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EP-4737470-A2 - C10-ALKYLENE SUBSTITUTED 13-MEMBERED MACROLIDES AND USES THEREOF

EP4737470A2EP 4737470 A2EP4737470 A2EP 4737470A2EP-4737470-A2

Abstract

Provided are 13-membered macrolides for the treatment of infectious diseases. The 13-membered macrolides described herein are azaketolides. Also provided are methods for preparing the 13-membered macrolides, pharmaceutical compositions comprising the 13-membered macrolides, and methods of treating infectious diseases, and in particular, disease resulting from Gram negative bacteria using the disclosed macrolides.

Inventors

  • CLARK, ROGER B.
  • WANG, WENYING
  • ICHIKAWA, YOSHITAKA
  • MYERS, ANDREW G.
  • ZHANG, ZIYANG
  • CARLSEN, PETER NIELS
  • SANCHEZ, ANDRE
  • DHANDAPANI, Ganapathy
  • NEETIPALLI, Thrimurtulu
  • RAHMAN, Md. Ataur
  • LEPITRE, Thomas
  • ALM, RICHARD
  • AUSTIN, WESLEY FRANCIS
  • HOGAN, PHILIP
  • JEWETT, Ivan
  • LAHIRI, Sushmita D.
  • LAWRENCE, Jonathan F.
  • LI, Xiben
  • SHI, SHUHAO

Assignees

  • Zikani Therapeutics, Inc.
  • President and Fellows of Harvard College

Dates

Publication Date
20260506
Application Date
20191118

Claims (15)

