 29%. lon(s) found by LCMS: (M+H)+ = 514.2. Note: Only the polar isomer was taken forward to the next steps.

Step b.

lnt-22b

A solution of bis-ester from the previous step, dissolved in MeOEkTHFihEO (1 :1 :2), is treated with lithium hydroxide solid. The reaction mixture is stirred overnight. After the reaction is completed by monitoring with LCMS, the reaction is quenched with glacial acetic acid to pH 4, stripped of methanol and tetrahydrofuran then purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 45% acetonitrile and water, using 0.1 % TFA as modifier.

Step c.

The title compound Compound 28 is prepared from lnt-22b and lnt-6 using the procedure from Example 31 , step c. Example 37 - Synthesis of Compound 29

EDC is added to a stirring mixture of Isoleucine-methyl ester hydrochloride salt, HOBt, 2,2'- {[(benzyloxy)carbonyl]azanediyl}diacetic acid, and triethylamine in DMF (1 .5 ml_) and the reaction is stirred for 12 hours. The mixture is applied directly to RPLC using an Isco Combiflash liquid

chromatograph eluted with 20% to 95% acetonitrile and water using 0.1 % TFA modifier.

Step b.

The diester from the previous step is hydrolyzed by stirring in a 1 :1 :2 mixture THF/MeOH/DI water containing LiOH for 30 minutes at ambient temperature. Glacial acetic acid is added and the volume is reduced by 70% on the rotary evaporator. The residue is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 5% to 85% acetonitrile and water using 0.1 % TFA modifier.

EDC is added to a stirring mixture of lnt-23a, lnt-6, and HOBt in DMF. The reaction is stirred for 12 hours at ambient temperature. The mixture is then applied directly to RPLC using an Isco Combiflash liquid chromatograph eluted with 30% to 100% methanol and water using 0.1 % TFA modifier.

The Cbz-protected product is then dissolved in methanol and 5% Pd/C is added to the solution. The mixture is stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture is filtered and concentrated.

The Boc-protected intermediate is stirred in a 1 /1 mixture of TFA/DCM (10 ml_) at ambient temperature for 30 minutes. The solvent is removed by rotary evaporator and dried under high vacuum. The crude deprotected dimer is purified by RPLC using an Isco Combiflash liquid chromatograph eluted with 0% to 90% acetonitrile and water using 0.1 % TFA modifier. Example 38 - Synthesis of Compound 30

The title compound Compound 30 is prepared analogously to Example 37, where L-leucine is substituted for L-isoleucine in step a of Example 37. Example 39 - Synthesis of Compound 31

The title compound Compound 37 is prepared analogously to Example 17, Example 1 8, and Example 19, where propionaldehyde is substituted with butyraldehyde in step a of Example 17, and where lnt-4a is substituted with lnt-23a in step a of Example 19.

Example 40 - Synthesis of Compound 32

Step a.

EDC (3.2 g, 17 mmol) was added to a stirring mixture of racemic-transl -(ferf- butoxycarbonyl)pyrrolidine-3,4-dicarboxylic acid (2 g, 7.7 mmol), Isoluecine methyl ester HCI salt (3.5 g, 19.3 mmol), HOBt (2.6 g, 17 mmol), and triethylamine (2 g, 20 mmol) in 15 ml_ of DMF. The reaction was stirred for 12 hours, diluted with aqueous 1 N HCI (100 ml_), extracted into ethyl acetate, dried over sodium sulfate and concentrated. The diastereomers were separated by RPLC using an Isco Combiflash liquid chromatograph eluted with 15% to 95% acetonitrile and water using 0.1 % TFA modifier. The polar isomer was pooled and lyophilized to afford 1 .2 g of the boc-protected ester. Yield, combined 59%.LCMS [M-(1 boc)+H ⁺ ) = 414.2.

Step b.

The polar isomer boc-protected ester from step a is dissolved in THF and water. Powdered lithium hydroxide is added and the reaction is stirred at room temperature. After complete conversion, the reaction is made slightly acidic by adding concentrated HCI and then concentrated. The crude material is purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% acetonitrile and water, using TFA as the modifier.

Step C.

The title compound Compound 32 is prepared from lnt-24b and lnt-14c using the procedure from Example 31 , step c.

Example 41 - Synthesis of Compound 33

The title compound Compound 33 is prepared analogously to Example 31 , where lnt-19b is substituted with lnt-24b in step c of Example 31 . Example 42 - Synthesis of Compound 34

The title compound Compound 34 was prepared analogously to Example 31 , where Int019b is substituted with lnt-24b, and where lnt-4d is substituted with lnt-6 in step c of Example 31 .

Example 43 - Synthesis of Compound 35

Step a.

The dimethyl ester is prepared analogously to intermediate in Example 40, step a substituting L- leucine for L-isoleucine.

Step b.

The diacid is prepare analogously to intermediate in Example 40, step b.

Step c.

The title compound Compound 35 is prepared analogously to Example 31 , where lnt-19b is substituted with lnt-25b, and where lnt-4d is substituted with lnt-6 in step c of Example 31 . Example 44 - Synthesis of Compound 36

The title compound Compound 36 is prepared analogously to Example 31 , where lnt-19b is substituted with lnt-25b.

Example 45 - Synthesis of Compound 37

To a solution of dimethyl itaconate (1 .58 g, 10 mmol) in MeOH (8 ml_) was treated with t-butyl piperazine-1 -carboxylate (1 .86 g, 10 mmol). The mixture was heated at 60 °C for 1 day. It was then purified by HPLC (0 to 20 % acetonitrile and water, using 0.1 % TFA as modifier). Yield 1 .175 g, 34.1 %. Ion found by LCMS: [M + H] ⁺ = 345.0. Step b.

The step-b product (1 .175 g, 3.41 mmol) was dissolved in MeOH (5 ml_) and cooled in an ice- water bath. It was treated with a solution of LiOH monohydrate (378 mg, 9 mmol) in water (9 mL). After the reaction was stirred at 0 °C to room temperature overnight, it was re-cooled in an ice-water bath and acidified by 4N HCI solution in dioxane (2 mL). The mixture was partially concentrated by rotary evaporation at room temperature. The residue was purified by RPLC (150 g column, 0 to 80 % MeOH and water). Yield 336.5 mg, 31 .2 %. Ion found by LCMS: [M + H] ⁺ = 317.2.

Step c.

A mixture of the step b product (336.5 mg, 1 .064 mmol) and H-Nle-OMe HCI (464 mg, 2.552 mmol) was dissolved in anhydrous NMP (3 ml_) and DIPEA (520 mg, 4 mmol). To this was added HATU (810 mg, 2.13 mmol) in portions over 10 minutes. The reaction was stirred for another 30 minutes, then purified by RPLC (100 g column, 10 to 75 % acetonitrile and water, using 0.1 % TFA as modifier). Yield 261 .7 mg, 43.2 %. Ion found by LCMS: [M + H] ⁺ = 571 .4.

Step d.

The step c product is dissolved in MeOH and cooled in an ice-water bath. It is treated with a solution of LiOH monohydratein water. After complete conversion, the reaction is acidified by 4N HCI solution in dioxane and directly purified by HPLC. Step e.

To a solution of the diacid from step d and lnt-6 in anhydrous DMF (1 ml_), is added DIPEA and

HATU . The resulting solution is stirred for 30 minutes. The reaction is concentrated and redissolved in methanol. 5% Pd/C is added and the reaction is stirred under 1 atmosphere of hydrogen. The reaction mixture is then filtered through celite, concentrated, and purified by RPLC.

Step f.

The step-e product is dissolved in TFA and stirred for 15 minutes. It is directly purified by RPLC (0 to 50 % acetonitrile and water, using 0.1 % TFA as modifier).

Example 46 - Synthesis of Compound 38

Step a.

To a suspension of (4S)-Boc-amino-L-Proline methyl ester HCI salt (1 .222 g, 5 mmol) in DCM (6 mL) and DMF (2 mL) was added benzyl 2-bromoacetate (1 .375 g, 6 mmol) and DIPEA (975 mg, 7.5 mmol). The mixture was stirred at room temperature for 3 days. It was then concentrated and purified by RPLC (100 g column, 15 to 75 % acetonitrile and water, using 0.1 % TFA as the modifier). Yield 1 .71 g, 87.2 %. Ion found by LCMS: [M + H] ⁺ = 393.2. Step b.

The step a product is dissolved in methanol. The reaction mixture is cooled in an ice-water bath then treated with a solution of LiOH monohydrate. After complete conversion, the reaction is then acidified by 4N HCI solution in dioxane. The organic solvents are removed by rotary evaporation, and the residue is purified by RPLC (0 to 50 % acetonitrile and water).

Step c. Preparation of lnt-29

NHBoc

To a mixture of lnt-6 (2 g, 1 .28 mmol) and Z-L-norleucine (407.1 mg, 1 .535 mmol) in anhydrous DMF (3 mL) was added HATU (583.6 g, 1 .535 mmol) in portions over 10 minutes, followed by DIPEA (390 mg, 3 mmol). After the reaction mixture was stirred for 1 hour, it was poured into water (60 ml_). The white solid product was collected by filtration and washed with water. The material was re-dissolved in MeOH (30 ml_) and treated with Pd/C (5%) (1 g). The mixture was stirred under hydrogen overnight. Pd/C was then filtered, and the filtrate was concentrated and purified by RPLC (150 g, 40 to 95 % MeOH and water). Yield of lnt-16 was 2.02 g, 94.3 %. Ion found by LCMS: [(M - Boc + 2H)/2]+ = 789.2.

Step d.

The title compound is prepared from lnt-28 and lnt-29 using the procedure described in Example

14, step d.

Step e.

The title compound Compound 38 is prepared from lnt-30 using the procedure described in Example 14, step 3. Example 47 - Synthesis of Compound 39

To a solution of Z-L-norleucine (1 .062 g, 4 mmol) in anhydrous NMP (5 ml_) was added (S)- methyl 2-amino-4-((tert-butoxycarbonyl)amino)butanoate HCI salt (1 .182 g, 4.4 mmol) and DIPEA (1 .14 g, 8.8 mmol). The resulting mixture was treated with HATU (760.4 mg, 2.0 mmol) in portions over 10 minutes, and then stirred for 1 hour. It was then purified by RPLC (100 g column, 20 to 75 % acetonitrile and water). Yield 1 .9 g, 99.4 %. Ion found by LCMS: [M - Boc + H] ⁺ = 380.2. Step b.

