Peptide macrocycles against Acinetobacter baumannii

A process for the manufacture of a compound according to formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is C-L1-R11 or N;
• X2 is C-L2-R12 or N;
• X3 is C-L3-R13 or N;
• X4 is C-L4-R14 or N, with the proviso that not more than three of X1, X2, X3 and X4 are N;
• X5 is C-L5-R15 or N;
• X6 is C-L6-R16 or N;
• X7 is C-L7 R17 or N;
• X8 is C-L8-R18 or N, with the proviso that not more than three of X5, X6, X7 and X8 are N;
• R1 is —(CH2)m-heteroaryl or —(CH2)m-heterocycloalkyl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C1-7-alkyl, C1-7-haloalkyl, C3-7-cycloalkyl or C1-7-alkoxy;
• R2, R4 and R6 are each individually selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-haloalkyl, and C3-7-cycloalkyl;
• R3 is —C1-7-alkyl, —(CH2)n—NR20R21, —(CH2)n—C(O)NR20R21 or —(CH2)n—O—(CH2)q—NR20R21;
• R5 is hydrogen, C1-7-alkyl, hydroxy-C1-7-alkyl, —(CH2)o—NR22R23, —(CH2)o—C(O)—NR22R23, —(CH2)o—O—(CH2)q—NR20R21, —(CH2)o—NH—C(NH)—NR22R23, —(CH2)o—NH—C(O)—NR22R23, —(CH2)o—NH—C(O)—OR26, —(CH2)o—C3-7-cycloalkyl, —(CH2)o-heterocycloalkyl, —(CH2)o-heteroaryl, or —(CH2)o-aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C1-7-alkyl, C1-7-haloalkyl, C1-7-alkoxy or aryl;
• R5′ is hydrogen;
• R7 and R8 are each individually selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-haloalkyl, C3-7-cycloalkyl and C1-7-alkoxy;
• R11, R12, R13, R14, R15 and R16 are each individually selected from the group consisting of hydrogen, halogen, cyano, C1-7-alkyl, C1-7-haloalkyl, —NR24R25, C1-7-alkyl-NR24R25, hydroxy, C1-7-alkoxy, haloC1-7-alkoxy, —B(OH)2, benzyloxy-propynyl (—C≡C—CH2—O-benzyl), C3-7-cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein heteroaryl is optionally substituted with one C1-7-haloalkyl or C1-7-alkoxy;
• R17 is hydrogen, halogen, cyano, C1-7-alkyl, C1-7-haloalkyl, —NR24R25, C1-7-alkyl-NR24R25, hydroxy, C1-7-alkoxy, haloC1-7-alkoxy, B(OH)2, benzyloxy-prop-1-ynyl, C3-7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
• wherein heterocycloalkyl is optionally substituted with one —NR24R25,
• wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list group consisting of halogen, cyano, C1-7-alkyl, C1-7-haloalkyl, C1-7-hydroxyalkyl, hydroxy, C1-7-alkoxy, —NR24R25, —SO2—C1-7-alkyl, —SO2—NR24R25, heterocycloalkyl and heterocycloalkyl substituted with C1-7-alkyl;
• R18 is hydrogen, halogen, cyano, C1-7-alkyl, C1-7-haloalkyl, hydroxy, C1-7-hydroxyalkyl, C1-7-alkoxy, C1-7-haloalkoxy, —NR24R25, C1-7-alkyl-NR24R25, C3-7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
• wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the group consisting of halogen, cyano, C1-7-alkyl C1-7-haloalkyl, hydroxy, C1-7-alkoxy, —NR24R25, C1-7-alkyl-NR24R25, —CO—NH—(CH2)r—NR24R25, —CO—NH—(CH2)r—OH, —CO—NH—(CH2)r-heterocycloalkyl, —CO—OH, —O—C1-7-hydroxyalkyl, —O—(CH2)r—CO—OH, —SO2—C1-7-alkyl, —SO2—NR24R25, heterocycloalkyl, —O-heterocycloalkyl and heterocycloalkyl substituted with C1-7-alkyl;
• R20 and R22 are each individually selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-haloalkyl, C3-7-cycloalkyl and —C(═NH)—NH2;
• R21 and R23 are each individually selected from the group consisting of hydrogen and C1-7-alkyl;
• R24 and R25 are each individually selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-haloalkyl, C1-7-hydroxyalkyl and C3-7-cycloalkyl;
• R26 is hydrogen, C1-7-alkyl or benzyl;
• L1, L2, L3, L4, L5, L6, L7 and L8 are each individually selected from the group consisting of a single bond, —C(O)—, —SO2—, —(CH2)p—, —CH═CH— and —C≡C—;
• m is 1, 2, 3, or 4;
• n is 1, 2, 3, or 4;
• o is 0, 1, 2, 3, or 4;
• p is 1, 2, 3, or 4;
• q is 1, 2, 3, or 4;
• and
• r is 1, 2, 3, or 4;
• the process comprising the steps of:
• a) reacting a compound of formula (III) with a compound of formula (IV) using sodium cyanoborohydride (NaCNBH3) to provide a compound of formula (II);
• b) cleaving off the protecting group (PG) and the resin from the compound of formula (II);
• and
• c) followed by cyclisation of the cleaved compound of formula (II) using HATU and Hünig's base.