  1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: one of R 2a and R 2b is selected from the group consisting of H, halo, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 1-10 alkenyl, wherein C 1-10 alkyl, C 1-10 alkoxy, and C 1-10 alkenyl are optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and the other of R 2a and R 2b is selected from the group consisting of halo, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 1-10 alkenyl, wherein C 1-10 alkyl, C 1-10 alkoxy, and C 1-10 alkenyl are optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, substituted amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; each of R 4a and R 4b is independently selected from the group consisting of H and optionally substituted C 1-10 alkyl; R 5 is selected from the group consisting of H, an oxygen protecting group, and wherein " " indicates appoint of attachment; R 6a is optionally substituted C 1-10 alkyl; R 6b is H, C 1-10 alkyl, C 1-10 hydroxyalkyl, allyl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which can be optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 8a and R 8b are each independently selected from the group consisting of H and optionally substituted C 1-10 alkyl; R 9a is -H or C 1-4 alkyl; one of R 10a and R 10b is H, and the other of R 10a and R 10b is: (a) optionally substituted C 2 - 6 alkylene-R 101 , optionally substituted C 2-10 alkenylene-R 101 , and optionally substituted C 2-10 alkynylene-R 101 ; wherein: R 101 is selected from the group consisting of H, (C 1-6 alkyl)-S-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, -OH, optionally substituted -O-(C 1-6 alkyl), - NR x R x' , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein: R x and R x' are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ), wherein R y' and R y" are each independently H or optionally substituted alkyl; or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; or (b) optionally substituted R 101a2 -CH 2 -; wherein R 101a2 is NR x R x' , wherein R x and R x' are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, and optionally substituted alkylene-heteroaryl group and -C(=O)-alkylene-N(R y' )(R y" ), wherein R y' and R y" are each independently H or optionally substituted alkyl; or R 101a2 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 11a and R 11b are each independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula IA: or a compound of formula IB: or a compound of formula IC: or a compound of formula ID: optionally wherein R 6b is selected from the group consisting of -H, C 1 -optionally substituted C 10 alkyl, optionally substituted C 1 -C 10 hydroxyalkyl, and optionally substituted allyl; and further optionally wherein R 6b is selected from the group consisting of methyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, - CH 2 CHOHCH 2 OH, and allyl; or a compound of formula IE: or a compound of formula IF: or a compound of formula IG:
  3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: (a) either (i) R 11a and R 11b are -H; or (ii) one of R 11a and R 11b is -H and the other is optionally substituted C 1-10 alkyl, optionally wherein one of R 11a and R 11b is -H and the other is methyl; or (iii) R 11a and R 11b are each independently optionally substituted C 1-10 alkyl, optionally wherein R 11a and R 11b are each methyl; and/or (b) one of R 2a and R 2b is optionally substituted C 1-10 alkyl; optionally wherein: (i) one of R 2a and R 2b is methyl and the other of R 2a and R 2b is H, or both of R 2a and R 2b are methyl; or (ii) one of R 2a and R 2b is methyl and the other is halo and more particularly fluoro or chloro; or (iii) one of R 2a and R 2b is methyl and the other is optionally substituted C 1-10 alkyl; or (iv) one of R 2a and R 2b is methyl and the other is selected from the group consisting of optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 1-10 alkenyl, wherein optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 1-10 alkenyl are optionally substituted with one or more selected from the group consisting of halo, aryl, and heteroaryl; and/or (c) the compound is a compound of formula IH:
  4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, which is a compound of formula IIA, IIB, IIC, or IID: wherein R 9a , R 10a and R 10b are as defined in any one of the preceding claims; optionally wherein the compound is a compound of formula IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a, or IID-2a: and/or R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 10a is an optionally substituted C 3 alkylene-R 101 ; R 101 is selected from the group consisting of -H, -OH, -O-alkyl, -NR x R x' , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein R x and R x' are each independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ); or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; optionally wherein: R 10a is selected from the group consisting of an optionally substituted R 101 -CH 2 CH 2 CH 2 -, optionally substituted R 101 -CH 2 CH 2 CH-OH-, and optionally substituted R 101 -CH 2 CH 2 CH-OMe-; and further optionally wherein: R 101 is selected from the group consisting of -H, -OH, -O-alkyl, -N(Me)(Et), -N(Me) 2 , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2 , -N(Me)(cyclopropyl), - NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), - NH(cyclopentyl), -N(Me)(cyclohexyl), -NH(cyclohexyl), optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrollidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl, and optionally substituted isoindolinyl; yet further optionally wherein R 10a is selected from the group consisting of: and wherein NR x R x' is selected from the group consisting of -N(Me)(Et), -N(Me) 2 , -N(Me)(t-Bu), - N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2 , -N(Me)(cyclopropyl), -NH(cyclopropyl), - N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl),-N(Me)(cyclohexyl), and -NH(cyclohexyl); and wherein " " indicates a point of attachment.
  6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein: R 10a is an optionally substituted C 2 alkylene-R 101a1 ; R 101a1 is selected from the group consisting of H, (C 1-6 alkyl)-S-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, -OH, -O-alkyl, -NR x R x' , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein: R x and R x' are each independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ); or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein: each R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; optionally wherein: (a) R 10a is R 101a1 -CH 2 CH 2 - and further optionally wherein R 101a1 is an optionally substituted heterocycloalkyl; and/or (b) R 10a is selected from the group consisting of: MeSCH 2 CH 2 -, MeSOCH 2 CH 2 -, MeSO 2 CH 2 CH 2 -, wherein " " indicates a point of attachment.
  7. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R 101a2 is selected from the group consisting of -NHR z , and -NMeR z , wherein: R z is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted -CH 2 -cycloalkyl, optionally substituted -CH 2 -heterocycloalkyl, optionally substituted -CH 2 -aryl, optionally substituted -CH 2 -heteroaryl, -(C=O)-cycloalkyl or -(C=O)-alkylene-NR Z' R Z" ; wherein R z' and R z" are each independently H or alkyl; or R z is -optionally substituted alkylene-R 101a2' , wherein R 101a2' is optionally substituted heteroaryl; optionally wherein: R 101a2 -CH 2 - is -CH 2 NHMe, -CH 2 N(Me) 2 , -CH 2 N(Me)(cyclopropyl), - CH 2 NH(oxetanyl), -CH 2 NHCH 2 (cyclopropyl), and wherein " " indicates a point of attachment.