The step-a product (1 .9 g, 3.975 mmol) was dissolved in MeOH (5 ml_) and THF (10 ml_). After the solution was cooled in an ice-water bath, it was treated with a solution of LiOH monohydrate (250 mg, 6 mmol) in water (10 ml_). After the reaction was stirred for 30 minutes, DCM (100 ml_) was added, and the reaction was continued stirring for 30 minutes. It was then acidified with 4N HCI solution in dioxane (1 .5 mL), and diluted with water (30 ml_). Two layers were separated, and the aqueous layer was back- extracted with EtOAc (80 mL x 2). The combined organic layers were dried over Na2SC>4, concentrated by rotary evaporation, and further dried under high vacuum. Yield 1 .72 g, 93 %. Ion found by LCMS: [M - Boc + H] ⁺ = 366.

Step c.

To a solution of the step-b product (535.9 mg, 1 .2 mmol) and PMB heptapeptide (1 .06 g, 1 mmol, lnt-1 ) in anhydrous DMF (2 mL) was added HATU (456.2 mg, 1 .2 mmol) in portions over 10 minutes, followed by DIPEA (312 mg, 2.4 mmol). After the reaction was stirred for 1 hour, it was purified by RPLC (100 g, 40 to 95 % MeOH and water). The collected fractions were concentrated by rotary evaporation to a white solid (Ion found by LCMS: [(M -2Boc + 2H)/2] ⁺ = 655.6). The material was re-dissolved in MeOH (30 mL) and treated with Pd/C (5%). The mixture was stirred at room temperature overnight. Pd/C was filtered, and the filtrate was concentrated by rotary evaporation to dryness. Yield 1 .177 g, 85 % over two steps. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 638.4. Step d.

To a solution of the step-b product (475.1 mg, 1 .02 mmol) and the step-c product (1 .177 g, 0.851 mmol) in anhydrous DMF (2 ml_) was added HATU (388 mg, 1 .02 mmol) in portions over 10 minutes, followed by DIPEA (260 mg, 2 mmol). After the reaction was stirred for 1 hour, it was purified by RPLC (100 g, 40 to 95 % MeOH and water). The collected fractions were concentrated by rotary evaporation to a white solid (Ion found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 821 .1 ). The material was re-dissolved in MeOH (30 mL) and treated with Pd/C (5%). The mixture was stirred at room temperature overnight. Pd/C was filtered, and the filtrate was concentrated by rotary evaporation to dryness. Yield 1 .196 g, 83.3 % over two steps. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 795.

Step e.

To a mixture of lnt-33 and 2,2'-{[(benzyloxy)carbonyl]azanediyl}diacetic acid in anhydrous DMF is added HATU and DIPEA. The resulting mixture is stirred for 30 minutes and is purified by RPLC (column 40 to 95 % MeOH and water, using 0.1 % TFA as modifier). Step f.

The Cbz-protected intermediate is dissolved in methanol and 5% Pd/C is added to the solution. The mixture is stirred at room temperature under a hydrogen atmosphere. The reaction mixture is then filtered through Celite, concentrated, and purified.

The Boc-protected intermediate is then stirred for 30 minutes in DCM and TFA and directly purified through RPLC (50 g column, 3 to 50% acetonitrile and water, using 0.1 % TFA as modifier).

Example 48 - Synthesis of Compound 40

The title compound is prepared from lnt-28 and lnt-33 using the procedure described in Example 14, step d. Step b.

The title compound Compound 40 is prepared from lnt-35 using the procedure described in Example 14, step 3.

Example 49 - Syntheses of Compound 41

Step a.

A solid mixture of norleucine methyl ester HCI salt (2.1 10 g, 1 1 .62 mmol), racemic trans-4- oxocyclopentane-1 ,2-dicarboxylic acid (1 .000 g, 5.81 mmol), EDCI (2.783 g, 14.52 mmol), HOAt (1 .976 g, 14.52 mmol) and NaHC03 (1 .952 g, 23.23 mmol) were mixed in 20 mL of DCM/DMF (5:1 ). The mixture was stirred for overnight (~15 hours) at room temperature. LC/MS analysis showed the completion of the reaction. Two diastereomers were separated by reversed phase HPLC. The polar diastereomer and less polar diastereomer have the retention time at 4.83 min. and 5.04 min. respectively with 8-minute 5-95% ACN/water method: (M + H) ⁺ = 427.0 and M - H ⁺ = 425.0. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1 N aq. HCI, saturated NaHCCb and brine respectively. The solution was dried with anhy. Sodium sulfate and the solvents were removed. The residue was dissolved in minimum amount of NMP and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30 - 60% acetonitrile and water. The pure polar diastereomer dimethyl ester, 1 .071 g, was obtained in 46% yield (50% in theory). The absolute stereochemistry of the polar and less polar isomers was determined by X-ray. The polar isomer was used in the next step.

Step b.

The polar dimethyl ester (1 .071 g, 2.51 1 mmol) was treated with LiOH (0.1302 g, 5.273 mmol) in 20 mL of THF/Water (1 :1 ). Stirred for less than 1 hrs. 1 N HCI to acidify. Removed THF and extracted with EtOAc to give diacid (1 .000 g, 100%). Positive mass ions was found as (M + H ⁺ ): 399.0, tr = 1 .3 minutes with 5-minute 40-95% ACN/water method.

A solid mixture of diacid (1 .000 g, 2.510 mmol), N-v-Boc-L-2,4-diaminobutyric acid methyl ester HCI salt (1 .349 g, 5.020 mmol), EDCI (1 .203 g, 6.274 mmol), HOAt (0.8540 g, 6.274 mmol) and NaHCOs (0.8424 g, 10.04 mmol) were mixed in 20 mL of DCM/DMF (5:1 ). The mixture was stirred for overnight (-15 hours) at room temperature. LC/MS analysis showed the completion of the reaction. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1 N aq. HCI, saturated NaHC03 and brine respectively. The solution was dried with anhy. Sodium sulfate and the solvents were removed. The residue was dissolved in minimum amount of NMP and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30 - 60% acetonitrile and water. The cyclopentanonyl central linker, 1 .760 g, was obtained in 85% yield. Ions found by LCMS: (M - 2Boc + 2H ⁺ )/2 = 314.0.

Step c.

The diester from step b is treated with LiOH in THF/Water (1 :1 ). After complete conversion, the reaction mixture is acidified with 1 N HCI. The solvent is concentrated to give the diacid intermediate.

Step d.

A solid mixture of lnt-6, the diacid intermediate described previously, EDCI, and HOAt are dissolved in dry DMF immediately followed by addition of triethylamine. The mixture is stirred for overnight (~15 hours) at room temperature. After complete conversion, most of the solvent (DMF) of the reaction mixture is removed by reduced pressure rotovap to give a viscous oily residue. The residue is triturated with methanol.

The Boc-protected intermediate is dissolved with 100% TFA and stirred for 30 minutes. TFA is removed by rotovap. The residue is dissolved in minimum amount of water and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 5 % to 35% acetonitrile and water using 0.1 % TFA modifier. Example 50 - Syntheses of Compound 42

A solid mixture of lnt-4d (0.6544 g, 0.451 1 mmol), the diacid product from step b of Example 50, EDCI, and HOAt are dissolved in dry DMF immediately followed by adding triethylamine. The mixture is stirred for overnight (~15 hours) at room temperature. After complete conversion, most of the solvent (DMF) of the reaction mixture is removed by reduced pressure rotovap to give a viscous oily residue. To this residue methanol is added with gentle stirring to triturate the reaction product.

The Boc-protected intermediate is then dissolved in TFA and stirred for 30 minutes. The TFA is removed by rotovap. The residue is dissolved in water and purified by RPLC.

Example 51 - Synthesis of Compound 43

Step a.

To a 0 °C stirring solution of NY-Boc-L-2,4-diaminobutyric acid methyl ester hydrochloride (0.750 g, 2.791 mmol), L-Z-Nleu-OH (0.740 g, 2.791 mmol), and 2,4,6-collidine (1 .217 ml_, 9.210 mmol) in DMF (5.0 ml_), was added HATU (1 .082 g, 2.847 mmol). Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 25% to 100% water and methanol, using no modifier. Yield 1 .230 g, 92% yield of Z-Nor-leu-(Ny-Boc)Dab-OMe. ¹ FI NMR (Methanol-cfc) d: 7.49 - 7.20 (m, 5H), 5.09 (br s, 2H), 4.46 (dd, J = 9.4, 4.8 Hz, 1 H), 4.09 (dd, J = 8.5, 5.7 Hz, 1 H), 3.71 (s, 3H), 3.26 - 2.93 (m, 2H), 2.15 - 1 .92 (m, 1 H), 1 .90 - 1 .54 (m, 3H), 1 .43 (s,

1 1 H), 1 .36 (d, J = 8.1 Hz, 4H), 0.94 (br d, J = 6.7 Hz, 3H).

Step b.

To a stirring solution of Z-Nleu-(Ny-Boc)Dab-OMe (0.123 g, 2.565 mmol) in tetrahydrofuran (1 5.0 mL) and water (5.0 ml_) it was added lithium hydroxide (0.064 g, 2.693 mmol). Upon completion (HPLC monitoring), the reaction was concentrated to about 5 mL per rotatory evaporation. Ethyl acetate (25 mL) was added and subsequently a 1 .0 M solution of sulfuric acid (5.0 mL), while the mixture was stirred vigorously for 10 minutes. The organic phase was separated and then washed with water (10 mL) and brine (10 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The residue was dissolved in DMF (1 5 mL) with L-Threonine methyl ester hydrochloride (0.435 g, 2.565 mmol), and 2,4,6-collidine (1 .356 mL, 10.259 mmol). At 0 °C, HATU (0.995, 2.616 mmol) was added. Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 25% to 100% water and methanol, using no modifier. Yield 1 .398 g, 94% yield of Z-Nleu-(Ny-Boc)Dab-Thr-OMe. ¹ H NMR (Methanol-aL) d: 7.46 - 7.19 (m, 5H), 5.09 (s, 2H), 4.56 - 4.38 (m, 2H), 4.30 (m, 1 H), 4.10 (m,1 H), 3.74 (s, 3H), 3.27 - 2.98 (m, 2H), 2.12 - 1 .53 (m, 4H), 1 .44 (s, 10H), 1 .34 (br s, 4H), 1 .1 7 (d, J = 6.4 Hz, 3H), 0.91 (br t, J = 6.6 Hz, 3H). Step C.

