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WO 2017/218922 A2 21 December 2017 (21.12.2017) W !P O PCT

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WO 2017/218922 A2 21 December 2017 (21.12.2017) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/218922 A2 21 December 2017 (21.12.2017) W !P O PCT (51) International Patent Classification: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, A61K 38/12 (2006.01) A61K 47/48 (2006.01) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (21) International Application Number: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, PCT/US20 17/037924 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (22) International Filing Date: KM, ML, MR, NE, SN, TD, TG). 16 June 2017 (16.06.2017) Declarations under Rule 4.17: (25) Filing Language: English — of inventorship (Rule 4.1 7(iv)) (26) Publication Langi English Published: (30) Priority Data: — without international search report and to be republished 62/35 1,537 17 June 2016 (17.06.2016) US upon receipt of that report (Rule 48.2(g)) 62/397,045 20 September 2016 (20.09.2016) US 62/434,268 14 December 2016 (14.12.2016) US (71) Applicant: CIDARA THERAPEUTICS, INC. [US/US]; 63 10 Nancy Ridge Dr., Suite 101, Sandiego, CA 92121 (US). (72) Inventors: BALKOVEC, James M.; 2144 Gilbride Road, Martinsville, NJ 08836 (US). BENSEN, Daniel C ; 1635 = Basswood Avenue, Carlsbad, CA 92008 (US). BLIZ- = ZARD, Timothy; 43 Bertrand Drive, Princeton, NJ 08540 = (US). BORCHARDT, Allen; 5419 Via Carancho, San = Diego, CA 92 111 (US). BRADY, Thomas P.; 756 1 Wind- = song Road, San Diego, CA 92126 (US). CHEN, Zhi-Yong; = 8344 Via Sonoma Unit D, La Jolla, CA 92037 (US). DO, = Quyen-Quyen Thuy; 10414 Rosedust Glen Drive, San = Diego, CA 92127 (US). JIANG, Wanlong; 7417 Via Cres- Ξ ta Road, San Diego, CA 92129 (US). LAM, Thanh; 10865 = Parkdale Avenue, San Diego, CA 92126 (US). LOCKE, ≡ Jeffrey B.; 564 Arenas Street, La Jolla, CA 92037 (US). = NONCOVICH, Alain; 8420 Via Mallorca, Unit 103, La ≡ Jolla, CA 92037 (US). ≡ (74) Agent: BELLFVEAU, Michael, J.; Clark & Elbing LLP, = 101 Federal Street, 15th Floor, Boston, MA 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, ≡ AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, = CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, ≡ DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, = HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, ≡ KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL NO, NZ, = OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every f kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 0 0 l (54) Title: COMPOSITIONS AND METHODS FOR THE TREATMENT OF BACTERIAL INFECTIONS © (57) Abstract: Compositions and methods for the treatment of bacterial infections include compounds containing dimers of cyclic heptapeptides. In particular, compounds can be used in the treatment of bacterial infections caused by Gram-negative bacteria. 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, which 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 one aspect, the disclosure features a compound described by formula (I) : M2-U-M1 (I) wherein M 1 includes a first cyclic heptapeptide including a linking nitrogen and M2 includes a second cyclic heptapeptide including a linking nitrogen ; L' is a linker covalently attached to the linking nitrogen in each of M 1 and M2, or a pharmaceutically acceptable salt thereof; wherein L' is not wherein L" is a remainder of L'; and each of R'L and RL is, independently, C 1-C1 0 alkyl. In some embodiments, L' in formula (I) is described by: —A2— L— A1— \ wherein L is a remainder of L'; A 1 is a 1-5 amino acid peptide covalently attached to the linking nitrogen in M 1 or is absent; and A2 is a 1-5 amino acid peptide covalently attached to the linking nitrogen in M2 or is absent. In some embodiments, the compound is described by formula (II) : (II) wherein L is a remainder of L'; each of each of R , R 2 , R' , and R' 2 is, independently, a lipophilic moiety, a polar moiety, or H; each of R , R 3 , R 4 , R' , R' 3 , and R' 4 is, independently, optionally substituted C 1- C5 alkamino, a polar moiety, a positively charged moiety, or H; each of R 5 and R' 5 is, independently, a lipophilic moiety or a polar moiety; each of R2, R3, R4, R5, R6, R7, R8, R9, R 0, R'2, R'3, R'4, R'5, R'6, R'7, R'8, R'9, and R' 0 is, independently, a lipophilic moiety, a positively charged moiety, a polar moiety, H , optionally substituted C 1-C5 alkamino, optionally substituted C 1-C20 alkyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C4-C20 cycloalkenyl , optionally substituted C8-C20 cycloalkynyl, optionally substituted C5-C1 5 aryl, optionally substituted C 1-C20 heteroalkyl, optionally substituted C3- C20 heterocycloalkyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C3-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 5-8 membered ring ; each of a', b', c', a , b, and c is, independently, 0 or 1; each of N , N2, N3, N4, N' , N'2, N'3, and N'4 is a nitrogen atom , each of C , C2, C3, C' , C'2, and C'3 is a carbon atom, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound includes at least one optionally substituted 5-8 membered ring formed by joining (i) R2, R3, and C ; (ii) R3, R4, N , and C ; (iii) R5, R6, and C2; (iv) R6, R7, N2, and C2; (v) R8, R9, and C3; (vi) R9, R 0 , N3, and C3; (vii) R'2, R'3, and C' ; (viii) R'3, R'4, N' , and C' ; (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' 0 , N'3, and C'3. In some embodiments, the compound is described by formula (III) (II I) wherein L is a remainder of L'; or a pharmaceutically acceptable salt thereof. In some embodiments, each of R , R 2 , R' , and R' 2 is, independently, a lipophilic moiety; each of R , R 3 , R 4 , R' , R' 3 , and R' 4 is, independently, optionally substituted C 1-C5 alkamino, a polar moiety, or a positively charged moiety; and/or each of R 5 and R' 5 is, independently, a polar moiety. In some embodiments, each of R , R 2 , R' , and R' 2 is a lipophilic moiety. In particular, each lipophilic moiety is, independently, optionally substituted C 1-C20 alkyl, optionally substituted C5-C1 5 aryl, optionally substituted C6-C35 alkaryl, or optionally substituted C3-C1 5 heteroaryl. In some embodiments, each lipophilic moiety is, independently, C 1-C8 alkyl, methyl substituted C2-C4 alkyl , (C1 - C 10)alkylene(C6)aryl, phenyl substituted (C1 -C1 0)alkylene(C6)aryl, or alkyl substituted C4-C9 heteroaryl. In particular, 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 , R 3 , R 4 , R' , R' 3 , and R' 4 is independently optionally substituted C 1-C5 alkamino. In particular, each of R , R 3 , R 4 , R' , R' 3 , and R' 4 is CH2CH2NH2. In some embodiments, each of R 5 and R' 5 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 particular, each polar moiety is hydroxyl substituted C 1-C4 alkyl.
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