  8. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 10a is an optionally substituted R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, or R 101a2- C(=O)-, wherein " " indicates a point of attachment; and wherein: R 101a2 is an optionally substituted wherein R 101a2' is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, -C(=O)-H, -C(=O)-optionally substituted cycloalkyl, -C(=O)-optionally substituted alkylene-R 101a2" , optionally substituted alkylene-R 101a2" , wherein R 101a2" is selected from the group consisting of H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkenyl, and wherein " " indicates a point of attachment; optionally wherein R 10a is selected from the group consisting of: and wherein " " indicates a point of attachment.
  9. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 10a is an optionally substituted C 2-10 alkenylene-R 101 ; R 101 is selected from the group consisting of -H, -OH, -O-alkyl, -NR x R x' , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein R x and R x' are each independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ); or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; optionally wherein: (a) R 10a is an optionally substituted C 2-5 alkenylene-R 101 selected from the group consisting of wherein R 101e is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and NRxRx', R x and R x' are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ); or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; and wherein " " indicates a point of attachment; and further optionally wherein R 10a is an optionally substituted C 2-5 alkenylene-R 101 selected from the group consisting of or (b) R 10a is an optionally substituted alkenylene-R 101 which is wherein A is an optionally substituted cycloalkyl or heterocycloalkyl and R 101e is selected from the group consisting of -H, alkyl, and -NR x R x' , wherein R x and R x' are each independently selected from the group consisting of -H and optionally substituted alkyl, and wherein " " indicates a point of attachment; optionally wherein R 10a is an optionally substituted alkenylene-R 101 selected from the group consisting of and
  10. The compound of claim 4, which: (a) is a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein: R 101b is -H, methyl, or methoxy; R 10b is -H; R 11a and R 11b are independently selected from the group consisting of -H and methyl; R x and R x' are each independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y ) 2 ; or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein each R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; optionally wherein NR x R x' is selected from the group consisting of -N(Me)(Et), - N(Me) 2 , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2 , -N(Me)(cyclopropyl), - NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), - NH(cyclopentyl), -N(Me)(cyclohexyl), and NH(cyclohexyl); or (b) is a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: R 101b is -H, methyl, or methoxy; R 10b is -H; R 11a and R 11b are independently selected from the group consisting of -H and methyl; and is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; optionally wherein is selected from the group consisting of optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrollidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl, and optionally substituted isoindolinyl; or (c) is a compound of formula V: or a pharmaceutically acceptable salt thereof, wherein: R 101b is -H, methyl, or methoxy; R 10b is -H; R 11a and R 11b are independently selected from the group consisting of -H and methyl; and is selected from the group consisting of optionally substituted heterocycloalkyl; optionally wherein is optionally substituted piperidinyl; or (d) is a compound of formula VI: or a pharmaceutically acceptable salt thereof, wherein: R 101b is -H; R 10b is -H; R 11a and R 11b are independently selected from the group consisting of -H and methyl; and R x and R x' are each independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y' )(R y" ); or R x and R x' together with the atom to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring optionally containing an additional heteroatom selected from the group consisting of O, S, SO, SO 2 , NR y , and N-C 1 -C 10 alkyl; and wherein each R y is independently selected from the group consisting of -H and optionally substituted C 1-10 alkyl; or one of R x and R x' is -H or alkyl and the other is R z , wherein R z is -(C=O)-cycloalkyl or -(C=O)-alkylene-NR z" R Z‴ ; wherein R z" and R z‴ are each independently -H or alkyl; or R z is -alkylene-R 101a wherein R 101a is optionally substituted heteroaryl; or (e) is a compound of formula VII: or a pharmaceutically acceptable salt thereof, wherein: R 101c is -H; R 101b is -H, -OH, -OMe, or -OCH 2 OMe-; or R 101b and R 101c form C=O-; and R 101 is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted azetinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted triazolyl; R 10b is -H; R 11a and R 11b are independently selected from the group consisting of -H and methyl; and is selected from the group consisting of is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted azetinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted triazolyl.
  11. A compound according to any one of the preceding claims, wherein the compound is depicted in Table A, or a pharmaceutically acceptable salt thereof.
  12. A pharmaceutical composition comprising a compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  13. The compound of any of claims 1-11, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, for use in the treatment of an infectious disease in a subject in need thereof; optionally wherein: (a) the infectious disease is a bacterial infection, optionally wherein the bacterial infection is an infection with a Gram positive bacteria, or a Gram negative bacteria, or the bacterial infection is a Staphylococcus infection, an Acinetobacter infection, a Klebsiella infection, an Escherichia infection, or a Pseudomonas infection; or (b) the infectious disease is a parasitic infection.
  14. A compound of formula N-a: or a salt thereof, wherein R 4a , R 4b , R 6a , R 6b , R 8a , R 8b , R 10a , R 10b , R 11a , and R 11b are as defined in claim 1; each instance of R 15 is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R 15 groups are joined to form an optionally substituted heterocyclyl or heteroaryl ring; and each instance of R 16a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and PG is a protecting group.
  15. A process of preparing a compound of formula I of claim 1, wherein the process: (a) comprises cyclization of a compound of formula N-a, wherein compound N-a is as defined in claim 14: optionally wherein the process further comprises the step of preparing the compound of formula N-a, by combining N-1 with N-2 under reductive amination conditions: wherein R s is PG is a protecting group, and " " indicates a point of attachment; or (b) comprises cyclizing a compound of formula N-a as defined in claim 14 and wherein R 9a is H, to provide a compound of formula P wherein R 9a is H; followed by reductive amination and deprotection to provide a compound of formula I wherein R 9a is C 1-4 alkyl, or (c) comprises alkylating a compound of formula A with R 2b -LG in the presence of base, wherein LG is a leaving group, to provide after deprotection a compound of formula I