Z-Nleu-(NY-Boc)Dab-Thr-OMe (1 .398 g, 2.408 mmol) was dissolved in methanol (25 ml_) and suspended with SiliaCatPd(O)® (0.241 g, 0.048 mmol) under hydrogen atmosphere (~1 atm). When all the starting material was consumed by HPLC analysis, the mixture was filtered over a short Celite pad, and all the volatiles were removed by rotary evaporation. HPLC analysis for the residues revealed one component in high purity, so it was used in the next step without further purification. Yield 1 .075 g, 99% yield of H-Nleu-(Ny-Boc)Dab-Thr-OMe. ¹ H NMR (Methanol-aL) d: 4.49 (dd, J = 8.8, 5.8 Hz, 1 H), 4.45 (d, J = 2.8 Hz, 1 H), 4.31 (qd, J = 6.4, 3.0 Hz, 1 H), 3.74 (s, 3H), 3.36 (d, J = 6.7 Hz, 1 H), 3.26 - 3.01 (m, 2H), 2.08 - 1 .49 (m, 5H), 1 .44 (s, 9H), 1 .41 - 1 .29 (m, 4H), 1 .17 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H)

Step d.

To a 0 °C stirring solution of lnt-6 (2.50 g, 1 .599 mmol), L-Z-Nleu-OH (0.424 g, 1 .599 mmol), and 2,4,6-collidine (0.274 mL, 2.078 mmol) in DMF (20 mL), it was added HATU (0.638 g, 1 .679 mmol) in DMF (5.0 mL), dropwise. Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using no modifier. Yield 2.720 g, 94% yield.

Step e.

Product from step d (2.720 g, 1 .502 mmol) was dissolved in methanol (100 ml_) and suspended with SiliaCatPd(O)® (0.751 g, 0.150 mmol) under hydrogen atmosphere (~1 atm). When all the starting material was consumed by HPLC analysis, the mixture was filtered over a short Celite pad, and all the volatiles were removed by rotary evaporation. Yield 1 .075 g, 99% yield. ¹ H NMR for the diagnostic peaks: ¹ H NMR (Methanol-dt) d: 7.39 - 7.09 (m, 5H), 4.58 - 3.92 (m, 13H), 3.52 (br s, 1 H), 1 .44 (br d, J = 4.6 Hz, 45H), 1 .20 (dd, J = 6.6, 3.7 Hz, 6H), 1 .02 - 0.83 (m, 3H), 0.69 (br d, J = 1 9.8 Hz, 6H). Step f.

To a 0 °C stirring solution of product from step g (0.300 g, 0.177 mmol), 2,3-O-methylene-L- tartaric acid (0.058 g, 0.354 mmol, described in PCT Int. Appl. , 2007139749), and 2,4,6-collidine (0.070 mL, 0.532 mmol) in DMF (3.0 ml_), was added HATU (0.069 g, 0.181 mmol) in DMF (1 .5 ml_), dropwise. Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco

CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using no modifier. Yield 0.212 g, 66% yield. ¹ H NMR for the diagnostic peaks: ¹ H NMR (Methanol-dt) d: 7.40 - 7.17 (m, 5H), 5.29 (s, 1 H), 5.14 (s, 1 H), 4.74 (d, J = 3.8 Hz, 1 H), 4.68 (d, J = 3.8 Hz, 1 H), 4.55 - 3.97 (m, 13H), 3.54 (br s,

1 H), 1 .44 (br s, 45H), 1 .20 (br d, J = 6.4 Hz, 7H), 0.92 (br s, 3H), 0.70 (br d, J = 19.4 Hz, 6H). Step g.

To a 0 °C stirring solution of product from step f (0.212 g, 0.1 16 mmol), H-Nleu-(y-Boc)Dab-Thr- OMe (0.052 g, 0.1 16 mmol), and DIEA (0.051 ml_, 0.291 mmol) in DMF (3.0 ml_), it was added HATU (0.045 g, 0.1 19 mmol). Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using no modifier. Yield 0.214 g, 82% yield. ¹ H NMR for the diagnostic peaks: ¹ H NMR (Methanol-dt) d: 7.36 - 7.17 (m, 5H), 5.22 (d, J = 7.6 Hz, 2H), 4.66 (br s, 2H), 4.57 - 3.96 (m, 17H), 3.74 (s, 3H), 3.54 (br s, 1 H), 1 .44 (s, 54H), 1 .26 - 1 .07 (m, 9H), 1 .03 - 0.82 (m, 6H), 0.70 (br d, J = 18.0 Hz, 6H).

Step h.

Product from step g (0.1 mmol) is taken up in 1 ,2-dichloroethane (5.0 ml_), treated with trimethyltin hydroxide (1 .0 mmol), and the mixture is refluxed until completion. Upon cooling, the mixture is treated under stirring with SiliaMetS® (2.0 mmol) for 1 h. All the volatiles are removed by rotary evaporation. The residue is taken up in acetic acid (5 ml_) and filtered over a short celite pad. All the volatiles are removed by rotary evaporation, to afford the desired product. Step i.

Boc HN

Boc

To a 0 °C stirring solution of tri-Boc polymyxin B cycloheptapeptide (0.400 g, 0.376 mmol, described at Example 1 as lnt-1 ), Na-Z-Ny-Fmoc-L-2,4-diaminobutyric acid (0.179 g, 0.376 mmol), and 2,4,6-collidine (0.104 ml_, 0.791 mmol) in DMF (5.0 ml_), was added HATU (0.150 g, 0.395 mmol) in DMF (1 .5 mL), dropwise. Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 1 00% water and methanol, using no modifier. Yield 0.526 g, 92% yield. ¹ H NMR for the diagnostic peaks: ¹ H NMR (Methanol-aL) d: 7.79 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.52 - 7.1 1 (m, 16H), 5.18 - 4.98 (m, 2H), 3.54 (br s, 1 H), 1 .67 - 1 .25 (m, 27H), 1 .18 (d, J = 6.4 Hz, 3H), 0.70 (br d, J = 18.8 Hz, 6H)

Step j.

0 ^{0C HN} Boc

To a stirring solution of product from step i (0.526 mmol, 0.346 mmol), 1 -octanethiol (0.090 mL, 0.520 mmol) in dichloromethane (5.0 mL), it was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL, 0.381 mmol). Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using 0.1 % TFA as the modifier. Yield 0.370 g, 82% yield. ¹ H NMR for the diagnostic peaks: Ή NMR (300 MHz, MeOD) d 7.58 - 7.10 (m, 10H), 5.10 (q, J = 12.4 Hz, 2H), 3.56 (br s, 1 H), 1 .45 (br s, 27H), 1 .21 (d, J = 6.5 Hz, 3H), 0.72 (br d, J = 19.1 Hz, 6H). Step k.

B ^{oc HN} Boc

To a 0 °C stirring solution of product from step j (0.215 g, 0.166 mmol), monomethyl succinate (0.022 g, 0.166 mmol), and DIEA (0.072 ml_, 0.414 mmol) in DMF (5.0 ml_), it was added HATU (0.066 g, 0.174 mmol) in DMF (2.0 ml_), dropwise. Temperature was slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles were removed by rotary evaporation. The residue was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using no modifier. Yield 0.201 g, 86% yield.

Step I.

Boc HN

Boc

Product from step k (0.201 g, 0.143 mmol) was dissolved in methanol (10 ml_) and suspended with SiliaCatPd(O)® (0.071 g, 0.014 mmol) under hydrogen atmosphere (~1 atm). When all the starting material was consumed by HPLC analysis, the mixture was filtered over a short Celite pad, and all the volatiles were removed by rotary evaporation. HPLC analysis of the residue revealed a single peak , which was used in the next step without further purification. Yield 1 .075 g, 99% yield. ¹ H NMR for the diagnostic peaks: ¹ H NMR (Methanol-dt) d: 7.37 - 7.20 (m, 5H), 3.67 (s, 3H), 2.63 (t, J = 6.7 Hz, 2H), 2.49 (t, J = 6.7 Hz, 1 H), 1 .44 (br s, 27H), 1 .20 (d, J = 6.4 Hz, 3H), 0.67 (br d, J = 18.1 Hz, 6H). Step m.

To a 0 °C stirring solution of product from step I (0.1 mmol), product from step h (0.1 mmol), and DIEA (0.2 mmol) in DMF (5.0 ml_), is added HATU (0.1 mmol) in DMF (1 .5 ml_), dropwise. Temperature is slowly allowed to reach ambient temperature over 15 min. Upon completion, all the volatiles are evaporated by rotary evaporation. The residue is purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% water and methanol, using no modifier.

Step n.

Product from step m (0.1 mmol) is taken up in 1 ,2-dichloroethane (5.0 ml_), treated with trimethyltin hydroxide (1 .0 mmol), and the mixture is refluxed until completion. Upon cooling, the mixture is treated under stirring with SiliaMetS® (2.0 mmol) for 1 h. All the volatiles are evaporated by rotary evaporation. The residue is taken up in acetic acid (5 ml_) and filtered over a short celite pad. All the volatiles are evaporated by rotary evaporation, to afford the desired product. Example 52 - Preparation of Extended Threonines

Extended threonine analogs were prepared as described in Aiker et al. , Tetrahedron 54:6089- 6098 (1998).

Example 53 - Synthesis of lnt-38

A solution of 1 ,1 '-carbonyldiimidazole (972.6 mg, 6 mmol) in anhydrous DMF (6 ml) was cooled in an ice-water bath and treated with benzyl carbazate (1 .097 g, 6.6 mmol). After stirring to dissolve all the solids, the resulting mixture was treated with DIPEA (390 mg, 3 mmol). The ice-water bath was removed, and the reaction mixture was stirred for 1 hour. PMBH (2.126 g, 2 mmol, lnt-1 ) was slowly added, and the reaction was continued overnight. The reaction mixture was then precipitated into water (100 ml) containing 4N HCI in dioxane (6 ml). The precipitated product was collected by vacuum filtration and washed with water. It was then re-dissolved in MeOH and concentrated to a white solid. The material was dissolved in DMF (2 ml) and purified by RPLC (150 g, 65 to 80 % MeOH and water, using 0.1 % TFA as modifier). Yield 1 .32 g, 52.6 %. Ions found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 527.8, [(M - 2Boc - tBu + 2H)/2] ⁺ = 499.8, [(M - 3Boc + 2H)/2] ⁺ = 477.8.

Step b.

Acetyl chloride (108.9 mg, 1 .39 mmol) was added drop-wise in MeOH/water (30 ml/1 ml). The solution was added to the step a product (1 .16 g, 0.925 mmol). The reaction atmosphere was flushed with nitrogen, then Pd/C (dry basis, 270 mg) was added and the resulting mixture was stirred under hydrogen for 2 hours. Pd/C was filtered, and the filtrate was concentrated by rotary evaporation and purified by RPLC (150g, 30 to 65 % acetonitrile and water). Yield 1 .02 g, 98.4 %. Ions found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 460.8, [(M - 2Boc -tBu + 2H)/2] ⁺ = 432.6, [(M - 3Boc + 2H)/2] ⁺ = 410.8.

Step c.

To a solution of a mixture of extended threonine-Dab-Z (366.5 mg, 0.7 mmol) and HATU (266.1 mg, 0.7 mmol) in DMF (1 ml) was added DIPEA (150 mg, 1 .15 mmol). After stirred for 10 minutes, the reaction mixture was added with the step b product (560.2 mg, 0.5 mmol) and continued stirring at room temperature for 30 minutes. It was then purified by RPLC (100 g, 50 to 90 % MeOH and water). Yield 559.6 mg, 73.4 %. Ion found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 713.5. Step d.

A 50 ml reaction flask was filled with nitrogen and charged with the step c product (250 mg, 0.154 mmol) and MeOH (20 ml). Pd/C (dry basis, 1 00 mg) was then added, and the resulting mixture was stirred under hydrogen for 4 hours. Pd/C was filtered, and the filtrate was concentrated by rotary evaporation and purified by RPLC (100 g, 40 to 85 % MeOH and water). Yield 125.2 mg, 54.5 %. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 696.3, [(M - 3Boc + 2H)/2] ⁺ = 596.3.

Example 54 - Synthesis of Compound 44

Step a.

To a solution of lnt-15 in anhydrous DMF is added H-NLe-OMe-HCI and DIPEA. HATU is then added in portions over 5 minutes. The reaction is stirred for 30 minutes and directly purified by RPLC (100 g column, 5 to 70 % acetonitrile and water).

Step b.

A solution of the step-a product in MeOH (2 ml) is cooled in an ice-water bath and treated with portions a solution of LiOH in water over 1 hour. The reaction is stirred for 3 more hours, then the pH is adjusted to neutral or slightly acidic by ion exchange Dowex 50W x 8 hydrogen form. The resin is filtered, and the filtrate is concentrated to dryness. Step c.

To a solution of the step b product in anhydrous DMF is added (S)-methyl 2-amino-4-((tert- butoxycarbonyl)amino)butanoate HCI. After stirring to dissolve the amino acid, HATU is added in portions over 5 minutes, followed by DIPEA. The reaction is stirred for 30 minutes and directly purified by RPLC (100 g column, 10 to 70 % acetonitrile and water). Step d.

A solution of the step c product in MeOH is cooled in an ice-water bath and treated in portions with a solution of LiOH in water over 30 minutes. After the reaction is stirred for 3 more hours, its pH is adjusted to neutral by 4N HCI solution in dioxane, and the solution is directly purified by RPLC (100 g column, 10 to 70 % acetonitrile and water).

Step e.

To a solution of the step d product in anhydrous DMF is added C3-extended threonine (described in Example 53). After stirring to dissolve the amino acid, HATU is added in portions over 5 minutes, followed by DIPEA. The reaction is stirred for 30 minutes and directly purified by RPLC (100 g column,

10 to 70 % acetonitrile and water). Step f.

A solution of the step e product in MeOH is cooled in an ice-water bath and treated with portions of a solution of LiOH in water over 30 minutes. After the reaction is stirred for 3 hours, its pH is adjusted to neutral by 4N HCI solution in dioxane, and the solution is directly purified by RPLC (100 g column, 10 to 70 % acetonitrile and water). Step g.

To a solution of a mixture of the step-f product and PMB-AzaGly-NH2 (lnt-38) in anhydrous DMF is added HATU. After stirring to dissolve all the solids, the reaction mixture is treated with DIPEA and stirred for 30 minutes. It is then purified by RPLC (100 g column, 60 to 95 % MeOH and water, using 0.1 % TFA as modifier).

Step h.

The step g product is dissolved in methanol. To this solution, 5% Pd/C is added. The reaction mixture is stirred under hydrogen atmosphere. The reaction is then filtered through Celite, concentrated, and purified by HPLC.

The Boc-protected intermediate is dissolved in TFA. The solution is stirred for 30 minutes, concentrated, and directly purified by HPLC (0 to 20 % acetonitrile and water, using 0.1 % TFA as modifier). Example 55 - Synthesis of Compound 45

Step a.

A mixture of Cbz-L-threonine-hydrazide (4g, 8.23 mmol), CDI (1 .33g, 8.23 mmol), DMAP (0.067g, 0.549 mmol, and N-Methyl morpholine (0.905 ml_, 8.23 mmol), where suspended in DMF (20mL) and heated in a 80 C oil bath until a homogeneous solution formed (~15min). To this solution was added polymyxin B heptapeptide (2.91 g, 2.74 mmol, described in Example 1 ). After stirring overnight the reaction was concentrated to an oil from which unreacted threonine hydrazide precipitates. The reaction was filtered, concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 30% to 75% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of product was 3.2 g, 86% yield lon(s) found by LCMS: [M-1 (Boc)/2]+1 = 561 .4, [M- 2(Boc)/2]+1 = 51 1 .4, [M-3(Boc)/2]+1 = 461 .4.

Step b.

Methanol (30mL) and acetyl chloride (0.173mL, 2.44mmol) where mixed to form an FICI/MeOFI solution. This solution was added to a flask charged with 5% Pd/C (1 g) and starting material (3.01 g, 2.22 mmol). The reaction was vacuum flushed with hydrogen and stirred with hydrogen from a balloon until complete by LCMS (~2h), then filtered through celite, concentrated to a solid and used in the next step without additional purification. Yield 2.59g, 96%. lon(s) found by LCMS: [M-1 (Boc)/2]+1 = 561 .4, [M- 2(Boc)/2]+1 = 51 1 .4, [M-3(Boc)/2]+1 = 461 .4. Step c.

A solution of product from the previous step (3.5g, 2.87 mmol) dissolved in DMF (15mL) was charged with Z-L-Dab(Boc)-OH (1 .1 1 g 3.15 mmol), DIEA (1 .75mL, 10.0 mmol) and HATU (1 .20g, 3.15mmol) at room temperature while stirring. After 30 minutes, the reaction was concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid

chromatograph eluted with 40% to 100% acetonitrile and water, using 0.1 % TFA as the modifier. Yield of product was 3.53 g, 79% yield lon(s) found by LCMS: [M-2(Boc)/2]+1 = 678.4

Step d.

n -

Boc NH

Boc'

A solution of methanol (30mL) and acetyl chloride (0.177mL, 2.50mmol) where mixed to form an HCI/MeOH solution. This solution was added to a flask charged with 5% Pd/C (1 .5g) and starting material (3.53g, 2.269 mmol). The reaction was vacuum flushed with hydrogen and stirred with hydrogen from a balloon until complete by LCMS (~2h), then filtered through celite, concentrated to a solid and used in the next step without additional purification. Yield 2.91 g, 90%. lon(s) found by LCMS: [M- 1 (Boc)/2]+1 = 661 .7, [M-2(Boc)/2]+1 = 61 1 .2, [M-3(Boc)/2]+1 = 561 .6. Step e.

A solution of lnt-39 and lnt-15bare dissolved in DMF then charged with DIEA and HATU (added via syringe pump over 1 h) at room temperature while stirring. After an additional 1 h of stirring, the reaction is concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 40% to 100% methanol and water, using 0.1 % TFA as the modifier.

Step f.

Product from the previous step is dissolved in TFA and stirred for 5 min then stripped of TFA and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid

chromatograph eluted with 5% to 100% methanol and water, using 0.1 % TFA as the modifier. Example 56 - Synthesis of Compound 46

Linker A, Polar peak by HPLC

lnt-40a

A solution of L-norleucine methyl ester HCI salt (10.014 g, 77.14 mmol), racemic-trans-1 -(ferf- butoxycarbonyl)pyrrolidine-3,4-dicarboxylic acid (10.000 g, 38.57 mmol), EDCI (18.485 g, 96.43 mmol), HOAt (13.125 g, 96.43 mmol), and sodium bicarbonate (12.962 g, 154.3 mmol) dissolved in

dichloromethane/DMF (5:1 , 120 ml_) was stirred in room temperature for 4h. The reaction was concentrated and the residue was precipitated in 1 .0 N aq. HCI (200 ml_, while stirring rapidly). The solid was collected and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 40% to 60% acetonitrile and water. Two products, Linker A (lnt-19) polar by re HPLC and Linker B hydrophobic by re HPLC, were isolated. Yield of Linker A is 8.905 g, 45%, theoretic yield 50%). Ions were found by LCMS (8-minute, 10-90%): Rt= 3.36 min., positive mass:(M- Boc+H) ⁺ = 414.2, negative mass: (M-H ⁺ ) = 512.2.

Step b.

lnt-40a (Linker A) dimethyl ester (0.500 g, 0.973 mmol, described in step a) was hydrolyzed stirring in a 1/1 mixture of THF/water (10 mL) containing LiOH (0.0505 g, 2.044 mmol) for 30 minutes. The mixture was adjusted to pH 5 with Amberlite IRN-77 resin. The solution was filtered and washed with methanol, then concentrated and dried (0.472 g, 100%). This material was used in the next step without further purification. Ion was found by LCMS (5-minute run, 10-90%): Rt = 3.12 min., lon(s) found by LCMS: (M-Boc)+H = 386.7

Step c.

Tetra-Boc-Aza-Gly-PMBD-NH2 (2.840 g, 1 .998 mmol, lnt-39), A/-Boc central linker diacid (0.0500 g, 0.103 mmol), EDCI (0.0494 g, 0.257 mmol), HOAt (0.0350 g, 0.257 mmol) and DIPEA (0.072 ml_, 0.41 mmol) were dissolved in DMF, then mixed at room temperature overnight. The reaction mixture was poured into 1 N aq. HCI (50 ml_) to precipitate the crude product. Then, the dried crude solid was dissolved in minimum amount of NMP and loaded to reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 65 % to 95% methanol and water using 0.1 % TFA modifier to give 0.1 13 g, 34% yield (7-minute run, 60-95%): Rt = 2.30 min., positive high molecular weight: (M- 3 Boc+3H ⁺ )/3 = 998.2.

The white solid was treated with 5 ml_ of TFA for 30 min followed by removal of excess TFA. The residue was applied to reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 5% to 45% acetonitrile and water using 0.1 % TFA modifier to give the desired product as TFA salt powder after lyophilization. Yield: 70%. lon(s) found by LCMS (5-minute run, 10- 95%) : Rt = 2.10 min. Ions found by LCMS (M+3H ⁺ )/3 = 798.2, (M+4H ⁺ )/4 = 598.5, (M+5H ⁺ )/5 = 479.3.

Example 57 - Synthesis of N-Methyl-PMB-heptapeptide intermediate (lnt-41)

lnt-41

Step a.