Description

CROss-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application 62/769,383 filed on November 19, 2018. The disclosure of this prior application is considered part of the disclosure of this application and is hereby incorporated by reference in its entirety. BACKGROUND Emerging resistance to existing antibiotics is rapidly developing as a crisis of global proportions, especially for infections originating from drug resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes coding for antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result antibiotic resistance can evolve quickly, particularly in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. More than 99,000 people die annually in the U.S. from healthcare-associated infections, more than all casualties from car accidents, HIV, and breast cancer combined, creating an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 122:160-166. The current crisis is exacerbated by decreased research in the development of new antibiotics by most major pharmaceutical companies. See, e.g., Projan, Curr. Opin. Microbiol. (2003) 6:427-430. The current rate of introduction of new antibiotics does not adequately address growing resistance, and with the ease of international travel and increasing population densities, the need for innovation in the field has never been higher. The macrolides are one of the few major clinically important classes of antibiotics for which the only practical access has been through semi-synthesis, or chemical manipulation of structurally complex fermentation products, in routes as long as 16 steps. See, e.g., Paterson, Tetrahedron (1985) 41:3569-3624; Omura, Ed., Macrolide Antibiotics: Chemistry, Biology, and Practice, Second Edition; Academic Press, 2002. The macrolide class of antibiotics has proven safe and effective in the battle against pathogenic bacteria since the discovery of erythromycin over 60 years ago. See, e.g., Wu et al., Curr. Med. Chem. (2001) 8:1727-1758. Erythromycin displays a spectrum of antibacterial activity against Gram-positive bacteria similar to that of penicillin but has a lesser propensity to induce allergic interactions, and it has been routinely prescribed for upper and lower respiratory tract infections and urogenital infections. See, e.g., Washington et al., Mayo. Clin. Proc. (1985) 60:189-203; Washington et al., Mayo. Clin. Proc. (1985) 60:271-278. However, erythromycin is known to undergo acid-promoted internal ketalization (cyclization of the C6 and C12 hydroxyl groups onto the C9 ketone) in the gut, which leads to adverse gastrointestinal events. See, e.g., Kurath et al., Experientia (1971) 27:362. Second-generation macrolide antibiotics clarithromycin and azithromycin addressed issues of acid instability and were prepared semi-synthetically in 4-6 steps from erythromycin, which is readily available through large-scale fermentation. See, e.g., Ma et al., Curr. Med. Chem. (2011) 18:1993-2015; Wu et al., Curr. Pharm. Des. (2000) 6:181-223; Ma et al., Mini-Rev. Med. Chem. (2010) 10:272-286; Asaka et al., Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) (2003) 3:961-989; Morimoto et al., J. Antibiot. (1990) 43:286-294; Morimoto et al., J. Antibiot. (1984) 37:187-189; Watanabe et al., J. Antibiot. (1993) 46: 1163-1167; Watanabe et al., J. Antibiot. (1993) 46:647-660; Bright et al., J. Antibiot. (1988) 41: 1029-1047; Djokic et al., J. Antibiot. (1987) 40:1006-1015; Mutak et al., J. Antibiot. (2007) 60: 85-122; and Retsema et al., Antimicrob. Agents Chemother. (1987) 31:1939-1947. Azithromycin has been shown to exhibit markedly improved efficacy against Gram negative organisms, and it has a longer half-life and higher tissue distribution than the other macrolide antibiotics, thought to correlate with its 15-membered ring containing a tertiary amine. See, e.g., Ferwerda et al., J. Antimicrob. Chemother. (2001) 47:441-446; Girard et al., Antimicrob. Agents Chemother. (1987) 31:1948-1954. The natural product tylosin, a 16-membered macrolide used in veterinary medicine, has been shown by X-ray crystallography to occupy the same binding pocket as erythromycin and azithromycin, suggesting that there is a high tolerance for variability in ring size and composition of the macrocycle. The three primary causes of resistance to macrolides in bacterial organisms are: ribosome methylation encoded by erm genes, mutations in ribosomal RNA or peptides, and cell efflux mediated by mef and msr genes. See, e.g., Leclercq et al., Antimicrob. Agents Chemother. (1991) 35:1273-1276; Leclercq et al., Antimicrob. Agents Chemother. (1991) 35:1267-1272; Weisblum, Antimicrob. Agents Chemother. (1995) 39:577-585; Vester et al., Antimicrob. Agents Chemother. (2001) 45:1-12; Prunier et