Dissolve PMBH (1 Og, 9.42 mmol, lnt-1 ) in methanol (100 ml_), add a few drops of glacial acetic acid (to pH~5-6), then add benzaldehyde (1 .2 g, 1 1 .3 mmol) and let stir for 15 minutes. Cool to 0 ^* C, ice/water bath and add half (1 .5 eq, 921 mg, 14.66 mmol) of sodium cyanoborohydride in 3 portions over 10 minutes. Remove ice bath and let stir ~12 hours (overnight). Check by LC/MS to insure complete conversion to the mono benzylated PMBH intermediate. Cool to 0 °C and add formaldehyde (7 eq, 5 ml_, 67.7 mmol) followed by the additon of sodium cyanoborohydride (1 eq, 606 mg, 9.64 mmol) in 3 portions over 10 minutes, let stir at 0 ^* C for 20 minutes and remove ice bath. Let reaction stir for 2 hours then add additional 3 eq of formaldehyde (2.1 mL, 29.0 mmol) and sodium cyanoborohydride (320 mg, 5.1 mmol) stir for 6 more hours. Dilute with saturated sodium bicarb (pH~8) and remove approx half the methanol by rotovap. Dilute with ethyl acetate and saturated sodium bicarb and extract into ethyl acetate (3x). Dry the combined organic extracts over sodium sulfate, filter and concentrate. Purify by normal phase silica gel chromatography (0-5% methanol in dcm containing 1 % triethylamine, 35 minute gradient). The product elutes at -3.3% methanol. 8.2 grams (74%) of the product was isolated as a white solid. LC/MS [M-Boc+2H+] = 533.8

Step b.

lnt-41

8.2 gram of the N-methyl, benzyl PMBH(trisBoc) intermediate was dissolved in 100 mL of methanol in a 250 round bottom flask. 20% Pd(OH)2 (2g) was added followed by a few drops of glacial acetic acid (to pH~6). The flask was evacuated and flushed with hydrogen gas (3x) and then the mixture was stirred under 1 atm of hydrogen gas for 12 hours. The reaction was monitored by LC/MS and HPLC to insure complete removal of the benzyl group. Upon completion the mixture was filtered through celite and the pH was adjusted to -7 with a few drops of triethylamine. The solvent was removed by rotovap and the residue was purified by normal phase silica gel chromatography (0-7% methanol in dcm containing 1 % triethylamine, 35 minute gradient). The product elutes at -4.2% methanol. 6.65 grams (87%) of the product was isolated as a white solid. LC/MS [M-Boc+2H+] = 488.8. Example 58 - Synthesis of Compound 47

Step a.

A stirring solution of methyl (2S)-2-[(N-{(2S)-2-amino-4-[(tert-butoxycarbonyl)amino]butan oyl}-L- threonyl)amino]-4-[(tert-butoxycarbonyl)amino]butanoate, 2,2'-{[(benzyloxy)carbonyl]azanediyl}diacetic acid, and DIEA , in DMF are treated with a solution of HATU, dropwise over 30 minutes, at room temperature. The desired product is isolated by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier.

Step b.

A solution of the product from the previous step in methanol is treated with a solution of lithium hydroxide, in water, then stirred at room temperature for 30 minutes. The reaction is made slightly acidic (pH=5) with concentrated HCI (several drops). The desired product is isolated directly by RPLC using an

Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier.

Step c.

A solution of the product from the previous step, lnt-41 , DIEA, and DMF is treated with a solution of HATU in DMF, dropwise over 30 minutes. The crude reaction mixture is taken on to the next step without purification. Step d.

Crude Cbz deca Boc intermediate from step c (DMF solution) is diluted with methanol, charged with 5%Pd/C, and hydrogen from a balloon. The reaction is monitored by LCMS. After 2hr the mixture is filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid

chromatograph eluted with 10% to 100% methanol and water, using no modifier.

Step e.

The product from step d is dissolved in DCM and treated with TFA while stirring at room temperature. After the 5 minutes, the product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 0% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier.

Example 59 - Synthesis of lnt-42b

Step a.

lnt-41 and tripeptide acid (lnt-3) are dissolved in DMF and then treated with DIEA and HATU. The reaction is monitored by LCMS.

The crude Cbz-product is diluted with methanol, charged with 5%Pd/C, and placed under a hydrogen atmosphere. After complete conversion, the reaction mixture is filtered through Celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier.

Step b.

Int-42b

A solution of lnt-42a, Cbz-aminooctanoic acid, and DIEA, is treated with a solution of HATU dissolved in DMF, dropwise over 60 minutes. The reaction is monitored by LCMS.

The crude product is treated with 5% Pd/C, vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2hr or until complete conversion by LCMS. The crude reaction is then filtered through Celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 20% to 100% methanol and water, using no modifier.

Example 60 - Synthesis of Compound 48

A solution of lnt-5, lnt-42a, and DIEA in DMF, is treated with a solution of HATU in DMF, dropwise over 1 h. After stirring for an additional 30 minutes, the reaction is charged with 5% Pd/C (1 .5 g), vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture is filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier.

Step b. Synthesis of Compound 48

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier.

Example 61 - Synthesis of Compound 49

A solution of lnt-12, lnt-42a, and DIEA in DMF is treated with a solution of HATU in DMF, dropwise over 1 h. After stirring for an additional 30 minutes the reaction is charged with 5% Pd/C, vacuum flushed with hydrogen, and stirred under a hydrogen atmosphere for 2h. The resulting mixture is filtered through celite, concentrated, and purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using no modifier.

Step b.

The product from step a is dissolved in DCM and treated with TFA while stirring at room temperature. The product is concentrated and purified by RPLC using an Isco CombiFlash liquid chromatograph eluting with 5% to 100% acetonitrile and water, using trifluoroacetic acid as the modifier.

Example 62 - Synthesis of Compound 50

Step a.

A solution of lnt-15b, lnt-42a, and DIEA dissolved in DMF is treated with a solution of HATU in DMF, dropwise, over 60 minutes. Product is isolated by RPLC using an Isco CombiFlash liquid chromatograph eluted with 30% to 100% methanol and water, using 0.1 % TFA as the modifier.

Step b.

A solution of the Boc-protected product from the previous step is stirred in TFA for five minutes, and then stripped of TFA using a rotary evaporator. Product is isolated by RPLC using an Isco

CombiFlash liquid chromatograph eluted with 5% to 100% methanol and water, using 0.1 % TFA as the modifier.

Example 63 - Degradation of polymyxin E to tri-Boc cycloheptapeptide (lnt-43)

Step a.

Colistin sulfate (5.0 g, 3.95 mmol) was dissolved in acetonitrile (50 ml_) and water (25 ml_) and stirred at room temperature for 10 minutes. Triethylamine (3.2 ml_, 23.0 mmol) was added and the mixture stirred for a further 10 minutes. Di-tert-butyl dicarbonate (5.0 g, 23.0 mmol) was subsequently added in one portion and the mixture stirred for 16 hours. Savinase (Novozymes) (15 ml_) was then added, followed by 4 M sodium hydroxide solution (0.5 ml_) and the reaction mixture stirred at room temperature for 5 days. The mixture was diluted with ethyl acetate and water. After separation of the layers, the organic phase was washed with 0.1 M sodium hydroxide solution (x2), then water. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated at reduced pressure. The residue was purified by reversed phase chromatography (1 0-95% acetonitrile/di water containing 0.1 % formic acid: 25 minute gradient). The pure fractions were pooled and lyophilized to afford title compound lnt-43 as a formate salt, white powder. (2.28 g, 56%). m/z 1028, [M+H] ⁺

Step b.

Colistin sulfate (50.0 g, 39.89 mmol) was dissolved in acetonitrile (500 ml_, 10V) and water (250 ml_, 5V) and stirred at room temperature for 10 mins. TEA (24.2 g, 6.0eq) was added and the mixture stirred for a further 10 mins. B0C2O (52.2 g, 6.0 eq) was subsequently added in one portion and the mixture stirred for 29 hrs. LCMS showed material no being detected. Savinase (1 50 ml_) was then added. The pH of the resulting mixture was adjusted to 9.0 with aq 4M sodium hydroxide solution (5 ml_) and the reaction mixture stirred at 25°C. Additional savinase (50 ml_, 1 V) was added after 79 hrs, and another quantity of savinase (50 ml_, 1 V) was added after 103 hrs. After an overall reaction time of 162 hrs, the mixture was diluted with EA (1000 ml_, 20V). After separation of the layers, the organic phase was washed with 0.1 M NaOH solution (500 ml_ x2, 10V x2), then water (500 ml_, 10V). The organic layer was dried over anhydrous Na2S04, filtered and the solvent evaporated at reduced pressure. The residue was purified by silica gel chromatography eluting with 80% (EtOAc:MeOH:H2O-NH3=40:10:1 ) in ethyl acetate to give the title compound lnt-43 (20.2 g, 49.3%). LCMS: m/z [M+H] ⁺ calculatedd for

C47H85NI I OI ₄ :1027.63; found:1028.5. Example 64 - Synthesis of Tri-Boc-c-PME-Hept-Gly-Thr-Na-H-Ny-Boc-Dab (lnt-44)

Step a. Synthesis of Tri-Boc-c-PME-Hept-Z-Gly

A 0 °C stirring solution of tri-Boc polymyxin E cycloheptapeptide (lnt-43) (5.00 g, 4.86 mmol), Z- Gly-OH (1 .02 g, 4.86 mmol), and 2,4,6-trimethylpyridine (1 .61 mL, 12.16 mmol) in DMF (20 mL), was treated with a solution of HATU (1 .94 g, 5.10 mmol) in 10 mL of DMF, dropwise. After 1 .5 hour, all the volatiles were evaporated per vacuum techniques. The desired product was isolated by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% methanol and water, using no modifier. Yield 5.62 g, 95% yield. Ion found by LCMS: [(M - 2Boc)/2] ⁺ = 510.

Step b. Synthesis of Tri-Boc-c-PME-Hept-H-Gly

A stirring suspension of tri-Boc-c-PME-Hept-Z-Gly (5.62 g; 4.61 mmol) and SiliaCat-Pd(O) (1 .15 g; 0.230 mmol) in methanol (300 ml_) was subjected to hydrogen gas (1 atm) until full conversion was observed by HPLC analysis. The mixture was filtered through a short celite pad with the aid of methanol. The filtrate was concentrated and all the volatiles were evaporated per vacuum techniques. This material was used in the next step without further purification. Yield 5.00 mg, quant. Ion found by LCMS: [(M - Boc)/2] ⁺ = 493, [(M - 3Boc)/2] ⁺ = 393.

Step c. Synthesis of Tri-Boc-c-PME-Hept-Gly-Z-Thr

Prepared in the same fashion as tri-Boc-c-PME-Hept-Z-Gly from tri-Boc-c-PME-Hept-H-Gly (5.00 g; 4.61 mmol), Z-Thr-OH (1.17 g; 4.61 mmol), 2,4,6-trimethylpyridine (1 .28 ml_, 9.68 mmol) in DMF (25 ml_) and HATU (1 .84 g; 4.84 mmol in 10 mL of DMF). Yield 5.37 g, 88% yield. Ion found by LCMS: [(M- 2Boc)/2] ⁺ = 560.9

Step d. Synthesis of Tri-Boc-c-PME-Hept-Gly-H-Thr

Prepared in the same fashion as tri-Boc-c-PME-Hept-H-Gly form tri-Boc-c-PME-Hept-Gly-Z-Thr (5.37 g; 4.07 mmol), SiliaCat-Pd(O) (2.03 g; 0.41 mmol) and methanol (300 mL). Yield 4.82 mg. Ion found by LCMS: [(M - 2Boc)/2] ⁺ = 493.9, [(M - 3Boc)/2] ⁺ = 443.8.

Step e. Synthesis of Tri-Boc-c-PME-Hept-Gly-Thr-Na-Z-Ny-Boc-Dab

Prepared in the same fashion as tri-Boc-c-PME-Hept-Z-Gly from tri-Boc-c-PME-Hept-Gly-H-Thr (4.82 g; 4.07 mmol), Na-Z-Ng-Boc-Dab-OH (1 .43 g; 4.07 mmol), 2,4,6-trimethylpyridine (1 .61 mL, 12.20 mmol) in DMF (25 mL) and HATU (1 .62 g; 4.27 mmol in 10 mL of DMF). Yield 4.18 g, 68% yield. Ion found by LCMS: [(M- 2Boc)/3] ⁺ = 441 .0 Step f. Synthesis of Tri-Boc-c-PME-Hept-Gly-Thr-Na-H-Ny-Boc-Dab (lnt-44)

Prepared in the same fashion as tri-Boc-c-PME-Hept-H-Gly form tri-Boc-c-PME-Hept-Gly-Thr-Na- Z-Ng-Boc-Dab (4.18 g; 2.75 mmol), SiliaCat-Pd(O) (687 mg; 0.137 mmol) and methanol (400 ml_). Yield 3.56 mg, 93%.. Ion found by LCMS: [(M - 2Boc)/2] ⁺ = 593.9, [(M - 3Boc)/2] ⁺ = 543.9.

Example 65 - Synthesis of Compound 80

Step a. Synthesis of dimethyl 2,3-O-methylene-L-tartaric acid

To a stirring solution of 2,3-O-methylene-L-tartrate (1 .1 58 g, 6.090 mmol, prepared accordingly to International Application No. W02007/139749) in methanol (7.0 mL) and water (1 .0 mL), it was added sodium hydroxide (0.499 g, 12.48 mmol) and stirring was continued overnight. The reaction was concentrated to about half of its volume per rotatory evaporation. Ethyl acetate (40 mL) was added and subsequently a 1 .0 M solution of sulfuric acid (30 mL), while the mixture was stirred vigorously for 10 minutes. An excess amount of sodium chloride was added to the water layer to saturate the aqueous phase. The organic phase was separated and then washed with brine (30 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated to dryness per vacuum techniques. Yield 0.590 g, 60% yield, and this material was used in the next step without further purification. ¹ H NMR (Methanol- d4) d: 5.1 8 (s, 2H), 4.74 (s, 2H).

Step b. Synthesis of tartaric linker-3-dimethylester A stirring solution of L-norleucine methyl ester hydrochloride (0.676 g, 3.720 mmol), dimethyl 2,3- O-methylene-L-tartaric acid (0.300 g, 1 .851 mmol), and 2,4,6-trimethylpyridine (1 .492 ml_, 1 1 .29 mmol) in DMF (10 ml_), was treated with a solution of HATU (1 .422 g, 3.734 mmol) in 10 ml_ of DMF, dropwise) over 30 minutes. After 1 .5 hour, all the volatiles were evaporated per vacuum techniques. The desired product was isolated by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% methanol and water, using no modifier. Yield 0.694 g, 90% yield. Ion found by LCMS: (M+H) ⁺ = 421 .3.= 417.2.

Step c. Synthesis of deca-Boc-Compound 80

To a stirring solution of tartaric linker-3-dimethylester (0.694 g, 1 .666 mmol), in THF (5 ml_), and water (5 ml_) it was added lithium hydroxide (0.084 g, 3.499 mmol) and stirring was continued overnight. The reaction was concentrated to about half of its volume per rotatory evaporation. Ethyl acetate (40 ml_) was added and subsequently a 1 .0 M solution of sulfuric acid (30 ml_), while the mixture was stirred vigorously for 10 minutes. An excess amount of sodium chloride was added to the water layer to saturate the aqueous phase. The organic phase was separated and then washed with brine (30 ml_). The organic layer was then dried with sodium sulfate, filtered, and concentrated to dryness per vacuum techniques. Yield was considered quantitative and the material used in the next step without further purification. A 0Ό stirring solution of the herein above describe diacid (0.050 g, 0.129 mmol), lnt-44 (0.357 g, 0.257 mmol), and DIPEA (0.1 12 ml_, 0.644 mmol) in DMF (7 ml_), was treated with a solution of HATU (0.100 g, 0.264 mmol) in 10 ml_ of DMF, dropwise. After 1 .5 hour, all the volatiles were evaporated per vacuum techniques. The desired product was isolated by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% methanol and water, using no modifier. Yield 0.245 g, 61 % yield. ¹ H NMR diagnostic peaks were consistent with the desired structure.

Step d. Synthesis Compound 80

A solution of deca-Boc-Compound 80 (0.245 g, 0.078 mmol), dissolved in DCM (4 mL) and 2- methyl-but-2-ene (0.250 mL), was treated with TFA (2 mL), while stirring at room temperature. After 30 minutes, all the volatiles were evaporated per vacuum techniques. The desired product was isolated as the deca-TFA salt by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 0% to 100% methanol and water, using TFA as the modifier. Yield 0.205 g, 81 % yield. Main ions found by LCMS: (M+4H)/4 = 581 .8, (M+5H)/5 = 465.7. Example 66 - Synthesis of Compound 100

step b

Step a. Synthesis of dimethyl 2,3-O-methylene-L-tartaric acid

To a stirring solution of 2,3-O-methylene-L-tartrate (1 .158 g, 6.090 mmol, prepared accordingly to

International Application No. W02007/139749) in methanol (7.0 ml_) and water (1 .0 ml_), it was added sodium hydroxide (0.499 g, 12.48 mmol) and stirring was continued overnight. The reaction was concentrated to about half of its volume per rotatory evaporation. Ethyl acetate (40 ml_) was added and subsequently a 1 .0 M solution of sulfuric acid (30 ml_), while the mixture was stirred vigorously for 10 minutes. An excess amount of sodium chloride was added to the water layer to saturate the aqueous phase. The organic phase was separated and then washed with brine (30 ml_). The organic layer was then dried with sodium sulfate, filtered, and concentrated to dryness per vacuum techniques. Yield 0.590 g, 60% yield, and this material was used in the next step without further purification. ¹ H NMR (Methanol- d4) d: 5.18 (s, 2H), 4.74 (s, 2H).

Step b. Synthesis of tartaric linker-3

A stirring solution of L-norleucine methyl ester hydrochloride (0.676 g, 3.720 mmol), dimethyl 2,3- O-methylene-L-tartaric acid (0.300 g, 1 .851 mmol), and 2,4,6-trimethylpyridine (1 .492 mL, 1 1 .29 mmol) in DMF (10 mL), was treated with a solution of HATU (1 .422 g, 3.734 mmol) in 10 mL of DMF, dropwise) over 30 minutes. After 1 .5 hour, all the volatiles were evaporated per vacuum techniques. The desired product was isolated by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 50% to 100% methanol and water, using no modifier. Yield 0.694 g, 90% yield. Ion found by LCMS: (M+H) ⁺ = 421 .3.= 417.2. Step c. Synthesis of deca-Boc-Compound 100

The intermediated diacid was prepared in similar fashion to Example 65 (Step c.) from tartaric linker-3 (0.694 g, 1 .666 mmol), LiOH (0.084 g, 3.499 mmol), THF (5 ml_), and water (5 ml_). Yield was considered quantitative and the material used in the next step without further purification. Deca-Boc- Compound 100 was prepared in a similar fashion to Example 65 (Step c.) from lnt-6 (0.200 g, 0.128 mmol), the herein above described intermediated diacid (0.025 g, 0.064 mmol), DIPEA (0.057 ml_, 0.326 mmol) in DMF (5 ml_) by dropwise addition of HATU (0.050 g, 0.131 mmol in 1 .5 ml_ of DMF). Yield 0.1 76 g, 79% yield. Ion found by LCMS: [(M-3Boc)+3H]/4 = 795.5

Step d. Synthesis Compound 100

Prepared in a similar fashion to Example 65 (Step d.) from deca-Boc-Compound 100 (0.1 76 g, 0.050 mmol), DCM (4 ml_), triethylsilane (0.25 ml_) and TFA (2 ml_). Yield 0.122 g, 67% yield as the deca TFA salt. Ions found by LC-MS: (M+4H)/4 = 620.3, (M+5H)/5 = 496.4.

Example 67 - Synthesis of Compound 68

Step a.

TrisBocPMBH (500 mg, 0.47 mmol), Z-D-Ser-OH (120 mg, 0.50 mmol), HOBt (68 mg, 0.50 mmol), EDC (96 mg, 0.50 mmol), and DIEA (130 mg, 1 mmol) were stirred in DMF (3 ml_) at room temperature for 2 hours. The mixture was applied directly to reverse phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 25% to 95% acetonitrile, 0.1 % TFA modifier, 30 minute gradient. The pure fractions were pooled, concentrated and directly taken up in methanol (1 0 mL) and stirred in the presence of 5% Pd/C (75 mg) under 1 atmosphere of hydrogen gas for 1 hour. The mixture was filtered, concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile, no modifier, 25 min gradient The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield: 83%. LC/MS [(M-boc+2H ⁺ )/2] ⁺ 525.6.

Step b.

The product was prepared from Z-Thr-OH and intermediate from step-a of this example as described in the previous step. Yield: 81 %. LC/MS [(M-2 boc+2H ⁺ )/2] ⁺ =525.8. Step C.

The product was prepared from Z-(gBoc)Dab-OH and intermediate from step-b of this example as described in the previous step. Yield: 75%. LC/MS [(M-2 boc+2H ⁺ )/2] ⁺ = 625.9.

Step d.

Racemic cyclopentyl trans-di-carboxylic acid (1 g, 6.3 mmol), L-H-Nor-OMe (2.7 g, 14.4 mol) and trimethylamine (4.2g, 41 .7 mmol) were added to DMF (10 ml_) and cooled to 0 ^S C. HATU (5.2g, 13.9 mmol) was added (dry in 5 portions) to the stirring, cooled mixture over a period of 30 minutes. The reaction was stirred for 30 minutes then applied directly to reversed phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile, 0.1 % TFA modifier, 30 minute gradient. The 2 diastereomers were pooled and lyophilized separately into polar and hydrophobic pools and carried forward separately. LC/MS [M+H+] =413.2.

The di-ester (polar diastereomer) was stirred in a 1/1/2 mixture of THF/MeOH/water (15 mL)containing 3 eq of LiOH for 30 minutes. Glacial acetic acid was added until a pH of ~5 was attained. The mixture was concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 10% to 95% acetonitrile, 0.1 % TFA modifier, 30 minute gradient. The pure fractions were pooled and lyophilized. Yield; 86%. LC/MS [M+H+] ⁺ =385.0. LC/MS [M- H]- =383.2. Step e.

HATU (65 mg, 0.17 mmol) in DMF (1 ml_) was added, dropwise over a 20 minute period, to a stirring mixture of triethylamine (51 mg, 0.50 mmol), intermediate from step c of this example (250 mg, 0.17 mmol), and intermediate from step d of this example (300 mg, 0.078 mmol) in DMF (3 ml_). The mixture was stirred for 1 hour and applied directly to reversed phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 15% to 100% methanol and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized. The resulting material was stirred in a 1/1 mixture of TFA/DCM (5 ml_) for 30 minutes. The solvent was removed by the rotary evaporator and purified by reversed phase liquid chromatography (RPLC) using an Isco Combiflash liquid chromatograph eluted with 0% to 70% acetonitrile and water using 0.1 % TFA modifier. The pure fractions were pooled and lyophilized to afford the product as a TFA salt. Yield 46%. LC/MS [(M+4H)/4] ⁺ = 612.8.

Example 68 - Synthesis of trans-cyclopentane-(Bis-norleu-y ^Boc Dab-Thr) (linker-4)

Step a.

To a mixture of trans-DL-1 ,2-cyclopentanedicarboxylic acid (1 g, 6.323 mmol) and N-Nle-OMe HCI (2.544 g, 14 mmol) in anhydrous DMF (7 ml_) was added DIPEA (5.46 g, 14 mmol) , followed by drop-wise added of a solution of HATU (5.32 g, 14 mmol) in DMF (14 ml_) via syringe pump at a rate of 30 mL/hr. After the addition, the reaction mixture was purified through RPLC (150 g, 10 to 72% acetonitrile and water). Yield 1 .1 6 g of the more polar isomer, 44.3%. Ion found by LCMS: [M + H] ⁺ = 413.

Step b.

The step-a product (1 .1 6 g, 2.8 mmol) was dissolved in 1 :1 of MeOH:THF (10 mL). The solution was cooled in an ice-water bath and added with a solution of LiOH (1 68 mg, 6.73 mmol) in water (10 mL). The reaction was stirred for 6 hours, then acidified by 4N HCI solution in dioxane (2 mL). It was then extracted with water (20 mL) and EtOAc (100 mL). The aqueous layer was back extracted with 1 :1 EtOAc/hexane (60 mL). The combined organic layers were concentrated by rotary evaporation, and the residue was purified through RPLC (150 g, 5 to 45% acetonitrile and water). Yield 965 mg, 89.6%. Ion found by LCMS: [M + H] ⁺ = 385.

Step c.

To a mixture of the step-b product (682 mg, 1 .77 mmol) and (S)-methyl-2-amino-4-((ter- butoxycarbonylamino)butanoate hydrochloride (1 .05 g, 3.9 mmol) in anhydrous DMF (4 ml_) was added DIPEA (1 .01 g, 7.8 mmol), followed by drop-wise added of a solution of HATU (1 .48 g, 3.9 mmol) in DMF (4 ml_) via syringe pump at a rate of 8 ml/hr. After the addition, the reaction mixture was extracted with water (30 ml_) and EtOAc (100 ml_ X 2). The organic layer was concentrated by rotary evaporation, and the residue was purified through RPLC (150 g, 10 to 1 00% acetonitrile and water). Yield 1 .4 g, 97.3%. Ions found by LCMS: [M + H] ⁺ = 813, [M - Boc + H] ⁺ = 713. Step d.

The step-c product (1 .4 g, 1 .722 mmol) was dissolved in THF (15 ml_) and MeOH (5 ml_). After cooled in an ice-water bath, the solution was added with LiOH monohydrate (220 mg, 5.2 mmol) in water (2 ml_). The resulting mixture was stirred for 2 hours. It was then extracted with water (50 ml_), 1 .5 ml_ of 4N HCI in dioxane, and EtOAc/Hexane (1 :1 , 150 mL x 2). The combined organic layers was washed with water (30 mL), dried over Na2SC>4, and concentrated by rotary evaporation to dryness. The crude product was carried to the subsequent step without further purification. Yield 1 .3 g, 96.3 %. Ion found by LCMS: [M - Boc + H] ⁺ = 685.

Step e.

To a mixture of the step-d product (1 .3 g, 1 .658 mmol) and L-threonine hydrochloride (678.4 g, 4 mmol) in anhydrous DMF (4 mL) was added DIPEA (1 .3 g, 10 mmol), followed by drop-wise added of a solution of HATU (1 .41 g, 3.7 mmol) in DMF (4 mL) via syringe pump at a rate of 8 ml/hr. After the addition, the reaction mixture was extracted with water (100 mL) and EtOAc (150 mL X 2). The organic layer was dried over Na2SC>4 and concentrated by rotary evaporation to dryness. The crude product was carried to the subsequent step without further purification. Yield 1 .35 g, 3.31 mmol. Ion found by LCMS: [(M - 2Boc + 2H)/2] ⁺ = 408.

Step f.

The step-e product (1 .35 g, 3.31 mmol) in MeOH (30 mL) and THF (50 mL) was cooled in an ice water bath and added with a solution of LiOH monohydrate (205 mg, 4.88 mmol) in water (10 mL). The resulting mixture was stirred for 4 hours then added with a solution of 4N HCI solution in dioxane (1 mL). The organic solvent was partially removed by rotary evaporation at room temperature. The remaining was poured into water (50 mL), and the precipitate was collected by filtration. It was then purified through RPLC (100 g, 5 to 55% acetonitrile and water, using 0.1 % TFA as modifier). Yield 1 .26 g, 77%. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 494.

Example 69 - Synthesis of Compound 75

To a mixture of PMB(Boc)3 (3.18 g, 3 mmol) and Z-Gly-OH (753 mg, 3.6 mmol) in anhydrous DMF (5 mL) was added HATU (1 .37 g, 3.6 mmol) by portions over 10 minutes, followed by DIPEA (780 mg, 6 mmol). The reaction was stirred for 30 minutes and then drop-wise into 0.5% NFUCI solution (100 mL). The white solid was collected through celite filtration and washed with water. The material was re dissolved in MeOH (40 mL), and Pd/C was added. The mixture was stirred under hydrogen for 3 hours. Pd/C was filtered off, and the filtrate was concentrated by rotary evaporation. The residue was purified through RPLC (150 g, 1 5 to 90% MeOH and water). Yield 3.09 g, 92%. Ions found by LCMS: [(M - Boc + 2H)/2] ⁺ = 493.2, [(M - 3Boc + 2H)/2] ⁺ = 393.2.

Step b.

To a solution of the step-a product (270.9 mg, 0.242 mmol) and trans-cyclopentane-(Bis-norleu- y ^Boc Dab-Thr) (linker-4, Example 68) (108.6 mg, 0.1 1 mmol) in anhydrous DMF (1 .5 ml_) and DIPEA (65 mg, 0.5 mmol) was drop-wise added a solution of HATU (92 mg, 0.242 mmol) in DMF (0.5 ml_) via syringe pump at a rate of 1 ml/hr. After the addition, the mixture was purified through RPLC (100 g, 20 to 95% MeOH and water). Yield 264.2 mg, 75.3%. Ions found by LCMS: [(M - 3Boc)/3] ⁺ = 963.1 , [(M -

4Boc)/3] ⁺ = 930, [(M - 5Boc)/3] ⁺ = 896.6, [(M - 6Boc)/3] ⁺ = 863.9.

Step c.

The step-b product (264.2 mg, 0.0828 mmol) was dissolved in TFA (1 .5 mL), and the solution was stirred for 20 minutes. It was then directly purified through HPLC (0 to 20 % acetonitrile and water, using 0.1 % TFA as modifier). Yield 155 mg, 56.7%. Ions found by LCMS:[(M + 2H)/2] ⁺ = 1 194.2, [(M + 3H)/3] ⁺ = 796.5, [(M + 4H)/4] ⁺ = 597.6, [(M + 5H)/5] ⁺ = 478.4, [(M + 6H)/6] ⁺ = 398.8. Example 70 - Synthesis of Compound 77

Step a.

To a mixture of PME(Boc)3 (3.09 g, 3 mmol) and Z-Gly-OH (753 mg, 3.6 mmol) in anhydrous DMF (5 ml_) was added HATU (1 .37 g, 3.6 mmol) by portions over 10 minutes, followed by DIPEA (780 mg, 6 mmol). The reaction was stirred for 30 minutes and then drop-wise into 0.5% NH4CI (100 ml_). The white solid was collected through celite filtration and washed with water. The material was re-dissolved in MeOH (40 ml_), and Pd/C was added. The mixture was stirred under hydrogen for 3 hours. Pd/C was filtered, and the filtrate was purified through RPLC (150 g, 15 to 90% MeOH and water). Yield 3.07 g, 94.3 %. Ion found by LCMS: [(M - Boc + 2H)/2] ⁺ = 493.2, [(M - 3Boc + 2H)/2] ⁺ = 393.2. Step b.

To a solution of the step-a product (262.6 mg, 0.242 mmol) and trans-cyclopentane-(Bis-norleu- 'Y ^Boc Dab-Thr) (linker-4, Example 68) (108.6 mg, 0.1 1 mmol) in anhydrous DMF (1 .5 ml_) and DIPEA (65 mg, 0.5 mmol) was drop-wise added a solution of HATU (92 mg, 0.242 mmol) in DMF (0.5 ml_) via syringe pump at a rate of 1 ml/hr. After the addition, the mixture was purified through RPLC (100 g, 20 to 95% MeOH and water). Yield 274.1 mg, 79.8%. Ions found by LCMS: [(M - 3Boc)/3] ⁺ = 941 , [(M - 4Boc)/3] ⁺ = 907.2, [(M - 5Boc)/3] ⁺ = 873.8, [(M - 6Boc)/3] ⁺ = 840.6.

Step c.

The step-b (274.1 mg, 0.0878 mmol) product was dissolved in TFA (1 .5 ml_), and the solution was stirred for 20 minutes. It was directly purified through HPLC (0 to 20% acetonitrile and water, using 0.1 % TFA as modifier). Yield 130 mg, 45.8%. Ions found by LCMS: [(M + 3H)/3] ⁺ = 774.2, [(M + 4H)/4] ⁺ = 580.8, [(M + 5H)/5] ⁺ = 464.8, [(M + 6H)/6] ⁺ = 387.6, [(M + 7H)/7] ⁺ = 332.4.

Example 71 - Minimum Inhibitory Concentration (MIC) assays

MIC assays are performed according to CLSI broth microdilution guidelines (M07-A9, M100-S23) with the exception of using a 100 mI_ assay volume and preparing stock compounds at 25X final concentration. Briefly, stock solutions of all antibacterial agents is prepared fresh in appropriate solvents (i.e. , PBS, pH 7.4, DMSO, Dl, etc.). Stock concentrations for dimer compounds are made at 25X the highest final assay concentration. All were serially diluted 2-fold, 8 or 12 times in a 96-well PCR plate (VWR cat. no. 83007-374). Bacterial cell suspensions generated from Mueller-Hinton agar (MHA) plate cultures are prepared in 0.85% saline and adjusted to ~0.1 Oϋboo nm. Next, cell suspensions are diluted 1 :200 in cation adjusted Mueller-Hinton broth media (CA-MHB) to a concentration of ~5 x 10 ⁵ CFU (colony-forming units)/ml_. 96 mI_ of each cell suspension in CA-MHB is added to test wells in a 96-well assay plate (Costar cat. no. 3370). A Rainin model 20 mI_ Liquidator 96 is used to dispense 4 pL of each 25X stock compound into the plate containing 96 pL of each strain in CA-MHB. Compounds were tested against a 14-strain panel comprised of E. coli (Ec), A. baumannii (Ab), P. aeruginosa (Pa), and K.

pneumoniae (Kp) that were obtained from ATCC (Ec 25922, Ec 2469, Ab 19606, Pa 27853, Pa PA01 , Kp 43816, Kp 10031 ), Centers for Disease Control and Prevention (Ec AR0349), BEI Resources (Ab

AB5075), Micromyx LLC (Ab 8990, Kp 6951 ), and Belgian Coordinated Collections of Microorganisms (Pa LES431 ) or generated in-house (Ec 25922 64X-1 ). Four of the strains were colistin-resistant examples (COL ^R ) including: Ec 64X-1 (spontaneous mutant possessing a mutation in pmrB (A159V) that was selected by plating on MHA containing colistin at 64-fold the MIC concentration), Ec AR0349 (clinical isolate possessing the mobile mcr-1 colistin resistance gene), Ab 8990 (a clinical isolate possessing unknown colistin resistance mechanisms) and Kp 6951 (clinical isolate possessing a mutation in phoQ (T244N)). E. coli strain ATCC 25922 and P. aeruginosa strain LES431 are run in the presence and absence of 50% heat-inactivated fetal bovine serum (FBS; Sigma, cat. no. F4135-100mL). Plates are mixed by shaking then incubated at 35 °C overnight (16-20 h). MIC values are read visually at 100% growth inhibition.

Table 4. MIC values for compounds

ro

Abbreviations: Ec - Escherichia coii, Ab - Acinetobacter baumannii, Pa - Pseudomonas aeruginosa, Kp - Kiebsieiia pneumoniae, COL ^R - colistin-resistant, C het ^R - colistin-heteroresistant, FBS - fetal bovine serum (50%, heat-inactivated), ND - not determined

Example 72 - Measurement of binding of compounds to LPS using the Limulus Amebocyte Lysate (LAL) assay

The LAL assay (Charles River) is used to determine the binding affinity of test articles to LPS. A decrease in absorbance by test articles demonstrates neutralization of LPS and correlates with binding of test articles to LPS.

For the assay, 25 pL purified LPS from E. coli 01 1 1 :B4 (Sigma) at doses ranging from 1 - 10,000 ng/mL are incubated with 25 pL of test article at concentrations ranging from 0.25 - 10 mM. After 5 min incubation at 37°C, 50 pL of LAL reagent, which reacts with lipid A portion from LPS, is added to corresponding wells. After 15 min, absorbance at 405 nm is read on EnSpire plate reader (Perkin Elmer). The % LPS neutralization is calculated relative to a PBS control (background) and LPS control at each concentration (positive control).

LPS neutralization = (1 - (absorbance test article - PBS with LAL reagent) /

(absorbance no test article - PBS with LAL reagent)) x 100

To obtain a single value of LPS neutralization for each test article, the area under the curve (AUC) for dose-response of test articles from 0.25 - 10 pm for each LPS concentration is calculated using Prism 7 software. The % LPS neutralization is the sum of the AUCs for each LPS concentration determined relative to the maximal AUC achievable x 100.

Example 73- Measuring LPS neutralization using the HEK-Blue hTLR4 reporter cell line

This method measures the ability of compounds to neutralize lipopolysaccharide (LPS) and prevent the downstream activation of NF-KB-signaling mediated by LPS using the HEK-Blue hTLR4 reporter cell line (Fisher Scientific). HEK-Blue hTLR4 cells are cultured to 50-80% confluency in T150 cm ² flasks according to the manufacturer’s method, then gently rinsed with 20 ml 1 X PBS pH 7.4. After aspirating the rinse, 10 ml 1 X PBS is added and incubated for 1 -2 min at 37°C, 5% CO2. Cells are released from the flask by tapping the flask or by using a cell lifter. A single cell suspension is obtained by pipetting up and down, then 10 pi of cell suspension added to 80 pi of 1 X PBS and 10 pi of trypan blue (0.4% stock solution) for hemocytometer enumeration. The cell concentration is adjusted to 140,000 cells/ml in HEK-Blue Detection medium (Fisher Scientific). 20 pi of test compound at the desired concentration is added to a flat-bottom tissue culture treated 96-well plate (Corning). 20 pi LPS stock (1 mg/ml) is added in a dose-response at the desired concentration to corresponding wells. 180 pi of HEK- Blue hTLR4 cells (-25,000 cells/well) are added to corresponding wells, and the plate incubated at 37°C, 5% CO2 for 6-16 h. The absorbance at 650 nm is measured using a Perkin-Elmer Enspire Multimode plate reader. Percent LPS inactivation (1 -[absorbance test article with LPS / absorbance no test article with LPS] x 100%) is plotted versus concentration using GraphPad Prism software (version 7.0d, GraphPad Software, Inc.). The area under the curve (AUC) is used to rank-order compounds by LPS neutralizing activity. Example 74 - LPS neutralization activity of compounds in human blood

The ability of compounds to sequester LPS and inhibit immune cell activation in human blood is measured to rank order LPS-binding affinities. Hirudin anti-coagulated human blood (complement active) is diluted 1 :2 in in RPMI with L-glutamine and phenol red (Life Technologies) and 160 pi is added to wells of a non-binding 96-well plate (Corning 3641 ). 10 pi of 20X compound diluted in RPMI (2.5- 0.0006 mM final concentration) is added to wells, followed by 1 0 mI of 20X LPS from E. coli 01 1 1 :B4 (Sigma; 100 or 1 ,000 ng/ml final concentration), and 20 mI RPMI for a final blood concentration of 40%. The plate is incubated under static conditions at 37°C for 4 h, centrifuged at 500 x g for 5 min at room temperature, and 60 mI plasma is carefully aspirated and transferred to a non-binding plate for overnight storage at - 80°C. The following day, the concentration of TNF-a in plasma samples diluted 1 :10 is determined using the human TNF-a ELISA kit, as per the manufacturer’s instructions (BioLegend). The percent inhibition of TNF-a release, relative to the blood + LPS positive control (1 00% TNF-a release), is calculated and plotted for each compound concentration tested. The area under the curve (AUC) is calculated using GraphPad Prism software (version 7.0d, GraphPad Software, Inc.) and used to rank-order compounds by LPS neutralizing activity. LPS stimulation of whole blood is known to trigger the release of pro- inflammatory cytokine TNF-a (PMID: 26993088). Therefore, high levels of TNF-a inhibition, resulting in high AUCs, are indicative of compounds with good LPS neutralizing activity in human blood.

Example 75 - Activity of compounds in a bacteremia mouse model

In vivo screening of selected compounds was accomplished in an E. coli bacteremia model (N=3). Efficacy was assessed in an animal model of infection using CD-1 mice by evaluating bacteremia in immune competent mice challenged with 2x the LD95 of E. coli 25922 (dosed qd, intraperitoneally (IP) at T+1 hour, survival endpoint).

MICs for compounds against the challenge strain are shown with and without serum. Colistin (COL) was dosed at 0.3 mg/kg and test compounds were dosed at 3.0 mg/kg. Percent survival was determined 72 hours after bacterial challenge. Compounds with MICs against E. coli 25922 of less than 4 pg/ml were evaluated in the bacteremia model. As indicated in Table 5, compounds were significantly more active in the presence of serum, and in the case of Compound 100, the MIC was reduced by more than 16X. This serum synergy translated into potent activity in this model with most compounds achieving 100% efficacy.

Table 5. Activity of Compounds 58, 68, 75, 77, 80, and 100 in a bacteremia mouse model.

Example 76 - Rat model of nephrotoxicity

Preliminary kidney safety was determined for compounds by measuring Kidney Injury Marker 1 (KIM-1 ) in urine over time as an indicator of kidney damage in a rat nephrotoxicity study (25 mg/kg, bid, subcutaneous (SC)).

Rats were administered a total of 50 mg/kg/day SC of colistin or Compound 80. Urine was collected pre-dose and post-dose every 12 hours until 36 hours. The level of KIM-1 protein in the urine at each interval was measured using a commercially available Rat KIM-1 ELISA kit (GenWay®). Compound 80 showed no detectable KIM-1 signal, demonstrating significantly reduced nephrotoxicity compared to colistin (Fig. 1 ).

Example 77 - Thigh model of infection

The activity of several compounds were tested in a thigh bacterial burden model using neutropenic mice infected with colistin-resistant (COL-R) clinical isolate of E. coli ( 10 mg/kg, bid, IP or SC at T+1 hour). Mice were dosed on day -4 and -1 at 152 and 100 mg/kg of cyclophosphamide, respectively.

Compound 80 demonstrated improved efficacy compared to colistin when dosed either SC or IP (Fig. 2). When Compound 80 was dosed SC, the mean level of CFU reduction was greater than 1 -log relative to the starting inoculum, indicating bactericidal activity.

Other Embodiments

While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth.

All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

What is claimed is: