CA3240145A1

CA3240145A1 - Antimalarial agents

Info

Publication number: CA3240145A1
Application number: CA3240145A
Authority: CA
Inventors: John A. Mccauley; Manuel De Lera Ruiz; Zhuyan Guo; Philippe Nantermet; Michael J. Kelly Iii; Alvaro GUTIERREZ BONET; Lianyun Zhao; Zhiyu Lei; Bin Hu; Dongmei ZHAN; Anthony HODDER
Original assignee: Walter and Eliza Hall Institute of Medical Research; MSD R&D China Co Ltd; Merck Sharp and Dohme LLC
Current assignee: Walter and Eliza Hall Institute of Medical Research; MSD R&D China Co Ltd; Merck Sharp and Dohme LLC
Priority date: 2021-12-07
Filing date: 2022-12-05
Publication date: 2023-06-15
Also published as: TWI842251B; AU2022404966A1; TW202334161A; DOP2024000108A; CO2024007160A2; KR20240113588A; WO2023107356A1; IL313353A; PE20241517A1

Abstract

The present invention provides methods of treating malaria comprising administration of compounds of Formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the variables are as defined herein. The invention also provides uses of the compounds of Formula (I), as defined herein, for inhibiting plasmepsin X, plasmepsin IX or plasmepsin X and IX activity, for treating a Plasmodium infection, and for treating malaria. Also provided are methods of treatment further comprising administration of one or more additional anti-malarial compounds.

Description

TITLE OF THE INVENTION
ANTIMALARIAL AGENTS
FIELD OF THE INVENTION
The present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections.
More specifically, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections, more particularly for the treatment of malaria.
B A CK GR OUND OF THE INVENTION
Malaria is a major disease in humans with several hundred million infections and over 450,000 deaths each year. The most lethal form of malaria is caused by Plasmodium falciparum. This protozoan parasite is responsible for almost all malarial deaths with most occurring in Africa. P. falciparum has a complex life cycle starting in the Anopheles mosquito vector when sporozoite forms are injected into the human host during a blood feed. These sporozoites migrate to the liver and invade hepatocytes in which they develop to form thousands of liver merozoites that egress into the blood where they invade erythrocytes to commence the asexual cycle of the parasite responsible for the symptoms of malaria. The parasite develops within the protected niche of the red cell to form 16-32 merozoites that, once mature, egress from the host cell to invade new red blood cells. Some of these parasites differentiate to form gametocytes, the sexual form of the parasite. These can be taken up by the mosquito where male and female gametes form, fuse and differentiate into oocysts on the mosquito midgut extracellular matrix. Sporozoites form within the oocyst and upon egress migrate to the salivary gland for delivery to the next host during blood feeding for perpetuation and survival of the parasite.
Other forms of malaria include a relapsing form of malaria caused by P. vivax which is responsible for significant morbidity, can cause virulent forms of this disease with some deaths and is mainly a problem outside Africa. P. knowlesi is found in South East Asia and is a zoonotic parasite that normally infects long-tailed macaques but has been shown to infect humans in Malaysian Borneo.
Artemisinin combined with partner drugs have become a mainstay in the treatment and control of malaria. However, due to the increasing threat of artemisinin-based combination therapy (ACT) drug resistance, the development of new antimalarials with novel targets that inhibit multiple steps in the parasite life cycle is an urgent priority for the malaria control field. Such novel antimalarials, as monotherapies or ACT partner drugs, could make strides towards malaria elimination as there is a reduced likelihood of parasites with preexisting resistance mutations being present in the parasite population.
Currently, aspartic acid proteases are prime targets for drug development: the 111V aspartic acid protease has been successfully targeted with a drug in clinical use; inhibitors that target human renin, BACE1 and gamma-secretase have been or are in clinical development.
In the antimalarial drug space, P. falciparum aspartic acid proteases plasmepsin X and IX (PMX
and PMIX) have been identified as potential targets since inhibitors block parasite egress and invasion of the host cell and prevent maturation of some rhoptry and micronemal proteins required for this process (Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress.
Science. 2017;358(6362):522-8.) SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula (I):

N HW-k< X
HNAN V
.5,1I
N'"1/4O
I Ra (I) wherein A, X, V, Y, Z, Ra, Rb, R3, R4, It', RI', 105, m and p are described below.
Also described herein are methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also described herein are methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2 Also described herein are methods of treatment of malaria comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
The present invention further provides the use of compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent, for the treatment of malaria.
Moreover, the present invention provides methods for the use of pharmaceutical compositions comprising one or more of said compounds in the free form or in pharmaceutically acceptable salt form, together with one or more customary pharmaceutical excipient(s), for the treatment of Plasmodium infections, the treatment of malaria, the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX. Methods for the use of combinations of the compounds or salts of the invention together with one or more additional pharmaceutically active agents are also provided.
The present invention further provides methods for the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX activity and of treatment, prevention, amelioration and/or delaying onset of diseases or disorders in which the inhibition of plasmepsin X and/or plasmepsin IX has or may have a therapeutic effect, e g , malaria The present invention further provides methods for the inhibition of P.
falciparum aspartic acid proteases. The present invention further provides methods for blocking P.
fakiparum growth by inhibiting plasmepsin X. The present invention further provides methods for blocking P. .fakiparum growth by inhibiting both PMX and Plasmepsin IX.
The present invention further provides methods for the treatment of malaria by inhibiting plasmepsin X. The present invention further provides methods for the treatment of malaria by inhibiting both PMX and Plasmepsin IX.
These and other embodiments of the invention, which are described in detail below or will become clear to those of ordinary skill in the art, are included within the scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Described herein are compounds having the structural Formula (I):

3 N H*\/=-=< X

b Ra Rb (I) wherein A is a straight or branched, saturated or unsaturated (C3-Cio)alkylene, phenyl(C3-Cio)alkylene or cycloalkyl(C3-Cio)alkylene comprising at least one -CH2-group, wherein one or more additional -CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONR, NRCO, S02, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl, X is a bond, C(R14)2, 0, S. SO, SO2 or NH;
Y is CR9 or N, wherein when Y is N, Z is CR11 and V is CR1 ;
V is CR1 or N, wherein when V is N, Z is CR11 and Y is CR9;
Z is CR" or N, wherein when Z is N, V is CR1 and Y is CR9, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C,-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, COCi-C6alkyl or COOCi-C6alkyl;
Ra is hydrogen, halogen, CN, OH, C,-C6alkoxy, Ci-C6alkylOC1-C6alkyl, C,-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, C1-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C,-C6alkylN(R7)(1V) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycl alkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCi-Coalkyl, C,-C6alkylCOOH, COOH, oxo, COOCi-Coalkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, C,-Coalky101-1, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8), Rb is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, oxo, COOCi-Coalkyl, C1-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-

4 C6cycloalkyl, Ci-C6alkyl, -Ci-C6a1ky1Oha1oCi-C6a1ky1, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(R8) or when taken with Ra forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or three sub stituents selected from the group consisting of halogen, CN, OH, Ci-C6a1koxy, C1-C6alky1OC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alky1COOC1-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6a1ky1OhaloC1-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
R3 is hydrogen, halogen, CN, OH, Ci-Coalkoxy, Ci-CoalkylOCi-Coalkyl, Ci-CoalkylCOOH, COOH, C3-Cocycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-Coalkyl(OCH2CH2)nN(R7)(R8) or Ci-CoalkylOhaloCi-Coalkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;
R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, CI-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCI-Coalkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2)nN(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;
R7 is hydrogen, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6a1ky1OH, COCi-C6alkyl or CO0C1-C6alkyl;
R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, COCi-C6alkyl or COOCI-C6alkyl;
R9 is hydrogen, halogen, CN, OH, Cl-C6alkoxy, CI-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCI-C6alkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
R1 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6alky1OC1-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alky1, haloCi-C6alkyl, Ci-C6a1kylOH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(R8);
R11 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-Cocycloalkyl, C1-C6alky1, haloCi-C6a1kyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
R12 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6alky1OC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-Cocycloalkyl, Ci-Coalkyl, haloCi-Coalkyl, Ci-CoalkylOH, CON(R7)(R8), N(R7)(R8) or Ci-CoalkylN(R7)(R8);
R13 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);

5

6 each occurrence of R" is independently selected from the group consisting of hydrogen, halogen, CN, 01-1, CI-C6alkoxy, Ci-C6alky1OCI-C6alkyl, CI-C6alkylCOOH, COOH, C6cycloalkyl, Ci-Coalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
R15 is hydrogen, halogen, CN, OH, C1-C6alkoxy, Ci-C6alkylOCi-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
each occurrence of R'6 is independently selected from the group consisting of hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOC1-C6alky1, CI-C6alkylCOOH, COOH, C6cycloalkyl, Ci-C6alkyl, hal oCi-C6alkyl, Ci-CoalkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
m is 0 or 1, n is 1, 2, 3 or 4; and p is 0 or I.
In the embodiments described herein, X is a bond, C(R14)2, 0, S, SO, SO2 or NH.
In certain embodiments described herein X is a bond. In certain embodiments, X
is C(R14)2, wherein R" is discussed in further detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, 0, CH(OCH3), SO2 or CF2. In other embodiments X is CH2, 0, S, SO, SO2 or NH Tn certain embodiments, Xis CH2 In the embodiments described herein, Xis 0 Tn certain embodiments described herein, X is S. In certain embodiments described herein, X is SO.
In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH.
In the embodiments described herein, Y is CR9 or N. In certain embodiments, Y
is CR9, wherein R9 is discussed in detail below. In certain embodiments, Y is N.
In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CR"
and V is CR').
In the embodiments described herein, V is CRN or N. In certain embodiments, V
is CR19, wherein 10-9 is discussed in detail below. In certain embodiments, V
is N. In certain embodiments, V is CH. In certain embodiments, wherein when V is N, Z is CR"
and Y is CR9.
In the embodiments described herein, Z is CR" or N. In certain embodiments, Z
is CR", wherein R" is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, wherein when Z is N, V is CR1 and Y is CR9.
In certain embodiments, Xis 0, Y and V are each CH and Z is N. In certain embodiments, X is 0, Y and Z are each CH and V is N. In certain embodiments, X
is 0 and V, Y
and Z are all simultaneously CH.

In the compounds described herein, Ra is hydrogen, halogen, CN, OH, Ci-C6alkoxy, CI-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, oxo, COOC1-C6alky1, CI-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCt-Coalkyl, haloCt-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)R8) or Ci-C6alkylN(R7)(R9) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two sub stituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, oxo, COOCt-C6alkyl, Ct-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, CI-CoalkylC3-Cocycloalkyl, Ci-Coalkyl, -C1-CoalkylOhaloCt-Coalkyl, haloCt-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8).
In certain embodiments described herein, Ra is hydrogen.
In certain embodiments, Ra is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, It is CN
In certain embodiments, Ra is OH.
In certain embodiments, Ra is Ci-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, Ra is Ci-C6alkylOC1-C6alkyl.
In certain embodiments, Ra is Ci-C6alkylCOOH.
In certain embodiments, Ra is COOH
In certain embodiments, Ra is an oxo group.
In certain embodiments, Ra is COOCt-C6alkyl.
In certain embodiments, Ra is Ci-C6alkylCOOC1-Ccalkyl.
In certain embodiments, Ra is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, Ra is CI-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to In certain embodiments, Ra is Ci-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-tri methyl propyl, 1,2,2-trim ethylpropyl, 1 -ethyl-2-m ethyl propyl and 1 -ethyl -1 -methyl propyl. In certain embodiments, IV is methyl.

7 In certain embodiments, Ra is Ci-C6alkylOhaloCi-C6alkyl. Suitable examples of )(F
F
C1-C6alkylOhaloCi-C6alkyls include, but are not limited to, In certain embodiments, R is hal oCt-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, Ra is Ci-CoalkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, Ra is CON(R7)(R8). In certain embodiments, Ra is N(R7)(R8). In certain embodiments, Ra is Ci-C6a1kylN(R7)(Rg), wherein R7 and R8 will be described in detail below.
In certain embodiments, the compounds described herein have the Formula (II):
R13 Ri2 R4 R3 NH m X
HNAN
N =
14111 (II) IS In certain embodiments, Ra is taken with Rb and forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C 3 - C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, Ci-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, Ct-C6alky1C3-C6cycloalkyl, C1-C6alkyl, -CI-C6alkylOhaloCt-C6alkyl, haloCi-C6alkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(1e) and Ci-CoalkylN(R7)(R8).
In certain embodiments, Ra is taken with Rb and forms a C3-C6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two sub stituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH,

8 COOH, oxo, COOC1-C6a1kyl, C1-C6a1ky1COOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alky1C3-C6cycloalky1, C1-C6alkyl, -CI-C6a1kylOhaloC1-C6a1kyl, haloCi-Coalkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8).
Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, CI-C6alkoxy, C1-C6alkylCOOH, COOH, oxo, COOCI-Coalkyl, Ci-CoalkylCOOCI-Coalkyl, C3-Cocycloalkyl, C1-C6alky1C3-C6cycloalky1, Ci-C6alkyl, -C1-CoalkylOhaloCl-Coalkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and CI-CoalkylN(R7)(R8).
In certain embodiments, the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, Ci-C6alky1COOH, COOH, oxo, COOCI-C6alkyl, CI-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, CI-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6a1kylN(R7)(R8).
In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Cl-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, CI-C6alkylC3-C6cycloalkyl, CI-C6alkyl, haloCt-C6alkyl, CI-C6alky1OH, CON(R7)(R8), N(R7)(R8) and Ci-C6a1kylN(R7)(R8).
In certain embodiments, the cycloalkyl is substituted with OH.
In certain embodiments, It is taken with Rb and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alky1COOH, COOH, oxo, COOCI-C6alkyl, CI-C6alkylCOOCI-C6alkyl, C3-C6cycloalky1, CI-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(10.
Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting examples of heterocycloalkyl groups include, but are not limited to,

9 c0) 0) 0 and Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to, c0) 0 and In certain embodiments, Ra is taken with Rb and forms:
0.
In certain embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, C1-C6alkyl0C1-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-Coalkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6a1ky1C3-C6cycloalkyl, CI-Coalkyl, -Ct-CoalkylOhaloCt-Coalkyl, haloCt-Coalkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ct-C6alkylN(R7)(1e).
In certain embodiments, the heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, Cl-C6alkoxy, Cl-C6alkylOCt-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-Coalkyl, Ci-C6alkylCOOCI-C6alkyl, C3-C6cycloalky1, Ct-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -C1-C6alkylOhaloCt-Coalkyl, haloCt-C6alkyl, Ct-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8).
In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, Ct-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -C1-C6alkylOhaloCt-Coalkyl, haloCt-C6alkyl, Ct-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8).
In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of CI-C6alky1.
In the compounds described herein, Rb is hydrogen, halogen, CN, OH, C1-C6alkoxy, Ci-C6alkyl0C1-C6alkyl, Ci-Coalky1C001-1, COOH, oxo, COOC1-C6alkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R9) or when taken with Ra forms a C3-C6cycloalky1 or heterocycloalkyl, wherein the C3-C6cycloalky1 or heterocycloalkyl is unsubstituted or substituted with one or two sub stituents selected from the group consisting of halogen, CN, OH, CI-C6alkoxy, CI-C6alkylOCt-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCI-C6alkyl, Cl-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, Ci-Coalky1C3-C6cycloalkyl, Ci-Coalkyl, -Ct-CoalkylOhaloCt-C6alkyl, haloCt-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(1V) and Ci-C6alkylN(R7)(1e).
In certain embodiments described herein, Rb is hydrogen.
In certain embodiments, Rb is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, Rb is CN.
In certain embodiments, Rb is OH.
In certain embodiments, Rb is Ct-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, RI' is Ct-C6alkyl0C1-C6alkyl.
In certain embodiments, Rb is Ct-C6alkylCOOH.
In certain embodiments, le is COOH.
In certain embodiments, Rb is an oxo group.
In certain embodiments, Rb is COOCt-C6alkyl.
In certain embodiments, Rb is CI-C6alkylCOOC1-C6alkyl.
In certain embodiments, Rb is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cycl butyl, cyclopentyl and cyclohexyl In certain embodiments, Rb is CI-C6a1ky1C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to In certain embodiments, Rb is Ct-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, Rb is methyl.
In certain embodiments, Rb is Ct-C6alkylOhaloCi-C6alkyl. Suitable examples of Ci-C6alkylOhaloCt-C6alkyls include, but are not limited to, F

In certain embodiments, Rb is haloCt-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, Rb is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, Rb is CON(R7)(R8). In certain embodiments, kb is N(R7)(R8). In certain embodiments, Rb is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below.
In certain embodiments, Rb is taken with Ra and forms a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C t-C6alkoxy, C1-C6alkyl0C1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, CI-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alky1C3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloCt-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and CI-C6alkylN(R7)(R8).
In certain embodiments, le is taken with Ra and forms a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCt-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC 3-C6cycloalkyl, C1-C6alkyl, -Ct-C6alkylOhaloCt-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and CI-C6alkylN(R7)(R8) Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOCI-Coalkyl, CI-C6alkylCOOCI-C6alkyl, C3-Cocycloalkyl, CI-C6alky1C3-C6cycloalkyl, -Ct-C6alkylOhaloCt-C6alkyl, haloCt-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ct-C6alkylN(R7)(R8).
In certain embodiments, the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C6alkylCOOH, COOH, oxo, COOCI-C6alkyl, CI-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, Ci-CoalkylC3-Cocycloalkyl, -CI-C6alkylOhaloCt-C6alkyl, haloCt-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8) In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, CI-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8).
In certain embodiments, the cycloalkyl is substituted with OH.
In certain embodiments, Rb is taken with Ra and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C t-C6alkoxy, CI-C6alkylOCI-C6alkyl, Ci-C6alky1COOH, COOH, oxo, COOCI-Coalkyl, Ci-CoalkylCOOCI-Coalkyl, C3-Cocycloalkyl, Ci-C6a1ky1C3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-CoalkylOH, CON(R7)(R8), N(R7)(R8) and Ci-CoalkylN(R7)(R8).
Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta 'octane, and pyrrolidinone, and oxides thereof. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, OD a 0 and Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to, and 0.
In certain embodiments, Rb is taken with Ra and forms:
a.
In certain embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted.
In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one or two sub stituents selected from the group consisting of halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-C6a1kyl, C1-C6alkylCOOCi-C6alky1, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8).
In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkyl0C1-C6alkyl, Ci-C6alky1COOH, COOH, oxo, COOC1-C6alkyl, CI-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, C1-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ct-C6alkylOhaloCt-C6alkyl, haloCt-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, Ct-C6alkoxy, C1-C6alkyl0C1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, C1-C6alky1C3-C6cycloalkyl, CI-C6alkyl, -Ct-C6alkylOhaloCt-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ct-CoalkylN(R7)(R8).
In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of Ci-C6alkyl. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of Ct-C6alkyl. In certain embodiments, the cycloalkyl is unsubstituted.
In the embodiments described herein, 11_3 is hydrogen, halogen, CN, OH, Ci-C6a1koxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(117)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2),,N(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl.
In certain embodiments of the compounds described herein, IV is hydrogen, halogen, CN, 01-1, CI-C6alkoxy, CI-C6alky1OCt-C6alkyl, Ct-C6alkylC0OH, COON, C6cycloalkyl, Cl-C6alkyl, haloCt-C6alky1, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(11_8) or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is halogen.
Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R3 is CN. In certain embodiments, R3 is OH.
In certain embodiments, R3 is Ct-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R3 is Ct-C6alkyl0C1-C6alkyl. In certain embodiments, IV is COOH. In certain embodiments, R3 is Ci-C6alkylCOOH. In certain embodiments, R3 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is Ci-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R3 is haloCi-C6a1kyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R3 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R3 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R3 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R3 is C t-CoalkylN(R7)(R8).
Suitable examples of Ci-C6alkylN(R7)(R8) include, but are not limited to, 57"

and . R7 and R8 are discussed in further detail below.
In certain embodiments, R3 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of )<F
`222.-"0 F
haloalkyls include, but are not limited to, In certain embodiments, R3 is CI-C6alkyl(OCH2CH2),6N(R7)(R8). R7, R8 and n are discussed in detail below. Suitable examples of C1-C6alkyl(OCH2CH2)11N(R7)(1e) include, but ro,.0 are not limited to, , and o With regard to the compounds described herein, n is 1, 2, 3 or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl or C3-C6heterocycloa1kyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl.
Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6heterocycloalkyl. Suitable examples of heterocycloalkyls include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
In certain embodiments, It3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, OH NH2 \.
CON(CH3)2, 0 k µ2,/-=.0F
, )*L

(3µ(o or In certain embodiments, R3 is hydrogen, methyl, ethyl or In certain embodiments, R3 is taken with R4 to form oxetanyl.
In certain embodiments described herein, R4 is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2),,N(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, R4 is hydrogen, halogen, CN, OH, CI-C6alkoxy, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Cl-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8) or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R4 is CN. In certain embodiments, R4 is OH.
In certain embodiments, R4 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R4 is Ci-C6alkylOCi-C6alkyl. In certain embodiments, R4 is COOH. In certain embodiments, 10 is Ci-C6alkylCOOH. In certain embodiments, R4 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R4 is haloCi-C6a1kyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroerhyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R4 is Ci-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R4 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R4 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, N112 and N(CH3)2. In certain embodiments, R4 is Ci-C6alkylN(R7)(R8).

Suitable examples of C1-C6alkylN(R7)(R8) include, but are not limited to, N
and . R7 and R8 are discussed in further detail below.
In certain embodiments, R4 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of )..F
F
haloalkyls include, but are not limited to, In certain embodiments, R4 is CI-C6alkyl(OCH2CH2),1N(R7)(R8). R7, R8 are discussed in detail below and n is discussed above. Suitable examples of Ci-r. o NH 2 C6alky1(OCH2CH2)11N(R7)(R8) include, but are not limited to, =-=..õ--""'"N 0 , and In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl or C 3 -C6heterocycloalkyl. In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl.
Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is taken with R3 and forms a C 3 -C6heterocycloalkyl. Suitable examples of heterocycloalkyls include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen, methyl, ethyl or . In certain embodiments, R4 is taken with R3 to form oxetanyl. In certain embodiments, R3 and R4 are both hydrogen, methyl or ethyl.
In certain embodiments, R3 is hydrogen and R4 is hydrogen.
In certain embodiments, R3 and R4 are both halogen, where the halogen is selected from fluorine, chlorine, bromine and iodine. In certain embodiments, R3 and R4 are both fluorine.
In the embodiments described herein, R5 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, Ci-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, Ct-C6alky1C3-C6cycloalkyl, C1-C6alkyl, -Ci-CoalkylOhaloCi-Coalkyl, haloCi-Coalkyl, Ci-CoalkylOH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(R8).
In certain embodiments described herein, R5 is hydrogen.
In certain embodiments, R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, R5 is CN.
In certain embodiments, R5 is OH.
In certain embodiments, R5 is Ct-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, R5 is Ci-CoalkylOCi-C6alkyl.
5 In certain embodiments, R5 is Ct-C6alkylCOOH.
In certain embodiments, R5 is COOH.
In certain embodiments, R5 is an oxo group.
In certain embodiments, R5 is COOCt-C6alkyl.
In certain embodiments, R5 is Ct-C6alkylCOOCi-C6alkyl.
In certain embodiments, R5 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R5 is Ct-C6alky1C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .

In certain embodiments, R5 is CI-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R5 is methyl.
In certain embodiments, R5 is Ct-C6alkylOhaloCt-C6alkyl. Suitable examples of FF
"ear--0 F
Ct-C6alkylOhaloCt-C6alkyls include, but are not limited to, In certain embodiments, R5 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, R5 is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R5 is CON(R7)(R8). In certain embodiments, RI- is N(R7)(R8). In certain embodiments, R5 is Ci-C6alkylN(R7)(R8), wherein R7 and Rg will be described in detail below.
In certain embodiments, R5 is hydrogen, methyl, ethyl or t-butyl.
In the embodiments described herein, R6 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylCOOH, COOH, oxo, COOCt-C6alkyl, Ci-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, Ct-C6alky1C3-C6cycloalkyl, C1-Coalkyl, -CI-C6alkylOhaloCt-C6alkyl, haloCt-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Cl-C6alkylN(R7)(10) In certain embodiments described herein, R6 is hydrogen.
In certain embodiments, R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, R6 is CN.
In certain embodiments, R6 is OH.
In certain embodiments, R6 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, R6 is Cl-C6alkylOCi-C6alkyl.
In certain embodiments, R6 is Cl-C6alkylCOOH.

In certain embodiments, R6 is COOH.
In certain embodiments, R6 is an oxo group.
In certain embodiments, R6 is COOCi-C6alkyl.
In certain embodiments, R6 is CI-C6alkylCOOC1-Coalkyl.
In certain embodiments, R6 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R6 is CI-C6alky1C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
In certain embodiments, R6 is CI-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl In certain embodiments, R6 is methyl.
In certain embodiments, R6 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of rk.F
F
C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, In certain embodiments, R6 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, R6 is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R6 is CON(R7)(R8). In certain embodiments, RI- is N(R7)(10). In certain embodiments, R6 is Ci-C6alkylN(R7)(10), wherein It7 and It8 will be described in detail below.
In certain embodiments, R6 is hydrogen, methyl, ethyl or t-butyl.
In the embodiments described herein, R7 is hydrogen, Ci-CoalkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCA-C6alkyl, Ci-C6alkylOH, COCI-C6alkyl or COOC1-C6alkyl.
In certain embodiments, IC is hydrogen, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi -C6alkyl or C -C6alkyl OH.

In certain embodiments, R7 is hydrogen. In certain embodiments, R7 is Ci-C6alkylCOOH. In certain embodiments, 117 is COOH. In certain embodiments, R7 is C3-C6cycloalky1. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R7 is C1-C6alkyl. Examples of Ct-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethy1-1-methylpropyl. In certain embodiments, R7 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluorom ethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R7 is C1-C6a1kylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R7 is COCi-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R7 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3.
In the embodiments described herein, R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOCi-C6alkyl.
In certain embodiments, R8 is hydrogen, CI-C6a1kylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCi -C6alkyl or C -C6alkyl OH.
In certain embodiments, R8 is hydrogen. In certain embodiments, R8 is CI-C6alkylCOOH. In certain embodiments, R8 is COOH. In certain embodiments, R8 is C6cycloalky1. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R8 is C1-C6alkyl. Examples of CI-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R8 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl In certain embodiments, R8 is Ci-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.

In certain embodiments, R8 is COCt-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R8 is COOCt-C6alkyl. Suitable examples include, but are not limited to, COOCH3 In the embodiments described herein, R9 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R9 is CN. In certain embodiments, R9 is OH.
In certain embodiments, R9 is Ci-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R9 is Ci-CGalkyl OCi-Coalkyl. In certain embodiments, R9 is COOH. In certain embodiments, R9 is Ci-C6alkylCOOH. In certain embodiments, R9 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R9 is CI-C6alkyl. Examples of CA-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R9 is haloCi-C6alkyl.
Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R9 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R9 is CON(R7)(R8). In certain embodiments, R9 is N(R7)(R8). In certain embodiments, R9 is C t-C6alkylN(R7)(R8).
With regard to the compounds described herein, Ri is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCI-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCi-C6alkyl, CI-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, Ri is hydrogen. In certain embodiments, Ri is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, Ri is CN. In certain embodiments, Ri is OH.
In certain embodiments, Ri is Ci-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, Ri is CI-C6alkylOCA-C6alkyl. In certain embodiments, RI is COOH. In certain embodiments, RI is Ci-C6alkylCOOH. In certain embodiments, Rio is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R1 is CI-Coalkyl. Examples of CI-C6alky1 groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R1 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R1 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R1 is CON(R7)(R8). In certain embodiments, R1 is N(R7)(R8). In certain embodiments, R1 is C1-C6alkylN(R7)(R8).
In the embodiments, described herein, R11 is hydrogen, halogen, CN, OH, C1-C6alkoxy, Ci-C6alkylOC1-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R11 is hydrogen. In certain embodiments, R11 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R11 is CN. In certain embodiments, R11 is OH.
In certain embodiments, R11 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. Tn certain embodiments, R"
is CI-C6alkylOC1-C6alkyl. In certain embodiments, R11 is COOH. In certain embodiments, RIA is CI-C6alkylCOOH. In certain embodiments, Rll is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R11 is C1-C6alkyl. Examples of C1-C6alky1 groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R11 is haloCi-C6alky1. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R11 is CI-CoalkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R11 is CON(R7)(R8). In certain embodiments, R11 is N(R7)(R8). In certain embodiments, R" is C1-C6alkylN(R7)(R8).
In the embodiments described herein, R12 is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8).
In certain embodiments, R12 is hydrogen. In certain embodiments, R12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R12 is CN. In certain embodiments, R12 is OH.
In certain embodiments, R12 is CI-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R12 is Cl-C6alkyl0C1-C6alkyl. In certain embodiments, R12 is COOH. In certain embodiments, R12 is C1-C6alkylCOOH. In certain embodiments, R12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R12 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromefhyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R12 is Ci-C6a1kylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R12 is CON(R7)(R8). In certain embodiments, R12 is N(R7)(R8). In certain embodiments, R12 is Cl-C6alkylN(R7)(R8).
In certain embodiments, R12 is hydrogen, methyl, ethyl, methoxy, OH or In certain embodiments, R12 is hydrogen or In the embodiments described herein, R" is hydrogen, halogen, CN, OH, Ct-C6alkoxy, Ci-C6alkylOC1-C6alkyl, Cl-C6alkylCOOH, COON, C3-C6cycloalkyl, Cl-C6alkyl, haloCi-C6alkyl, Cl-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Cl-C6alkylN(R7)(R8).
In certain embodiments, R13 is hydrogen. In certain embodiments, R13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R13 is CN. In certain embodiments, R13 is OH

In certain embodiments, R13 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R13 is Ci-C6alkylOC1-C6alkyl. In certain embodiments, R13 is COOH. In certain embodiments, R13 is Ci-C6alkylCOOH. In certain embodiments, R13 is C3-C6cycloa1kyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R13 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R13 is haloCi-C6alky1. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R13 is CI-C6a1kylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R13 is CON(R7)(R8). In certain embodiments, R13 is N(R7)(R8). In certain embodiments, R13 is C1-C6alkylN(R7)(R8).
In certain embodiments, R13 is hydrogen, methyl, ethyl, methoxy, OH or In certain embodiments, R13 is hydrogen or In certain embodiments, R12 and R13 are independently selected from the group consisting of hydrogen and Ci-C6alkylOCI-C6alkyl, Ci-C6alkyl.
In certain embodiments described herein, each occurrence of R'4 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6a1kylCOOH, COOH, C3-C6cycloalkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8). In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R14 is CN. In certain embodiments, R14 is OH.
In certain embodiments, R14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R14 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R" is COOH.
In certain embodiments, R14 is C,-C6alkylCOOH. In certain embodiments, R14 is C3-C6cycloa1kyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R" is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R14 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R14 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R14 is CON(R7)(R8). In certain embodiments, R14 is N(R7)(R8). In certain embodiments, R14 is Cl-C6alkylN(R7)(R8).
In certain embodiments, wherein X is C(R14)2, R14 is independently selected from the group consisting of hydrogen, halogen, OH, CI-CoalkylOH, CI-C6alkylalkoxy, Ci-C6alkyl0C1 -C6alkyl and Ci-C6alkyl.
In certain embodiments, R14 is hydrogen, methyl, ethyl, methoxy, OH or In the embodiments described herein, R15 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCi-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R15 is hydrogen. In certain embodiments, R15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R15 is CN. In certain embodiments, R15 is OH.
In certain embodiments, R15 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R15 is CI-C6alkylOCi-C6alkyl. In certain embodiments, R15 is COOH. In certain embodiments, R15 is C1-C6alkylCOOH. In certain embodiments, R15 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R" is C1-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R'5 is ethyl.

In certain embodiments, R15 is haloCt-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R1-5 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R15 is CON(R7)(R8). In certain embodiments, R15 is N(R7)(R8).
In certain embodiments, R15 is C1-C6alkylN(R7)(R8).
In certain embodiments, R15 is methyl or ethyl.
In the embodiments described herein, R16 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCI-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-Coalkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R16 is hydrogen. In certain embodiments, R16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R16 is CN. In certain embodiments, R16 is OH.
In certain embodiments, R16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R16 is CI-C6alkylOC1-C6alkyl. In certain embodiments, R16 is COOH. In certain embodiments, R16 is C1-C6alkylCOOH. In certain embodiments, R16 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R16 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dim ethyl propyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R16 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, RI-6 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R16 is CON(R7)(R8). In certain embodiments, R16 is N(R7)(10. In certain embodiments, R16 is Ci-C6alkylN(R7)(R8).
In the embodiments of the compounds described herein, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.
In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0 In certain embodiments, p is 1 In the embodiments described herein, A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene, phenyl(C3-C1o)alkylene or cycloalkyl(C3-C1o)alkylene comprising at least one ¨CH2- group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
In certain embodiments, A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene or cycloalkyl(C3-C1o)alkylene, wherein one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S and NH. In certain embodiment, A will always have at least one ¨CH2- group.
In certain embodiments, A is a straight (C3-C1o)alkylene. Examples of straight (C3-C1o)alkylenes include, õ,..\ ;22, .,..-\
)72, )721 X ..-(---- ...- ..--f -,-, ....-,v \. ...-I ..-...--,3,.,,,, I---- ,----In certain embodiments, A is a branched (C3-C1o)alkylene. Suitable branched (C3-Cio)alkylenes include but are not limited to:
f\ '221 221 X x\ scrry X?' '''''' ..\...-^,.....õ ,..., ..v "222- ...\..."....... N.
In certain embodiments, A is a saturated (C3-C1o)alkylene. Examples include, ,,..N
,i;
X ..-r- ,.. ...., ....- ....-f --r- ..---:\...-r ,- ....- ....--õL..... ..---,-----..., r , (.....c *".............)221 )221 \ .7, r .....-'''.---, ...õ..., ....... ,,,,..,..
"22.. ...y In certain embodiments, A is an unsaturated (C3-C1o)alkylene. Suitable unsaturated (C3-Cio)alkylenes include any of the saturated (C3-C1o)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-Cio)alkylenes include, but are not limited to, Jr' I
.....4=- ...-- ___...1 r In other embodiments, A is a straight cycloalkyl(C3-C1o)alkylene. Suitable straight cycloalkyl(C3-Cio)alkylenes include a cycloalkyl(C3-Cio)alkylene wherein two carbons in a chain are included in a (C3-C1o)cycloalkyl. Examples of straight cycloalkyl(C3-C1o)alkylenes include, but are not limited to, LN, In certain embodiments, A is a branched cycloalkyl(C3-C1o)alkylene. Suitable branched cycloalkyl(Ci-Cio)alkylenes include a branched (C3-Cio)alkylene wherein two carbons in a chain are included in a (C3-C1o)cycloalkyl. Examples of cycloalkyl(C3-C1o)alkylenes include, but are not limited to, In certain embodiments, A is a saturated cycloalkyl(C3-C1o)alkylene. Examples of saturated cycloalkyl(C3-C1o)alkylenes include, but are not limited to, r<r2"1, tzel, .:3111 "luv In certain embodiments, A is an unsaturated cycloalkyl(C3-C1o)alkylene.
Examples of unsaturated cyclo(C3-C1o)alkylenes include, but are not limited to, In certain embodiments, A is an unsaturated or saturated phenyl(C3-C1o)alkylene.
Examples of unsaturated and saturated phenyl(C3-C1o)alkylenes include, but are not limited to, c??, 4111:1 11111 `371, In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S. NR, CONR, NRCO, S02, and SO2NR. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S and NH. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with 0. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with NR. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with CONR. In other embodiments, one or more ¨CH2-groups in A are optionally and independently replaced with NRCO. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with S02.
In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with and SO2NR. R will be described in further detail below.
In the embodiments described herein, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl.
In certain embodiments, R is hydrogen, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCi-Coalkyl or Ci-CoalkylOH.
In certain embodiments, R is hydrogen. In certain embodiments, R is Ci-C6alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C1-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluorom ethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R is Ci-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOCi-C6alkyl. Suitable examples include, but are not limited to, COOCH3.
Examples of such embodiments include, but are not limited to, rw r)1, gf- 6 (!) :72;_ o) In certain embodiments, A is .....,.. , ...-- ..--- õ,.... ....-=%,..
.,õ,,õ. .õ....... r,..... r .A.r. "I.'''.
In certain embodiments, one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, A is , WV-V V-VIIV ,,,,,,, ..,-' Fsf F.,..--... F
..--' -"'C' F I õ ,, ;2( I =-:%'''' '12_ "I V V ' Also described herein are compounds haying the structural Formula (III):
12 .
R13 n p ' R4R3 NHX
HNANVILV
R1.51NrLo µ,1 P
Nl0 -.., (III) wherein, A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene, phenyl(C3-Cio)alkylene or cycloalkyl(C3-C1o)alkylene comprising at least one ¨CH2-group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONK, NRCO, S02, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl;
Q is C(R16)2, 0, S, SO, SO2 or NH;

X is a bond, C(R")2, 0, S, SO, SO2 or NH;
Y is CR9 or N, wherein when Y is N, Z is CR" and V is CR";
V is CR1 or N, wherein when V is N, Z is CR11 and Y is CR9;
Z is CR11 or N, wherein when Z is N, V is CR1 and Y is CR9;
R is hydrogen, Ci-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C,-C6alkyl, haloCi-C6alky1, Ci-C6alky1OH, COCi-C6alkyl or COOCi-C6alkyl;
R1 is hydrogen, halogen, CN, OH, C,-C6alkoxy, CI-C6alky1OC1-C6alkyl, C,-C6alkylCOOH, COOH, oxo, COOCI-C6alkyl, CI-C6alkylCOOCI-C6alkyl, C3-C6cycloalkyl, CI-C6alky1C3-Cocycloalkyl, Ci-Coalkyl, -Ci-CoalkylOhaloCi-Coalkyl, haloCi-Coalkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C,-C6alkylN(R7)(R8);
R2 is hydrogen, halogen, CN, OH, C,-Coalkoxy, Ci-CoalkylOCi-C6alkyl, C,-CoalkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alkylC 3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6a1kylOH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(R8);
R3 is hydrogen, halogen, CN, OH, Cl-C6alkoxy, CI-C6a1kylOCi-C6alkyl, Cl-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2)fiN(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R4 forms a C3-C6cycloa1kyl or C3-C6heterocycloa1kyl;
R4 is hydrogen, halogen, CN, OH, C,-C6alkoxy, Ci-C6alkylOCi-C6alkyl, C,-C6alkylCOOH, COOH, C3-C6cycloalkyl, haloCI-Coalkyl, CI-C6alkyl OH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2),,N(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;
R5 is hydrogen, halogen, CN, OH, C,-Coalkoxy, Ci-CoalkylOCi-C6alkyl, C,-CoalkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alky1, haloCi-C6alkyl, Ci-C6a1kylOH, CON(R7)(R8), N(R7)(R8) or C,-C6alkylN(R7)(R8);
R6 is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alky1, haloCi-C6a1kyl, Cl-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C,-C6alkylN(R7)(R8);
R7 is hydrogen, C,-CoalkylCOOH, COOH, C3-Cocycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Ci-C6a1ky1OH, COCi-C6alkyl or COOCi-C6alkyl;
R8 is hydrogen, C,-CoalkylCOOH, COOH, C3-Cocycloalkyl, Ci-C6alkyl, haloCi-Coalkyl, Ci-CoalkylOH, COCi-C6alkyl or COOCi-C6alkyl;
R9 is hydrogen, halogen, CN, OH, C,-C6alkoxy, Ci-C6alkylOCi-C6alkyl, C,-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(1e);
RI' is hydrogen, halogen, CN, OH, CI-C6alkoxy, CI-C6alky1OCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloa1kyl, Ci-C6alky1, haloCi-C6a1kyl, Cl-C6alkylOH, CON(R7)(R8), N(R7)(It8) or C1-C6alkylN(R7)(R8);
Rll is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloa1kyl, Ci-C6alkyl, haloCi-C6alkyl, Cl-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8);
R12 is hydrogen, halogen, CN, OH, CI-C6alkoxy, CI-C6alky1OCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-Cocycloalkyl, Ci-Coalkyl, haloCi-Coalkyl, CI-CoalkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8);
R13 is hydrogen, halogen, CN, OH, Ci-Coalkoxy, C1-Coalky1OC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
each occurrence of It34 is independently selected from the group consisting of hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alky1OCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
R15 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Cl-C6alkylOH, CON(R7)(R8), N(R7)(R8) or CI-C6alkylN(R7)(R8);
each occurrence of It' is independently selected from the group consisting of hydrogen, halogen, CN, OH, CI-C6alkoxy, CI-C6alkylOCt-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCl-C6alkyl, Ci-CcalkylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alky1N(R7)(R8);
1 is 0 or 1;
m is 0 or 1;
n is 1, 2, 3 or 4; and p is 0 or 1.
In the embodiments described herein, Q is C(R16)2, 0, S, SO, SO2 or NH. In certain embodiments, Q is C(R16)2, wherein 106 is discussed in further detail below. In certain embodiments, Q is CH2, CH(CH3), C(CH3)2, 0, CH(OCH3), SO2 or CF2. In other embodiments Q is CH2, 0, S, SO, SO2 or NH. In certain embodiments, Q is CH2. In certain embodiments described herein, Q is 0. In certain embodiments described herein, Q is S. In other embodiments described herein, Q is SO. In other embodiments described herein, Q is SO2. In certain embodiments described herein, Q is NH. In other embodiments described herein, Q is 0 or S02. In still other embodiments described herein, Q is 0 or CH2.
In the embodiments described herein, X is a bond, C(R14)2, 0, S, SO, SO2 or NH.
In certain embodiments described herein X is a bond. In certain embodiments, X
is C(R14)2, wherein R14 is discussed in further detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, 0, CH(OCH3), SO2 or CF2. In other embodiments X is CH2, 0, S, SO, SO2 or NH. In certain embodiments, X is CH2. In the embodiments described herein, X is 0. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO.
In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH.
In the embodiments described herein, Y is CR9 or N. In certain embodiments, Y
is CR9, wherein R9 is discussed in detail below. In certain embodiments, Y is N.
In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CRll and V is CR".
In the embodiments described herein, V is CR' or N. In certain embodiments, V
is CR", wherein R1 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, wherein when V is N, Z is CR11 and Y is CR9.
In the embodiments described herein, Z is CR11 or N. In certain embodiments, Z

is CR11, wherein R11 is discussed in detail below. In certain embodiments, Z
is CH. In certain embodiments, Z is N. In certain embodiments, wherein when Z is N, V is CR' and Y is CR9.
In certain embodiments, Xis 0, Y and V are each CH and Z isN In certain embodiments, X is 0, Y and Z are each CH and V is N. In certain embodiments, X
is 0 and V, Y
and Z are all simultaneously CH.
In certain embodiments, X is a bond, Y and V are each CH and Z is N. In certain embodiments, X is a bond, Y and Z are each CH and V is N. In certain embodiments, X is a bond and V, Y and Z are all simultaneously CH.
Also described herein are compounds of Formula III represented by structural Formula (IIIA):

H N "jj'N (PO
=

(IIIA) wherein R1, R2, R3, R4, R5, R6, Rls, A, and Q, are as described herein. An embodiment of this invention is realized when RI, R2, R3, R4, R5, R6, R15, A, and Q, are as described in Formula III. Another embodiment of Formula IRA is realized when R3 and R4 are both hydrogen, methyl, ethyl, or halogen. Another embodiment of Formula IIIA
is realized when R3 and R4 are both halogen selected from chlorine and fluorine. Another embodiment of Formula IIIA is realized when Q is CH2, CH(CH3), C(CH3)2, 0, CH(OCH3), SO2 or CF2. In other embodiments described herein, Q in Formula IIIA is 0 or S02. In still other embodiments described herein, Q in Formula IIIIA is 0 or CH2. Another embodiment of Formula IIIA is realized when A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene comprising at least one ¨CH2- group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONR, NRCO, S02, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
Also described herein are compounds of Formula III represented by structural Formula (IIIB):

HNANH allo R3 N
Rl.Lso =

(II1B) wherein R', R2, R3, R4, R5, R6, RI', A, and Q, are as described herein. An embodiment of this invention is realized when R', R2, R3, R4, IV, R6, R", A, and Q, are as described in Formula III. Another embodiment of Formula IIIB is realized when R3 and R4 are both hydrogen, methyl, ethyl, or halogen. Another embodiment of Formula IIIB
is realized when R3 and R4 are both halogen selected from chlorine and fluorine. Another embodiment of Formula IIIB is realized when Q is CH2, CH(CH3), C(CH3)2, 0, CH(OCH3), SO2 or CF2. In other embodiments described herein, Q in Formula IIIB is 0 or S02. In still other embodiments described herein, Q in Formula IIIIB is 0 or CH2. Another embodiment of Formula IIIB is realized when A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene comprising at least one ¨CH2- group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S. NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
Certain embodiments are represented as Formulas IV - VI:

, R1 2 R1 3 i 2 R4R3 R3 R4 R'3 R4R3 NH\)10 NH 0 NH 0 =

\
I R2 crtirRs Q I Q I
R6 (w) R6 (v) R6 (VI) In the embodiments described herein, RI is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, CI-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-Coalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(1e), N(R7)R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments described herein, R1 is hydrogen.
In certain embodiments, RI- is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, It' is CN.
In certain embodiments, It' is OH.
In certain embodiments, TO is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, It' is CI-C6alkylOC1-C6a1kyl.
In certain embodiments, is CI-C6alkylCOOH.
In certain embodiments, is COOH.
In certain embodiments, 1:11 is an oxo group.
In certain embodiments, It' is COOCI-Coalkyl.
In certain embodiments, R1 is Ct-C6alkylCOOC1-C6alkyl.
In certain embodiments, RI is C3-Cocycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, RI is CI-C6alky1C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to In certain embodiments, It' is Ct-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.
In certain embodiments, It' is Ct-C6alkylOhaloCi-C6alkyl. Suitable examples of )(F
F
Ci-C6alkylOhaloCi-C6alkyls include, but are not limited to, In certain embodiments, is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, RI is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R1 is CON(R7)(R'). In certain embodiments, R' is N(10(10). In certain embodiments, It" is Ci-C6alkylN(10(10), wherein It' and It8 will be described in detail below.
In certain embodiments, is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.
In the embodiments described herein, R2 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-CoalkylCOOCi-C6alkyl, C3-C6cycloalkyl, C1-CoalkylC3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloC1-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments described herein, R2 is hydrogen.
In certain embodiments, R2 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, R2 is CN.
In certain embodiments, R2 is OH.
In certain embodiments, R2 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, R2 is CI-C6alkylOCI-C6alkyl.
In certain embodiments, R2 is CI-C6alkylCOOH.
In certain embodiments, R2 is COOH.
In certain embodiments, R2 is an oxo group.
In certain embodiments, R2 is COOC1-C6alkyl.
In certain embodiments, R2 is CI-C6alkylCOOC1-C6alkyl.
In certain embodiments, R2 is C3-C6cycloalky1 Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R2 is CI-C6alkylC3-C6cycloalkyl. Suitable examples of µCDcycloalkyls include, but are not limited to In certain embodiments, R2 is Ci-Coalkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.
In certain embodiments, R2 is Ct-C6alkylOhaloCi-C6alkyl. Suitable examples of Ci-C6alkylOhaloCi-C6alkyls include, but are not limited to, F

In certain embodiments, R2 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, R2 is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R2 is CON(R7)(R8). In certain embodiments, RI- is N(R7)(R8). In certain embodiments, R2 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below.
In certain embodiments, R2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.
In certain embodiments, RI and R2 are both hydrogen. In certain embodiments, R' is OH and R2 is hydrogen.
In the embodiments described herein, R3 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-Coalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(IV), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl.
In certain embodiments of the compounds described herein, IV is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycl alkyl, CI-C6a1kyl, ha] oC1-C6alkyl, CI-C6a1kyl OH, CON(R7)(R8), N(R7)(128) or CI-C6alkylN(R7)(R8) or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is halogen.
Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R3 is CN. In certain embodiments, R3 is OH.
In certain embodiments, R3 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R3 is Ci-C6alkylOCi-C6alkyl. In certain embodiments, R3 is COOH. In certain embodiments, R3 is Ci-C6alkylCOOH. In certain embodiments, R3 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is Ci-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R3 is haloCt-C6a1kyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R3 is Ci-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R3 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R3 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NI-I2 and N(CH3)2. In certain embodiments, R3 is CI-C6alkylN(R7)(R8).

Suitable examples of Ci-C6alkylN(R7)(R8) include, but are not limited to, `2-N'iL" N
and . R7 and R8 are discussed in further detail below.
In certain embodiments, It3 is CI-C6alkylOhaloC1-C6alkyl. Suitable examples of )<F
`V"---- 0 F
haloalkyls include, but are not limited to, In certain embodiments, R3 is CI-C6alkyl(OCH2CH2)11N(R7)(R8). R7, Rg and n are discussed in detail below. Suitable examples of C1-C6alkyl(OCH2CH2)11N(R7)(R8) include, but are not limited to, , and 0 ly With regard to the compounds described herein, n is 1, 2, 3 or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl.
Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6heterocycloa1kyl. Suitable examples of heterocycloalkyls include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
In certain embodiments, R3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, OH NH2 '722.
, CON(CH3)2, 0 k 0 )<.F
\-^0 F I

0 )*L
N
co JVVVV, or In certain embodiments, R3 is hydrogen, methyl, ethyl or In certain embodiments, R3 is taken with R4 to form oxetanyl.
In certain embodiments described herein, R4 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2),,N(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, le is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOC1-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCI-C6alkyl, CI-CoalkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8) or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, It4 is CN. In certain embodiments, 11:4 is OH.
In certain embodiments, R4 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R4 is Ci-C6alkylOCi-C6alkyl. In certain embodiments, R4 is COOH. In certain embodiments, R4 is Ci-C6alkylCOOH. In certain embodiments, R4 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R4 is haloCi-C6alkyl.
Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R4 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R4 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R4 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NI-12 and N(CH3)2. In certain embodiments, R4 is Ci-C6alkylN(R7)(R8). Suitable examples of Ci-rk L.0 C6alkylN(R7)(R8) include, but are not limited to, µ2-and . R7 and R8 are discussed in further detail below.
In certain embodiments, R4 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of õk=F
haloalkyls include, but are not limited to, F
In certain embodiments, R4 is CI-C6alkyl(OCH2C1-17),N(R7)(R8). R7, R8 are discussed in detail below and n is discussed above. Suitable examples of Ci-ro C6alky1(OCH2CH2)11N(R7)(1e) include, but are not limited to, J'L

, and In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl.
Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is taken with R3 and forms a C3-C6heterocycloa1kyl. Suitable examples of heterocycloalkyls include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
In certain embodiments, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen, methyl, ethyl or c) . In certain embodiments, R4 is taken with R3 to form oxetanyl. In certain embodiments, R3 and R4 are both hydrogen, methyl or ethyl.
In certain embodiments, R3 is hydrogen and R4 is hydrogen.
In the embodiments described herein, R5 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, CI-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alkylCOOCi-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments described herein, R5 is hydrogen.
In certain embodiments, R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, R5 is CN.
In certain embodiments, R5 is OH.
In certain embodiments, R5 is Ct-Coalkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, R5 is Ci-C6alkylOCi-C6alkyl.
In certain embodiments, R5 is Ci-C6alkylCOOH.
In certain embodiments, R5 is COOH.
In certain embodiments, R5 is an oxo group.
In certain embodiments, R5 is COOCi-C6alkyl.
In certain embodiments, R5 is CI-C6alkylCOOCi-C6alkyl.
In certain embodiments, R5 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R5 is Ci-C6alky1C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
In certain embodiments, R5 is Ct-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R5 is methyl.
In certain embodiments, R5 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of rk.F
F
C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, 't In certain embodiments, R5 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl In certain embodiments, R5 is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R5 is CON(117)(R8). In certain embodiments, RI- is N(R7)(R8). In certain embodiments, R5 is Ci-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below.
In certain embodiments, R5 is hydrogen, methyl, ethyl or t-butyl.
In the embodiments described herein, R6 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOCi-C6alkyl, Ci-C6alky1COOC1-C6alkyl, C3-C6cycloalkyl, Ci-C6alky1C3-C6cycloalkyl, Ci-C6alkyl, -Ci-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments described herein, R6 is hydrogen.
In certain embodiments, R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
In certain embodiments, R6 is CN.
In certain embodiments, R6 is OH.
In certain embodiments, R6 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
In certain embodiments, R6 is CI-C6alkylOCi-C6alkyl.
In certain embodiments, R6 is CI-C6alkylCOOH.
In certain embodiments, R6 is COOH.
In certain embodiments, R6 is an oxo group.
In certain embodiments, R6 is COOC1-C6alkyl.

In certain embodiments, R6 is CI-C6alkylCOOC1-C6alkyl.
In certain embodiments, R6 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R6 is CI-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to In certain embodiments, R6 is CI-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R6 is methyl.
In certain embodiments, R6 is CI-C6alkylOhaloCi-C6alkyl. Suitable examples of F
C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, In certain embodiments, R6 is haloCi-Coalkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.
In certain embodiments, R6 is CI-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R6 is CON(R7)(R8). In certain embodiments, 10- is N(R7)(R8). In certain embodiments, R6 is Ci-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below.
In certain embodiments, R6 is hydrogen, methyl, ethyl or t-butyl.
In the embodiments described herein, R7 is hydrogen, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCt-C6alkyl, Ci-C6alkylOH, COC1-C6alkyl or COOCi-C6alkyl.
In certain embodiments, R7 is hydrogen, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl or Ci-C6alkylOH.
In certain embodiments, R7 is hydrogen. In certain embodiments, R7 is Ci-C6alkylCOOH. In certain embodiments, IC is COOH. In certain embodiments, R7 is C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R7 is C1-C6alkyl. Examples of Cl-C6a1kyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R7 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R7 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R7 is COCI-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R7 is COOCi-C6alkyl. Suitable examples include, but are not limited to, COOCH3.
In the embodiments described herein, It8 is hydrogen, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, COCi-C6alkyl or COOCi-C6alkyl.
In certain embodiments, R8 is hydrogen, C1-C6alky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl or Ci-C6alkylOH.
In certain embodiments, R8 is hydrogen. In certain embodiments, R8 is Ci-C6a1kylCOOH. In certain embodiments, R8 is COOH. In certain embodiments, R8 is C.3-C6cycl alkyl Suitable examples of cycloalkyl s include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R8 is Ci-C6alkyl. Examples of CI-C6a1kyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R8 is haloCi-C6a1kyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R8 is Ci-CoalkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R8 is COCI-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R8 is COOCi-C6alkyl. Suitable examples include, but are not limited to, COOCH3.

In the embodiments described herein, R9 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCI-C6alkyl, C1-C6alky1COOH, COOH, C3-C6cycloalkyl, C1-Coalkyl, haloCi-C6alkyl, Cl-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
In certain embodiments, R9 is CN. In certain embodiments, R9 is OH.
In certain embodiments, R9 is CI-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R9 is Ci-CoalkylOCI-Coalkyl. In certain embodiments, R9 is COOH. In certain embodiments, R9 is Ci-C6alkylCOOH. In certain embodiments, R9 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R9 is C1-C6alkyl. Examples of C1-C6alkyl groups can include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R9 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R9 is CI-C6alkyl OH Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R9 is CON(R7)(R8). In certain embodiments, R9 is N(R7)(R8). In certain embodiments, R9 is C1-C6alkylN(10(R8).
With regard to the compounds described herein, Rl is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOCi-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCI-C6alkyl, CI-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R1 is hydrogen. In certain embodiments, Rm is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, Rl is CN. In certain embodiments, R1 is OH.
In certain embodiments, 10 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, Rth is Ci-CoalkylOCI-Coalkyl. In certain embodiments, Rio is COOH. In certain embodiments, Rl is Ci-C6alkylCOOH. In certain embodiments, RI is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R1 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R1 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluorom ethyl, difluorom ethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R1 is CI-CoalkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R1 is CON(R7)(R8). In certain embodiments, Rm is N(R7)(R8). In certain embodiments, R1 is C1-C6alkylN(R7)(R8).
In the embodiments, described herein, R" is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCI-C6alkyl, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-Coalkyl, haloCi-C6alkyl, CI-C6alkylOH, CON(R7)(R8) and N(R7)(1e). In certain embodiments, R11 is hydrogen. In certain embodiments, R11 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R11 is CN. In certain embodiments, R11 is OH.
In certain embodiments, R11 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R"
is CI-C6alkylOCI-C6alkyl In certain embodiments, R11 is COOH In certain embodiments, R" is Ci-C6a1kylCOOH. In certain embodiments, R11 is Cl-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R" is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R11 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R11 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R" is CON(R7)(R8). In certain embodiments, R11 is N(R7)(R8). In certain embodiments, R" is C1-C6alkylN(R7)(R8).

In the embodiments described herein, 111-2 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCI-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-Coalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments, R12 is hydrogen. In certain embodiments, R12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R12 is CN. In certain embodiments, R12 is OH.
In certain embodiments, R12 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R12 is Ci-CoalkylOCI-Coalkyl. In certain embodiments, R12 is COOH. In certain embodiments, R12 is Ci-C6alkylCOOH. In certain embodiments, R12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 is C1-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R12 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. Tn certain embodiments, R12 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R12 is CON(R7)(R8). In certain embodiments, R12 is N(R7)(R8). In certain embodiments, R12 is Ci-C6alkylN(R7)(R8).
In certain embodiments, R12 is hydrogen, methyl, ethyl, methoxy, OH or ?5 In certain embodiments, R12 is hydrogen or In the embodiments described herein, R13 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkyl0C1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Ci-CoalkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8).
In certain embodiments, R13 is hydrogen. In certain embodiments, R13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R13 is CN. In certain embodiments, R13 is OH.
In certain embodiments, R13 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R13 is CI-C6alkylOC1-C6alkyl. In certain embodiments, R13 is COOH. In certain embodiments, R13 is CI-C6alkylCOOH. In certain embodiments, R13 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R13 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-m ethylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethy1-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R13 is haloCi-C6alkyl Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R13 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R13 is CON(R7)(R8). In certain embodiments, R13 is N(R7)(118). In certain embodiments, R13 is Ci-C6alkylN(R7)(R8).
In certain embodiments, R13 is hydrogen, methyl, ethyl, methoxy, OH or In certain embodiments, R13 is hydrogen or In certain embodiments, R12 and R13 are independently selected from the group consisting of hydrogen and Ci-C6alkylOCi-C6alkyl, Ci-C6alkyl.
In certain embodiments described herein, each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6alkylOCi-C6alky1, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8). In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R14 is CN. In certain embodiments, R14 is OH.
In certain embodiments, R14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, RN is Ci-CoalkylOCi-C6alkyl. In certain embodiments, R14 is COOH.
In certain embodiments, RN is Ci-C6alkylCOOH. In certain embodiments, R14 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R14 is Cl-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R14 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R14 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R14 is CON(R7)(R8). In certain embodiments, R14 is N(R7)(R8). In certain embodiments, R14 is C1-C6alkylN(R7)(R8).
In certain embodiments, wherein X is C(R14)2, R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, Ci-C6alkylOCI-C6alkyl and CI-Coalkyl.
In certain embodiments, R14 is hydrogen, methyl, ethyl, methoxy, OH or In the embodiments described herein, R15 is hydrogen, halogen, CN, OH, Ci-C6alkoxy, Ci-C6alkylOCi-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R15 is hydrogen. In certain embodiments, R15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R15 is CN. In certain embodiments, R15 is OH.
In certain embodiments, R15 is Ci-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R15 is Ci-C6alkylOCi-C6alkyl. In certain embodiments, R15 is COOH. In certain embodiments, R15 is C1-C6alkylCOOH. In certain embodiments, R15 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R15 is Ci-Coalkyl. Examples of Ci-Coalkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R15 is ethyl.

In certain embodiments, R15 is haloCt-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R1-5 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R15 is CON(R7)(R8). In certain embodiments, R15 is N(R7)(1e).
In certain embodiments, R15 is C1-C6alkylN(R7)(R8).
In certain embodiments, R15 is methyl or ethyl.
In the embodiments described herein, R16 is hydrogen, halogen, CN, OH, CI-C6alkoxy, Ci-C6alkylOCI-C6alkyl, Ci-C6alkylCOOH, COOH, C3-C6cycloalkyl, Ci-Coalkyl, haloCi-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R16 is hydrogen. In certain embodiments, R16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R16 is CN. In certain embodiments, R16 is OH.
In certain embodiments, R16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R16 is CI-C6alkylOC1-C6alkyl. In certain embodiments, R16 is COOH. In certain embodiments, R16 is C1-C6alkylCOOH. In certain embodiments, R16 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In certain embodiments, R16 is C1-C6alkyl. Examples of C1-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-m ethyl butyl , 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R16 is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R16 is CI-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R16 is CON(R7)(R8). In certain embodiments, R16 is N(R7)(10. In certain embodiments, R16 is Ci-C6alkylN(R7)(R8).
In the embodiments of the compounds described herein, 1 is 0 or 1. In certain embodiments, 1 is 0. In certain embodiments, 1 is 1.
In the embodiments of the compounds described herein, m is 0 or 1. In certain embodiments, m is 0 In certain embodiments, m is 1 In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1.
In certain embodiments, m and p are 1 and X is 0.
In certain embodiments, m and p are 1 and X is CH2.
In certain embodiments, m is 0, p is 1 and X is 0.
In certain embodiments, m and p are 1 and X is S02.
In certain embodiments, m is 0, p is 1 and X is C(R14)2, wherein each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, OH, Ci-C6alkoxy and Ci-C6alkyl.
In certain embodiments, m is 1 and X is 2 C(R14,), wherein each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, OH, Ci-C6alkoxy and C1-C6alkyl.
For example, in certain embodiments of Formula (I), 1 is 0; m is 1; p is 1;
Xis 0;
V, Y and Z are CH; and Q is CH2 as shown in formula (VII).
p12 HN A N

R11.5,,Aso =

I
(VII).
For example, in certain embodiments of Formula (I),1, m and p are 1; X is 0;
V, Y and Z are CH; and Q is 0 as shown in Formula (VIII).

HN N =
.10 =

R6 (VIII).

In the embodiments described herein, A is a straight or branched, saturated or unsaturated (C3-C1o)alkylene, phenyl(C3-Cto)alkylene or cycloalkyl(C3-COalkylene comprising at least one ¨CH2- group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONR, NRCO, S02, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3haloalkyl.
In certain embodiments, A is a straight or branched, saturated or unsaturated (C3-C10)a1ky1ene or cycloalkyl(C3-Cto)alkylene, wherein one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S and NH. In certain embodiment, A will always have at least one ¨CH2- group.
In certain embodiments, A is a straight (C3-C1o)alkylene. Examples of straight (C3-C1o)alkylenes include, ;221 ;221 X , .--- .--f -,-- ..,-..õ

L.
r.- -I- V
.
In certain embodiments, A is a branched (C3-C1o)alkylene. Suitable branched (C3-Cto)alkylenes include but are not limited to:
, r.õ( --,,,,,,z, ;221 ;221 ( 2 24 art 1 ,"'...
.."'-' ../.
'..../...
'111.
..µzza ....--- ',......... ...õ -V X.
.2.2z.
\ .
In certain embodiments, A is a saturated (C3-C1O)alkylene. Examples include, ,,..N
,i;
X ..-r- ,.. ...., ....- ....-f --r- ..---:\...-r ,- ....- ....--õL..... ..---,-----..., r , (.....c *".............)221 )221 \

'''.---, ...õ..., ....... ,,,,..,..
"22.. ...y In certain embodiments, A is an unsaturated (C3-C1o)alkylene. Suitable unsaturated (C3-Cio)alkylenes include any of the saturated (C3-C1o)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-Cio)alkylenes include, but are not limited to, Jr' I
.....4=- ...-- ___...1 r In other embodiments, A is a straight cycloalkyl(C3-C1o)alkylene. Suitable straight cycloalkyl(C3-Cio)alkylenes include a cycloalkyl(C3-Cio)alkylene wherein two carbons in a chain are included in a (C3-C1o)cycloalkyl. Examples of straight cycloalkyl(C3-C1o)alkylenes include, but are not limited to, LN, In certain embodiments, A is a branched cycloalkyl(C3-C1o)alkylene. Suitable branched cycloalkyl(Ci-Cio)alkylenes include a branched (C3-Cio)alkylene wherein two carbons in a chain are included in a (C3-C1o)cycloalkyl. Examples of cycloalkyl(C3-C1o)alkylenes include, but are not limited to, In certain embodiments, A is a saturated cycloalkyl(C3-C1o)alkylene. Examples of saturated cycloalkyl(C3-C1o)alkylenes include, but are not limited to, r<r2"1, tzel, .:3111 "luv In certain embodiments, A is an unsaturated cycloalkyl(C3-C1o)alkylene.
Examples of unsaturated cyclo(C3-C1o)alkylenes include, but are not limited to, In certain embodiments, A is an unsaturated or saturated phenyl(C3-C1o)alkylene.
Examples of unsaturated and saturated phenyl(C3-C1o)alkylenes include, but are not limited to, c??, 4111:1 11111 `371, In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S. NR, CONR, NRCO, S02, and SO2NR. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S and NH. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with 0. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with NR. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with CONR. In other embodiments, one or more ¨CH2-groups in A are optionally and independently replaced with NRCO. In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with S02.
In other embodiments, one or more ¨CH2- groups in A are optionally and independently replaced with and SO2NR. R will be described in further detail below.
In the embodiments described herein, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl.
In certain embodiments, R is hydrogen, CI-C6alkylCOOH, COOH, C3-C6cycloalkyl, CI-C6alkyl, haloCi-Coalkyl or Ci-CoalkylOH.
In certain embodiments, R is hydrogen. In certain embodiments, R is Ci-C6alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C1-C6alkyl. Examples of Ci-C6alkyl groups can include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-l-methylpropyl. In certain embodiments, R is haloCi-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluorom ethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R is Ci-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
In certain embodiments, R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOCi-C6alkyl. Suitable examples include, but are not limited to, COOCH3.
Examples of such embodiments include, but are not limited to, rw r)1, gf- 6 (!) :72;_ o) In certain embodiments, A is "1.4 z .., "-,... I ....... ,V. I /".
!=-=
-42,../-,,,,,, r r .A.r. "I.'''.
In certain embodiments, one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1_3 haloalkyl.
Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, A is "'WV
4,1\11/ VVIIV I
) ,J1I ' F
41.11.1V
..,-' Fsf ..--' -\.."
-1z_ 0 ..\..., =,-----F,.../
" IV V ' In each of the various embodiments of the invention, in the compounds used in the methods herein, each variable (including those in each of Formulae (I) -(VIII), and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.
In each of the various embodiments of the invention, the compounds described herein, including those in each of Formulae (I) - (VIII)and the various embodiments thereof, may exit in different forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof In certain embodiments, compounds described herein include:

HNJ.L.N

OH

HNAN

OH

HNAN

HNAN

HNAN
JL

r". OH

HNAN

OH

HN'ic HNAN
Jó

HNAN

HNAN
JU

--....

HNAN

/

HWII.'N

NH

HNAN

HNAN

OH
0' HNAN

NH
HNAN

HNAN

HNAN

NH
HNAN
Já
HN

NH
HNAN

NH
HNAN
Ió
HN
NH
HNAN
Iá
ID
HN

HN)-(N /1101 NW-11'N 1101 NH
/"'. 0 NH

In certain embodiments, compounds described herein include:
NH
HNJ-N

,,,OH

NH /--'''0 HNAN ¨
/t,õ

HNAN' /H..

NH --'0 HNAN -/1,..

NH
HNAN

HNAN's.
/ " 0 "t-'-NH
HNAN -/oõ

NH
HN N
//,,.

NH
HNAN
/1,..

NH
HNAN

NO

NH
HNAN

HNAN -/I ..=

--,_ NH
HN'll'N

/

NH --'-'0 HN A N

NH "...'(:) ' ,---L.

NH /.---'10 HN AN
/1,. =

HKN's.

NH
HN,;k1"N"' NH"= 0 HN
* HN 0 NH
HN ANN'.
/11Lo .=

HN 'IL Nµ
LT
/II..

A =
HN* N

-...._ HNAN'.
/1,..

* HN 0 *

NH

HNA N lb zoõ

NH -'0 )- 7 HN* N
Ii HN

NH

HN* N

NH
HNANo.
/1.,.

NH
or a pharmaceutically acceptable salt thereof.

Definitions and Abbreviations:
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl", "haloalkyl", arylalkyl-, alkylaryl-, -alkoxy" etc.
It shall be understood that, in the various embodiments of the invention described herein, any variable not explicitly defined in the context of the embodiment is as defined in Formula (I).
In the various embodiments described herein, each variable is selected independently of the others unless otherwise indicated.
"Drug resistant" means, in connection with a Plasmodium parasite strain, a Plasmodium species which is no longer susceptible to at least one previously effective drug;
which has developed the ability to withstand attack by at least one previously effective drug. A
drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs "Patient" includes both human and non-human animals. Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, dogs, and house cats.
"Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers or diluents.
The term -pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of one or more (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents" The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
"Halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Alkylene," by itself or as part of another substituent means a divalent hydrocarbon chain radical having the stated number of carbon atoms. For example, -(Ci-05)alkylene, would include, e.g., -CH2-, -CH2CH2-, -CH2CH2C+12-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2- Of -CH2CH2CH2CH2CH2-. A straight alkylene means a divalent straight hydrocarbon chain radical having the stated number of carbon atoms. A branched alkylene means a divalent branched hydrocarbon chain radical having the stated number of carbon atoms.
A saturated alkylene means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms. An unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and one or more double or triple covalent bonds within the chain. A cycloalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl"
means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
"Aryl" means an aromatic monocy clic or multi cycli c ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
The aryl group can be optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 12 carbon atoms, preferably about 3 to about 10 carbon atoms.
Preferred cycloalkyl rings contain about 5 to about 10 ring atoms. The cycloalkyl can be optionally substituted with one or more sub stituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Multicyclic cycloalkyls refers to multicyclic, including bicyclic, rings that include a non-aromatic ring. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. In certain embodiments, a non-aromatic ring is fused to an aromatic ring.
"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic, saturated or partially saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination There are no adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any ¨NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term "oxide," when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-di oxide "Heterocycly1"
also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =0 groups may be referred to herein as HNO

cc oxo." An example of such a moiety is pyrrolidinone (or pyrrolidone): .
As used herein, the term "monocyclic heterocycloalkyl" refers monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, 0, S, S-oxide, 5(0), and S(0)2.
The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. A non-limiting example of a monocyclic heterocycloalkyl group include the moiety: O.
Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to, - and "Alkoxy" means an alkyl-0- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
When a variable appears more than once in a group, e.g., R8 in ¨N(R8)2, or a variable appears more than once in a structure presented herein, the variables can be the same or different.
A solid line ¨, as a bond generally indicates a mixture of, or either of, the possible isomers, e g , containing (R)- and (S)-stereochem stry For exam pl e-means containing either one of or both N and --hr The wavy line '-u-v1A), as used herein shown crossing a line representing a chemical bond, indicates a point of attachment to the rest of the compound.
Lines drawn into the ring systems, such as, for example 0¨indicates that the indicated line (bond) may be attached to any of the substitutable ring atoms.

"Oxo" is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or another ring described herein, ___________________ 0 e.g., H
In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system.
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise For example.
H3c cH, represents =
In another embodiment, the compounds useful in the methods of the invention, and/or compositions comprising them useful in said methods, are present in isolated and/or purified form. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof Thus, the term "purified", "in purified form" or -in isolated and purified form" for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It shall be understood that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W.
Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.
Another embodiment provides prodrugs and/or solvates of the compounds of the invention. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A
discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound useful in the methods of the invention or a pharmaceutically acceptable salt thereof, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1¨C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as 13-dimethylaminoethyl), carbamoy1-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoy1-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound used in the methods of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, 1-((Ci-C6)alkanoyl oxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, a-amino(C1-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)2, -P(0)(0(Ci-C6)alky1)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound used in the methods of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, -C(OH)C(0)0Y1 wherein Y1 is H, (CI -C6)alkyl or benzyl, -C(0Y2)Y3 wherein Y2 is (Ci-C4) alkyl and Y3 is (CI-C6)alkyl, carboxy (Ci-C6)alkyl, amino(Ci-C4)alkyl or mono-N- or di-N,N-(C1-C6)alkylaminoalkyl, -C(Y4)Y5 wherein Y4 is H
or methyl and Y5 is mono-N- or di-N,N-(C1-C6)alkylamino morpholino, piperidin-l-yl or pyrrolidin-l-yl, and the like.
One or more compounds used in the methods of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate"
is a solvate wherein the solvent molecule is H20.
One or more compounds used in the methods of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example M. Caira et al., J. Pharmaceutical Sci ., 1993, 3, 601-611, describe the preparation of the solvates of the antifungal tluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et at., AAPS
PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem.
Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R.
spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition used in the methods of the present invention effective in inhibiting the above-noted diseases or enzyme activity and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
Another embodiment provides pharmaceutically acceptable salts of the compounds to be used in the methods of the invention. Thus, reference to a compound used in the methods of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds used in the methods of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts.
Properties, Selection and Use. (2002) Zurich. Wiley-VCH; S Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International .1 of Pharmaceutics (1986) 33 201-217;
Anderson et al., 'The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Another embodiment provides pharmaceutically acceptable esters of the compounds used in the methods of the invention. Such esters include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, CI-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
As mentioned herein, another embodiment provides tautomers of the compounds of the invention to be used in the methods herein, and salts, solvates, esters and prodrugs of said tautomers. It shall be understood that all tautomeric forms of such compounds are within the scope of the compounds used in the methods of the invention. For example, all keto-enol and imine-enamine forms of the compounds, when present, are included in the invention.
The compounds used in the methods of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms Tt is intended that all stereoisomeric forms of the compounds used in the methods of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces use of all geometric and positional isomers. For example, if a compound used in the methods of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, (E) and (Z) forms, as well as mixtures, are embraced within the scope of the invention.
Another embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds used in the methods of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds used in the methods of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds used in the methods of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridy1).
(For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the methods of the invention).
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S
or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
Another embodiment provides isotopically-labelled compounds to be used in the methods the invention. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31p, 32p, 35s, 18F, and 36C1, respectively.
Certain isotopically-labelled compounds of the invention (e.g., those labeled with 3H and 1-4C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 4C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 41) may afford certain therapeutic advantages resulting from greater metabolic stability (e g , increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Isotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
In the compounds used in the methods of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium ('H) and deuterium (2H). The presence of deuterium in the compounds of the invention is indicated by "D". Protium is the predominant hydrogen isotope found in nature Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Polymorphic forms of the compounds used in the methods of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention Methods of Treatment The present invention is directed to methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof. More specifically, the methods of the invention comprise administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are administered in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier or excipient.
The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I) described in the Summary of the Invention In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.
The invention also relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.
The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I) described in the Summary of the Invention. In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.
The invention also relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin TX
activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.
The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin X and plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I) described in the Summary of the Invention. In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.

The invention also relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X and plasmepsin IX
activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.
The methods of the present invention are useful for treating malaria in that they inhibit the onset, growth, or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition. Thus, in accordance with the presently disclosed subject matter, the terms "treat", "treating", and grammatical variations thereof, as well as the phrase "method of treating", are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject of infection, such as in a subject that has been exposed to a parasite as disclosed herein.
Embodiments of the invention also include one or more of the compounds of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof (i) for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for. (a) therapy (e.g., of the human body); (b) medicine; (c) inhibition of parasite/Plasmodium growth, (d) treatment or prophylaxis of infection by Plasmodium species; (e) reduction of the progression, onset or severity of pathological symptoms associated with Plasmodium infection and/or reduction of the likelihood of severe Plasmodium infection or, (f) treatment, prophylaxis of, or delay in the onset, severity, or progression of Plasmodium -associated di sease(s), including, but not limited to: malaria.
Accordingly, another embodiment provides methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described below. In certain embodiments, described herein are methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formulae (I) -(VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-malarial agents. In certain embodiments, described herein are methods for the treatment of malaria by inhibition of plasmepsin X, IX and at least one other mechanism, comprising administration of combinations comprising an amount of at least one compound of Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-malarial agents, wherein the additional anti-malarial agents act through a different mechanism than inhibiting plasmepsin IX or plasmepsin X. The pharmacological properties of the compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof may be confirmed by several pharmacological assays.
Dosage and Administration Another embodiment provides suitable dosages and dosage forms of the compounds used in the methods of the invention. Suitable doses for administering compounds used in the methods of the invention to patients may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound.
In another embodiment, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, in specific embodiments from about 1 mg to about 50 mg, in specific embodiments from about 1 mg to about 25 mg, according to the particular application. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, in specific embodiments 1 mg/day to 200 mg/day, in two to four divided doses.
As discussed above, the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
Liquid form preparations include solutions, suspensions and emulsions. As an example, may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
Another embodiment provides for use of compositions comprising a compound of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof formulated for transdermal delivery. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Another embodiment provides for use of compositions comprising a compound of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof formulated for subcutaneous delivery. Another embodiment provides for use of compositions suitable for oral delivery. In some embodiments, it may be advantageous for the pharmaceutical preparation comprising one or more compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof to be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Each of the foregoing alternatives is considered as included in the various embodiments of the invention When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds used in the methods of this invention, i.e., the compounds of Formulae (I) - (VIII), may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.
If formulated as a fixed dose, such combination products employ the compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
Combination Therapy Another embodiment provides for methods of treatment using pharmaceutically acceptable compositions comprising a compound of the invention, either as the neat chemical or optionally further comprising additional ingredients. Such compositions are contemplated for preparation and use alone or in combination therapy. For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Non-limiting examples of additional drugs and active agents useful in combination therapies for the treatment of malaria, include the following:
Coartem (Novartis International AG, Basel, Switzerland; artemether + lumefantrine), Eurartesim (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine), Pyramax (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronaridine-artesunate), ASAQ
Winthrop (Sanofi SA
(Gentilly, France)/DNDi (Geneva, Switzerland); artesunate + amodiaquine), ASMQ
(Cipla Limited (Mumbai, India)/DNDi, artesunate + mefloquine), SPAQ-COTM (Guilin Pharmaceutical Co., Ltd. (Shanghai), amodiaquine + sulfadoxine, pyrimethamine), Artesun (Guilin Pharmaceutical, artesunate), artemether, artesunate, dihydroartemisinin, lumefantrine, am odi aquine, mefloquine, piperaquine, quinine, chloroquine, atovaquone and proguanil and sulfadoxine-pyrimethamine, Tafenoquine (Glaxosmithkline), 0Z439/PQP (Sanofi), (Sanofi), KAE609 (Novartis), KAF156 (Novartis), D5M265 (NITI/Takeda), and 1V1K-(Merck & Co., Inc., Powles et at., Antimicrobial Agents and Chemotherapy 56(5): 2414-2419(2012)). Selection of such additional active ingredients will be according to the diseases or disorders present for which treatment is desired, as determined by the attending physician or other health care provider.
Thus, the invention also provides methods of using the compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof to inhibit plasmepsin X, plasmepsin IX
or plasmepsin X and IX, to treat Plasmodium infection or treat malaria wherein the method further comprises administering to a subject in need thereof, one or more additional anti-malarial agents. In some embodiments, the one or more additional anti-malarial agents are selected from the group consisting of: artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, metloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil.

EXAMPLES
The meanings of the abbreviations in Examples are shown below.
ACN = MeCN = CH3CN = acetonitrile AcOH = acetic acid AIBN = Azobisisobutyronitrile Ar = argon BBr3 = Boron tribromide BF3Et20 = Boron trifluoride etherate Boc20 = di-tert-butyl dicarbonate Cbz = carboxybenzyl Cbz0Su = N-(B enzyl oxycarbonyloxy)succinimi de CBr4 = Tetrabromomethane CC14= carbontetrachloride CELITE = diatomaceous earthConc. = concentrated Cs2CO3 = Cesium carbonate DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE = dichloroethane DCM = dichloromethane DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DM ALH = di i sobutyl alum i num hydride DIPEA = DIEA= N, N-Diisopropylethylamine, or Htinig's base DMA = dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N,N-Dimethylformamide DMP = Dess¨Martin periodinane DMSO = dimethyl sulfoxide DPPE = 1,2-Bis(diphenylphosphino)ethane DPPF = 1,1 '-Bis(diphenylphosphino)ferrocene EDCI = EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et20 = diethyl ether Et0Ac = ethyl acetate Et0H = ethanol Et3SiH = Tri ethyl silane h = hours H2= hydrogen HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HC1= hydrochloric acid HFBA= Heptafluorobutyric acid HOAc = acetic acid 12= iodine IPA= isopropyl alcohol [Ir(cod)C1]2 = cyclooctadiene iridium chloride dimer K2CO3= potassium carbonate K3PO4 = Tripotassium phosphate KF = Potassium fluoride KIIMDS = Potassium bis(trimethylsilyl)amide KOTMS = Potassium trimethylsilanolate LCMS = Liquid chromatography¨mass spectrometry LDA = Lithium diisopropylamide LHMDS = LiflIVIDS= lithium bis(trimethylsilyl)amide LiA1H4= lithium aluminum hydride LiOH = lithium hydroxide min = minutes Me = methyl MeCN = Acetonitrile Me0H = CH3OH = methanol MgSO4 = Magnesium sulfate MsCl= methanesulfonyl chloride N2= nitrogen NaBH4 = sodium borohydrate NaH = sodium hydride NaHCO3 = Sodium hydrogencarbonate NaI04= sodium periodate NaOH = sodium hydroxide Na2CO3 = sodium carbonate Na2S03= sodium sulfite Na7SO4= sodium sulfate NH4C1 = Ammonium chloride NH4OH = Ammonium hydroxide NH40Ac = Ammonium acetate NaHMDS = sodium bis(trimethylsilyl)amide OMs = mesylate OTs = tosylate OTf = trifluoromethanesulfonyl Pd(OH)2/C = Pearlman's Catalyst - Palladium hydroxide on carbon-C
Pd-C = Palladium on carbon-C
[Pd(C3H5)C12] = Allylpalladium(II) chloride dimer PdC12(dppf)-CH2C12 = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPh3 = Triphenylphosphine Ru02.H20 = ruthenium(IV)oxide hydrate RP-HPLC = reverse phase high performance liquid chromatography SFC = Supercritical Fluid Chromatography TBDPS-Cl = TB SCI = tert-Butyl (chloro)di phenyl si lane TEA = Et3N = triethylamine TBAF = Tetra-n-butylammonium fluoride TFA = trifluoroacetic acid THF = tetrahydrofuran Ti(Et0)4 = titanium ethoxide TMS = Tri methyl si 1 ylb TMSOTf = Trimethylsilyl trifluoromethanesulfonate Ts0H = p-Toluenesulfonic acid CDC13 = heavy chloroform CD3OD = heavy methanol 1 Standard atmosphere [atm] = 101325 pascal [Pa] = 14.6959488 psi The meanings of the abbreviations in the nuclear magnetic resonance spectra are shown below:
s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd =
double doublet, Sept =
septet, t = triplet, m = multiplet, br = broad, brs = broad singlet, q =
quartet J = coupling constant and Hz = hertz.
Several methods for preparing the compounds of this disclosure are described in the following Schemes and Examples. Starting materials and intermediates were purchased commercially from common catalog sources or were made using known procedures, or as otherwise illustrated. Some frequently applied routes to the compounds of Formula I are described in in the Schemes that follow. In some cases, the order of carrying out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.

H N N NH
HN N

macroiactamization .. 0 )n 02H
NH2 ) n HN 0 R' R' R" R"

Compounds of Formula S-2 are prepared from S-1 by macrolactamization using amide coupling reagents.

NH NH
HNAN HN NH
HN

RCM ( reduction ( n H,Me R' R' R' H,Me R" R"
R"

Intermediate compounds of Formula S-4 are prepared from S-3 after ring closing metathesis (RCM) reactions using catalysts such as the 2nd generation Grubbs', Zhan's and Hoveyda/Grubbs' catalysts. Double bonds in S-4 can be reduced under for example hydrogenation conditions to yield the products of Formula S-5 R" R¨
R"' NH NH NH
HNAN HNAN
HNAN
I ntramolecular R

coupling n reduction n X
R' R' R' R" R"
R"

Intermediate compounds of Formula S-7 are prepared from S-6, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as Heck reactions. Resulting double bonds in S-7 can be reduced under for example hydrogenation conditions to yield the products of Formula S-8.

R"' R"' NH NH
HNAN HNAN
I ntramolecular Rro R )n 0 coupling X
411 R' R' R" R'' Products of Formula S-10 are prepared from S-9, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as palladium catalyzed C-0 coupling reactions.

NH NH
HNN HN.-11,N
(ir.'=-=,-"LO OH,/ HN 0 etherification (0 HN
OH,X
R R.
R" R"

Products of Formula S-12 are prepared from S-11 after intramolecular SN2 reactions between an alcohol and X, in which X is a leaving group such as Cl, Br, I, OMs, OTs or OTf.
Products of Formula S-12 are also prepared from S-11 diols after dehydration conditions using an acid or other dehydration reagents.

NH NH NH
HN.11..N HNAN HN N
reductive c( Or c( etherification (r HO
R' R' " R' Rõ R" R

Products of Formula S-12 are prepared from intermediates S-13 or S-14 after intramolecular reductive etherification using conditions such as TMSOTf and Et3SiH.
Reactions sensitive to moisture or air were performed inside a glove-box or under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E.

Merck pre-coated TLC plates, silica gel 60E-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC/MS).
Typically, the analytical LC-MS system used consisted of a Waters ZQTM
platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC
with autosampler. The column was commonly a Waters Xterra MS C18, 3.0 x 50 mm, 5 pm or a Waters Acquity UPLC BEH C18 1.0 x 50 mm, 1.7 pm. The flow rate was 1 mL/min, and the injection volume was 10 [IL. UV detection was in the range 210-400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05%
TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min.
Preparative HPLC purifications were usually performed using either a mass spectrometry directed system or a non-mass guided system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System consisting of:
Waters ZQTM single quad MS system with Electrospray Ionization, Waters 2525 Gradient Pump, Waters 2767 Inject /Collector, Waters 996 PDA Detector, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters SUNFIRE C-18 5-micron, 30 mm (id) x 100 mm column. The mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1% TFA. Flow rates were maintained at 50 mL/min, the injection volume was 1800 pL, and the UV detection range was 210-400 nm. An alternate preparative HPLC
system used was a Gilson Workstation consisting of Gil son GX-281 Injector/Collector, Gilson UV/VIS-155 Detector, Gilson 333 and 334 Pumps, and either a Phenomenex Gemini-5-micron, 50 mm (id) x 250 mm column or a Waters XBridgeTM C-18 5-micron OBDTM, 30 mm (id) x 250 mm column. The mobile phases consisted of mixtures of acetonitrile (0-75%) in water containing 5mmo1 (NH4)HCO3. Flow rates were maintained at 50 mL/min for the Waters XbridgeTM column and 90 mL/min for the Phenomenex Gemini column. The injection volume ranged from 1000-8000 pL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for the individual compounds. Reactions performed using microwave irradiation were normally carried out using an Emrys Optimizer manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using either a Biotage' Flash Chromatography apparatus (Dyax Corp.), an ISCO
CombiFlashe Rf apparatus, or an ISCO CombiFlashC Companion XL on silica gel (32-63 litM, 60 A pore size) in pre-packed cartridges of the size noted. IHNMR spectra were acquired at 500 MHz spectrometers in CDC13 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CDC13 solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD
solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on one of CHIRALPAK AS, CH1RALPAK AD, CHIRALCEL OD, CHIRALCEL IA, or CHIRALCEL OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IPA/Elep) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of CHIRALPAK AS, of CHIRALPAK AD, CHIRALCELI)0D, CHIRALCELITA, CHIRALCEL 0.1 columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.
It is understood that a chiral center in a compound may exist in the "S" or stereo-configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center includes both the (R) and (S) stereoisomers as well as mixtures thereof Preparation of Intermediate 1-2 HO1i0 0 j DPPA, DBU
N3"

DBU (21.72 mL, 144 mmol) and diphenylphosphinyl was added to a mixture of methyl (S)-4-hydroxychromane-6-carboxylate (INT1-1) (10 g, 48.0 mmol) in THF
(80 mL).
Azide (35.0 g, 144 mmol) was then added under N2. The mixture was stirred at 50 C for 12 h.
The mixture was quenched with water (100 mL), and extracted with Et0Ac (3 x 100 mL). The organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated.
The crude product was purified by flash silica gel chromatography (ISCO ; 330 g SepaElash Silica Flash Column, Eluent of 15% Et0Ac/Pet.ether gradient @ 50 mL/min) to give methyl (R)-4-azidochromane-6-carboxylate (INT1-2).
MS (ESI) m/z 234.0(M+H ) NMR (500 MHz, CHLOROFORM-d) 6 7.93-7.96 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.65 (t, J=3.5 Hz, 1H), 4.29-4.35 (m, 2H), 3.90 (s, 3H), 2.14-2.26 (m, 1H), 2.06-2.12 (m, 1H) Preparation of Intermediate 1-3 Pd/C, H2 H2N1`..

Pd-C (2510 g, 4.72 mmol) was added to a solution of methyl (R)-4-azidochromane-6-carboxylate (INT1-2) (11 g, 47.2 mmol) in THF (200 mL) under atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 25 C for 12 h under H2 (15 psi) atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give methyl (R)-4-aminochromane-6-carboxylate (INT1-3).
MS (ESI) nilz: 191.1 (M-17-41+) Preparation of Intermediate 1 =
ooHN NHBoc H2Ns' B
. BocHNAN`s NaH, TFAA, THF

Sodium hydride (3.77 g, 94 mmol) was added to a solution of N,N-bisboc-thiourea (16.94 g, 61.3 mmol) in THF (250 mL) at 0 C in portions under N2.
After lhr at this temperature, 2,2,2-trifluoroacetic anhydride (8.82 mL, 61.3 mmol) was added dropwise. The mixture was stirred at 0 C for lh. A solution of methyl (R)-4-aminochromane-6-carboxylate (INTI-3) (9_77 g, 47.1 mmol) in THE (50 mL) was added dropwise at 0 C. The mixture was stirred at 0 C for 2 h. The mixture was quenched with water (80 mL), and extracted with Et0Ac (3 x 50 mL). The organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO ;
220 g SepaFlash Silica Flash Column, Eluent of 20% Et0Ac/Pet.ether gradient @
50 mL/min) to afford methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6-carboxylate (INT-1).
MS (ESI) nilz 367.1 (M+11 ) NMR (500 MHz, CHLOROFORM-d) 6 8.01 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.89 (dd, J=2.0, 9.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.34-4.41 (m, 1H), 4.19-4.26 (m, 1H), 3.88 (s, 3H), 2.25-2.40 (m, 2H), 1.47 (s, 9H) Preparation of Intermediate 2-2 MeONHMe=HCI, 0 0 EDCI, HOBt, DIEA), N-OH DCM, RI

To a solution of pent-4-enoic acid (INT2-1) (40 g, 400 mmol), EDCI (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazo1-1-ol (64.8 g, 479 mmol) and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,0-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 C for 12 h under N2 atmosphere. LCMS showed desired mass. The mixture was quenched with water (300 mL), and extracted with DCM (3 x 100 mL). The organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCOS; 220g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 50 mL/min) to afford N-methoxy-N-methylpent-4-enamide (INT2-2).
MS (ESI) nilz 144.1 (M+H)+
1-1-1 NMR (500 MHz, CHLOROFORM-d) 6 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of Intermediate 2-3 EtMgBr THF

A solution of N-methoxy-N-methylpent-4-enamide (INT2-2) (20 g, 140 mmol) in THF (200 mL) under N2 atmosphere at 0 C, was then added ethylmagnesium bromide (69.8 mL, 210 mmol) dropwise at 0 'C. The reaction was stirred at 25 "V for 1 h under N2 atmosphere.
TLC showed a new spot. The mixture was quenched with Sat. NH4C1 a. q.(100 mL) and water (100 mL), extracted with Et0Ac (3 x 100 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCOg; 120g Agela Silica Flash Column, eluent of 5%
ethyl acetate/pet. ether gradient @ 40 mL/min) to afford hept-6-en-3-one (INT2-3).
1H NMR (500 MHz, CHLOROFORM-d) 6 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J=7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J= 7.0 Hz, 3H) Preparation of Intermediate 2-4 (R)g o H2N - %
N-i' _______________________________________________________ \
Ti(OEt)4., THF

To a solution hept-6-en-3-one (INT2-3) (10 g, 89 mmol) in THF (100 mL) was added (R)-2-methylpropane-2-sulfinami de (12.97 g, 107 mmol) followed by Ti(Ft0)4 (37.5 mTõ
178 mmol), then the reaction was stirred at 75 C for 12 h under N2 atmosphere. TLC showed new spots. The final mixture was cooled to room temperature, then diluted with DCM (200 mL), stirred 15 min, then ice cold-saturated aqueous sodium bicarbonate solution (50 mL) and Na2SO4 then filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCOg; 120g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet, ether gradient @ 40 mL/min) to afford (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (IN T2-4).
MS (ESI) nilz 216.2 (m+il) 1H NMR_ (500 MHz, CHLOROFORM-d) 6 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of Intermediate 2-5 LDA, Ti(Oi-Pr)3C1, N¨e CH3COOMe ThN
\ -2\ ____________ THF
\COOMe To a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) at -78 C was added butyllithium (55.7 mL, 139 mmol) dropwise under N2 atmosphere. The reaction was stirred at 0 C for 30 min to make LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3C1 (116 mL, 116 mmol) were added to anhydrous THF (90 mL). LDA (76 mL, 93 mmol) was then added dropwise to the mixture at -78 C. After 1 h, a solution of (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4) (10 g, 46.4 mmol) in anhydrous THF
(20 mL) was then added dropwise and the mixture was stirred at -78 C for 3 h.
The color was no change and yellow. LCMS showed major DP mass. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with Et0Ac (200 mL) then filtered, rinsing with Et0Ac and water. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISC08; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford methyl 34(R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5).
MS (ESI) nilz 290.1 (M+H)+
1-E1 NMR (500 MHz, CHLOROFORM-d) 6 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J =
1.0, 10.0 Hz, 1H), 4.63 (br d, J = 17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J =
5.0, 16.0 Hz, 1H), 2.52 (dd, J= 2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 1H), i.76-1.81(m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J= 7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of Intermediate 2-6 SFC HIV"
'-00Me 00Me 00Me Methyl 3-4(R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5) (12 g, 41.5 mmol) was separated by SFC Column DAICEL CHIRALPAK AD(250mm x50mm, 10um) Condition 0.1%NH3H20 IPA Begin B 15 End B 15 Gradient Time(min) 100%B Hold Time(min) FlowRate(mL/min) 200 Injections 200) and Column DAICEL CHIRALPAK
AD(250mm x 50mm, 10um) Condition 0.1%NH3H20 IPA Begin B 12 End B 12 Gradient Time(min) 100%B Hold Time(min) FlowRate(mL/min) 200 Injections 240) to give methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6 P1, desired) (tR=1.978 min, UV
= 220 nm) and methyl (S)-34(R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (IN T2-6_P2) (tR=2.132min, UV = 220 nm).
MS (ESI) nilz 290.1 (M+II) INT2-6 P1:1EINMIR (500 MHz, CHLOROFORM-d) 6 5.79 (tdd, J = 6.56, 10.32, 16.99 Hz, 1H), 4.93-5.09 (m, 2H), 3.62-3.73 (m, 3H), 2.72 (d, J= 15.87 Hz, 1H), 2.52 (d, J= 15.87 Hz, 1H), 2.48 (s, 1H), 2.00-2.09 (m, 2H), 1.76-1.88 (m, 2H), 1.68-1.74 (m, 2H), 1.23 (s, 9H), 0.86-0.95 (m, 3H). INT2-6_P2: 1-H NMR (500 MHz, CHLOROFORM-d) 6 5.71-5.87 (m, 1H), 4.94-5.07 (m, 2H), 3.65-3.73 (m, 3H), 2.72 (d, J = 16.02 Hz, 1H), 2.52 (d, J =
16.02 Hz, 1H), 2.00-2.14 (m, 2H), 1.83-1.91 (m, 1H), 1.74-1.80 (m, 1H), 1.67-1.74 (m, 2H), 1.20-1.25 (m, 8H), 0.83-0.89 (m, 3H).
Preparation of Intermediate 2-7 HCI-dioxane \ NH2 __________________________________________________ AP- I
Me0H
COOMe tOOMe A solution of methyl (R)-3-(((R)-tert-buty1sulfinyl)amino)-3-ethylhept-6-enoate (INT2-6 Pl) (20 g, 69.1 mmol) in HC1-dioxane(4N) (100 mL) and Me0H (200 mL) was stirred at 25 C for 2 h. LCMS showed the reaction was complete. Solvent was evaporated under reduced pressure to give the product methyl (R)-3-amino-3-ethylhept-6-enoate hydrochloride (INT2-7).
MS (ESI) nilz 186.3 (M+H) -1-14 NMR (500 MHz, METHANOL-d4) 6 5.80-5.87 (m, 1H), 5.07-5.15 (m, 1H), 5.02-5.04 (m, 1H), 3.73 (s, 3H), 2.71-2.79 (m, 2H), 2.07-2.18 (m, 2H), 1.75-1.85 (m, 4H), 0.99 (t, ./= 7.6 Hz, 3H) Preparation of Intermediate 2-8 S Bo:`NI
Bocl-INAN

tOOMe EDCI, DIEA, ACN /I". 0 To a solution of DMB-BOC-THIOUREA (5 g, 15.32 mmol), methyl (R)-3-amino-3-ethylhept-6-enoate hydrochloride (INT2-7) (3.74 g, 16.85 mmol) and EDC
(7.34 g, 38.3 mmol) in Acetonitrile (100 mL) was added D1EA (12.04 mL, 68.9 mmol). The reaction was stirred at 15 C for 12 h under N2 atmosphere. LCMS showed desired mass, and some ring-opened byproduct ester. Then warmed to 50 C and stirred at 50 C for 2 h.
LCMS showed only desired product mass. The mixture was concentrated in vauo. The crude was dissolved Et0Ac (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with Et0Ac (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash column (ISCOe; 80 g Agela Silica Flash Column, eluent of 15% ethyl acetate/pet. ether gradient @ 30 mL/min) to afford tert-butyl (R,E)-(4-(but-3-en-1 -y 1 ) -1-(2,4-dimethoxybenzy1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8).
MS (ESI) nilz 390.1 (M+H-56) 1H NMR (400 MHz, CHLOROFORM-d) 6 9.92 (br s, 1H), 7.10 (br d, J= 8.8 Hz, 1H), 6.33-6.50 (m, 2H), 5.63-5.83 (m, 1H), 5.09 (s, 2H), 4.96-5.06 (m, 2H), 3.78 (dd, .1=
1.6, 4.4 Hz, 6H), 2.61 (s, 2H), 1.98-2.12 (m, 2H), 1.59-1.70 (m, 4H), 1.49 (s, 9H), 0.92 (t, J = 7.6 Hz, 3H) Preparation of Intermediate 2-9 NH
Boc'N '-'0 HN)L-NH
HN N AI TFA
/ "" .õ-k- 0 41Or 0-- 60 C, 16 113m' \
`=,.--INT2-8 /"rO
\

A solution of tert-butyl (R,E)-(4-(but-3-en-l-y1)-1-(2,4-dimethoxyb enzy1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) in TFA
(10 mL) was stirred at 60 C for 16 h. LCMS showed desired mass. The mixture was concentrated in vacuo. The residue was partitioned between Petether/Et0Ac (v/v=4:1, 10 mL) and water (10 mL). And LCMS showed the product was only in aqueous phase, and pretty clean.
(R)-6-(but-3-en-l-y1)-6-ethy1-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) in water (10 mL) was used for the next step directly.
MS (ESI) nilz 196.0 (M+H) Preparation of Intermediate 2 NH Boo HNANH ),L
r "
\ (Boc)20, NaHCO3 THF, H20, 25 C, 16 h).- HN NH
/" . _______________________________ /".. o \ INT-2 To a solution of (R)-6-(but-3-en-1-y1)-6-ethy1-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) (438 mg, 2.243 mmol) in Water (10 mL) and THF (3 mL) was added NaHCO3 (942 mg, 11.22 mmol) and (BOC)20 (1.042 mL, 4.49 mmol) at 0 C in portions. The reaction was stirred at 25 C for 16 h. LCMS showed desired mass. The mixture was extracted with Et0Ac (3 x 10 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash column (ISCOk; 12 g Agela Silica Flash Column, eluent of 20% EE(EtOAC/Et0H = 3:1)/Pet.ether gradient @
30 mL/min) to afford tert-butyl (R,E)-(4-(but-3-en-1-y1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate Intermediate 2 MS (ESI) nilz 296.2 (M+H) 1E1 NMR (400 MHz, CHLOROFORM-d) 6 9.37 (br s, 1H), 5.74-5.81 (m, 1H), 4.90-5.17(m, 2H), 2.59 (s, 2H), 2.07-2.10 (m, 2H), 1.62-1.78 (m, 4H), 1.51 (s, 9H), 0.97 (t, J= 7.2 Hz, 3H) HNJ-LN ' OH
(1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-9-methy1-23-oxa-2,4,17-tri azahexacycl o[17.6.2.22,5.210,13.012,16.022,26]hentriaconta-

10,12,19,21,26,28-hexaene-18,31-dione Preparation of Compound 1-2 Tf0H(5 eq) 11011.=N Br ,10H BS (1.1 eq) =.10H
DCM, 0 C to it, 1.5h Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) was added to a solution of (1R, 2R)-1-amino-2,3-dihydro-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) in DCM (10 mL) at 0 C. The reaction was stirred at 18 C for lh under N2 atmosphere. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 C, and extracted with DCM (1 x 10 mL) then extracted with Et0Ac (3 x 10 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum, the crude was purified by purified by flash silica gel chromatography (ISCO*); 12 g SepaFlash Silica Flash Column, Eluent of 10% Me0H/DCM (added 1% ammonium hydroxide) gradient @ 50 mL/min) with to afford (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (1-2).
MS (ESI) nilz: 228.1, 230.1(M+1-1 ) 1H N1VIR (400 MHz, METHANOL-d4) 6 7.50 (s, 1H), 7.33 (dd, 1=1.6, 8.0 Hz, 114), 7.10 (d, J=8.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 4.01-4.05 (m, 1H), 3.15 (dd, J=6.8, 15.6 Hz, 1H), 2.68 (dd, J=7.2, 15.6 Hz, 1H) Preparation of Compound 1-3 Boc HN'N
Br 2 HO 0 ro N H
=.10H HN 0 EDCI, HOBt, DIEA, THF
Z

DIEA (0.276 mL, 1.582 mmol) was added to a solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxo-4-(pent-4-en-1-y1)tetrahydropyrimidin-1(2H)-y1)chromane-6-carboxylic acid (1-2) (96 mg, 0.198 mmol), EDC (189 mg, 0.989 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (134 mg, 0.989 mmol) and (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (45.1 mg, 0.198 mmol) in THF (5 mL). The reaction was stirred at 18 C for 2 h.

The mixture was quenched with water (5 mL), and extracted with Et0Ac (3 x 5 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, and the crude was purified by prep-TLC (Pet. ether/Et0Ae=1:1) to afford tert-butyl ((R,E)-1-((R)-6-(((lR,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-l-y1)carbamoyl)chroman-4-y1)-4-ethy1-6-oxo-4-(pent-4-en-1-y1)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3).
MS (ESI) m/z: 695.1, 697.1 (M-41 ) Preparation of Compound 1-4A, 1-4B, and 1-4C
BocN Boc,N
_.,,,c) Boc,N ,, Boc--0 'N --'¨'0 ' /¨'=0 HN N di H N N 01 7IN N 10/ ,H, N
N /111.
7"¶ o ilir l 'A
P(oTo1)3G 2, Cy2Nivie HN 0 dioxane, 70 C, 16 h 16'.
V
,,.
OH \
7 ... 0 ,,OH

.00H
/Br S.' Chloro[tri(o-tolyl)phosphine][2-(2'-amino-1,11-biphenyl)]palladium(II) (8.83 mg, 0.014 mmol) and N,N-dicyclohexylmethylamine (140 mg, 0.719 mmol) was added to a solution of tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-yl)carbamoyl)chroman-4-y1)-4-ethyl-6-oxo-4-(pent-4-en-l-y1)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3) (100 mg, 0.144 mmol) in dioxane (1.5 mL) at 25 C in a glove box. The reaction was stirred at 70 C for 16h. The mixture was quenched with water (3 mL), and extracted with Et0Ac (3 x 5 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, and the crude was purified by reverse preparative HPLC (Instrument ED; Method Column Boston Prime C18 150 x 30mm, Sum; Condition water(0.04%NH3H20+ I OmM NH4HCO3)-ACN Begin B 65; End B 95 Gradient Tim e(min) 10;
100%B Hold Time(min) 2 FlowRate(mL/min) 25; Injections 5) to afford: tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4A); tert-butyl ((4aR,8R, 12Z, 18R, 18aR,28E)-8-ethyl-18-hydroxy-6,20-di oxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4B); and tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl- 17-hydroxy-12-methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12, 16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C).
MS (ESI) nilz: 486.2 (M-41+) 1-4A:1H NMIR (500 MHz, CHLOROFORM-d) 6 10.09 (s, 1H), 7.93 (dd, 1=1.5, 8.50 Hz, 1H), 7.21-7.26 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 6.91-6.98 (m, 2H), 6.42-6.54 (m, 3H), 5.82-5.92 (m, 1H), 5.25 (t, J=5.5 Hz, 1H), 4.94 (s, 111), 4.40-4.50 (m, 2H), 4.25-4.35 (m, 1H), 3.34 (dd, 1=8.0, 15.5 Hz, 1H), 2.99-3.05 (m, 1H), 2.67-2.86 (m, 2H), 2.57 (d, 1=13.5 Hz, 1H), 2.40 (d,1=15.5 Hz, 1H), 2.07 (s, 2H), 1.82 (d, 1=11.0 Hz, 2H), 1.62-1.67 (m, 4H), 1.49 (s, 9H), 0.96 (t, 1=7.5 Hz, 3H) 1-4B: IFINVIR (500 MHz, CHLOROFORM-d) 6 10.13 (s, 1H), 7.90 (dd, 1=2.0, 8.50 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.96 (d,1=8.50 Hz, 1H), 6.41-6.48 (m, 2H), 6.26 (dd, 1=7. 0, 9.0 Hz, 1H), 5.60-5.70 (m, 1H), 5.34 (t, 1=6.5 Hz, 1H), 4.60 (s, 1H), 4.46-4.54 (m, 1H), 4.42 (td, J=4.0, 11.0 Hz, 1H), 4.21 (dt, 1=2.5, 11.0 Hz, 1H), 3.34 (dd, J=7.5, 16.0 Hz, 1H), 2.97 (dd, J=7.5, 16.0 Hz, 1H), 2.60-2.72 (m, 2H), 2.49-2.53 (m, 2H), 2.22-2.30 (m, 1H), 2.13-2.18 (m, 1H), 2.03-2.12 (m, 2H), 1.72-1.82 (m, 4H), 1.49 (s, 9H), 1.00 (t, J=7.5 Hz, 3H) 1-4C: III NAIR (500 MHz, CHLOROFORM-d) 6 10.04 (s, 1H), 7.81 (dd, 12.0, 8.5 Hz, 1H), 7.52 (d, 1=8.0 Hz, 1H), 7.24 (d,1=8.0 Hz, 1H), 6.99-7.16 (m, 2H), 6.91 (d,1=8.50 Hz, 1H), 6.38-6.50 (m, 2H), 5.44 (s, 1H), 5.31 (t,1=6.5 Hz, 1H), 5.13 (s, 1H), 4.41-4.57 (m, 2H), 4.36 (s, 1H), 4.23 (dt,J=2.0, 11.50 Hz, 1H), 3.34 (dd, 1=8.0, 16.0 Hz, 1H), 2.98 (dd, 1=8.0, 16.0 Hz, 1H), 2.69-2.79 (m, 1H), 2.59-2.63 (m, 1H), 2.45-2.52 (m, 2H), 1.93-2.09 (m, 2H), 1.86 (d, 1=12.0 Hz, 2H), 1.53-1.65 (m, 4H), 1.45 (s, 9H), 0.98 (t, J=7.5 Hz, 3H) Preparation of Compound 1-5 Boc `N Boc 'N
HN N
IIJPd/C, H2 0 Me0H, r.t. HN 0 .õOH

Pd-C (1.731 mg, 3.25 [tmol) was added to a solution of tert-butyl ((4aR, 8R, 17R,17aR,E)-8-ethy1-17-hydroxy-12-methylene-6, 19-di ox o-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) in Me0H (2 ml) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (15 psi) at 25 C for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,17R,17aR,E)-8-ethy1-17-hydroxy-12-methyl-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-5).
MS (ESI) m/z: 617.3 (M-41+) Preparation of Example 1 Boc `N NH

/"" 0 ZnBr2 0 __________________________________________________ )0.
HN 0 15 DCM, it. HN
.õOH .00H

Zinc(II) bromide (29.2 mg, 0.130 mmol) was added to a solution of tert-butyl ((4aR, 8R, 17R,17aR,E)-8-ethy1-17-hydroxy-12-methy1-6,19-di ox o-4,4a,6,7, 8,9, 10,11, 12,16,17,17a,18,19-tetradecahydro-3H- 1,20-(epiethane[1,2] diylidene)-8,5-(epi mi nometh ano)-13,15-ethen ocy cl openta[h]pyrano [4,3 -b] [1,7] di azacycl ooctadeci n-27-ylidene)carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 ml), at 22 C under N2 atmosphere. The mixture was stirred at 22 C for 16 h. The mixture was cooled, the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ Method Column Boston Green ODS 150 x30mm, 5um Condition water(TFA)-ACN Begin B 22 End B 52 Gradient Time(min) 10 100%B Hold Time(min) FlowRate(ml/min) 25 Injections 1) to yield Example 1.
MS (ESI) in/z: 517.2 (M+H+) 1-E1 NMR (500 MHz, METHANOL-d4) 6 8.49 (d, J=9.0 Hz, 1H), 7.72 (dd, J=2.0, 8.5 Hz, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.19-7.24 (m, 1H), 7.14-7.19 (m, 1H), 6.91-6.96 (m, 2H), 5.30-5.39 (m, 2H), 4.38-4.53 (m, 2H), 4.13-4.15 (m, 1H), 3.18-3.29 (m, 1H), 2.75-2.94 (m, 3H), 2.61-2.72 (m, 2H), 2.20-2.30 (m, 1H), 1.74-1.85 (m, 3H), 1.58-1.68 (m, 2H), 1.50-1.57 (m, 1H), 1.31 (d, J=7.0 Hz, 3H), 1.24-1.29 (m, 1H), 1.11-1.20 (m, 1H), 0.97 (t, J=7.5 Hz, 3H) NH -"--`0 /".. 0 (1R,5R,16R,17R)-5-ethy1-16-hydroxy-3-imino-24-oxa-2,4,18-tri azahexacyclo [18.6.2.22,5 .211,14.013,17.023,27]doniaconta-

11,13,20,22,27,29-hexaene-19,32-dione Preparation of Compound 2-1 Boc Boc 'N 'N
HN N HN N

Pd/C, H2 Me0H, r.t.
õ,OH OH

Pd-C (2.250 mg, 4.23 umol) was added to a solution of tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethy1-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in Me0H (4 mL) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (15 psi) at 20 C for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,18R,18aR,E)-8-ethy1-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1).
MS (ESI) nilz: 617.2 (M-41+) Preparation of Example 2 BocN NH
' =
HN N HNAN

HN 0 DCM, r.t.

Zinc(II) bromide (47.5 mg, 0.211 mmol) was added to a solution of tert-butyl ((4aR, 8R,18R,18aR,E)-8-ethy1-18-hydroxy-6,20-di oxo-4,4a,7,8,9, 10,11,12,13,17, 18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in DCM (3 mL), under N2 atmosphere. The mixture was stirred at 22 C for 16 h.
The mixture was concentrated under reduced pressure to give the crude product.
The residue was purified by reverse preparative HPLC (Instrument EJ; Method Column Boston Green ODS 150 x 30mm, Sum, Condition water(TFA)-ACN Begin B 22; End B 52 Gradient Time(min) 10;
100%B Hold Time(min) 2 FlowRate(mL/min) 25; Injections 1) to give (4aR,8R,18R,18aR)-8-ethy1-18-hydroxy-28-imino-4,4a,8,9,10,11,12,13,17,18,18a,19-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecine-6,20(7H)-dione Example 2.
MS (ESI) nilz: 517.2 (MAI+) 1-E1 NMR (500 MHz, METHANOL-6) 6 7.76 (dd, J=2.0, 8.5 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.99-7.06 (m, 2H), 6.93 (d, J=8.5 Hz, 1H), 5.21 (t, J=7.5 Hz, 1H), 5.07 (d, J=5.5 Hz, 1H), 4.54-4.62 (m, 111), 4.38-4.49 (m, 1H), 4.09-4.19 (m, 1H), 3.23-3.28 (m, 1H), 2.90 (d, J=16.5 Hz, 1H), 2.79 (dd, J=6.0, 16.0 Hz, 1H), 2.62-2.74 (m, 2H), 2.50-2.61 (m, 2H), 2.20-2.34 (m, 1H), 1.81 (s, 1H), 1.62-1.76 (m, 3H), 1.49 (t, J=11.5 Hz, 1H), 1.12-1.44 (m, 6H), 0.95 (t, J=7.5 Hz, 3H) NH

(1R,5R,17S)-5-ethy1-3-imino-15,15-dimethy1-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]dotriaconta-10,12,20,22,27,29-hexaene-19,32-dione Preparation of Compound 3-2 MeONHMe=HCI, 0 EDCI, HOBt, DIEA 0 (!) N-OH DCM, r.t.

N,0-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added to a solution of pent-4-enoic acid (40 g, 400 mmol), EDC (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (3-1) (64.8 g, 479 mmol) and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL). The reaction was stirred at 25 C for 12 h under N2 atmosphere. The mixture was quenched with water (300 mL), and extracted with DCM (3 x 100 mL). The organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCOO;
220g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 50 mL/min) to afford N-methoxy-N-methylpent-4-enamide (3-2).
MS (ESI) nilz 144.1 (M+11 ) 11-1 NMR (500 MHz, CHLOROFORM-d) 6 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of Compound 3-3 EtMgBr THF

Ethylmagnesium bromide (69.8 mL, 210 mmol) was added dropwise to a solution of N-methoxy-N-methylpent-4-enamide (3-2) (20 g, 140 mmol) in THE (200 mL) under N2 atmosphere at 0 C. The reaction was stirred at 25 C for 1 h under N2 atmosphere. The mixture was quenched with saturated NH4C1 aqueous (100 mL) and water (100 mL), extracted with Et0Ac (3 x 100 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCOe; 120g Agela Silica Flash Column, eluent of 5% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford hept-6-en-3-one (3-3).
1H NMR (500 MHz, CHLOROFORM-d) 6 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J=7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J=7.0 Hz, 3H) Preparation of Compound 3-4 (R) g o H2N--N-e Ti(0E04, THF

(R)-2-methylpropane-2-sulfinamide (12.97 g, 107 mmol) was added to a solution hept-6-en-3-one (3-3) (10 g, 89 mmol) in THF (100 mL). Ti(Et0)4 (37.5 mL, 178 mmol) was also added and the reaction was stirred at 75 C for 12 h under N2 atmosphere.
The mixture was cooled to room temperature, diluted with DCM (200 mL) and stirred for 15 min.
Ice cold-saturated aqueous sodium bicarbonate solution (50 mL) and Na2SO4 was added and the mixture was filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISC08; 120g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4).
MS (ESI) nilz 216.2(M+11 ) 1H NIVIR (500 MHz, CHLOROFORM-d)6 5 73-5 88 (m, 1H), 4.94-5_10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of compound 3-5 LDA, 0 0 Ti(Oi-P03D1, \\ N---e CH3COOMe \ HNAIK--\ 2\ __ THF
HflCOOMe Butyllithium (55.7 mL, 139 mmol), at -78 C, was added dropwise to a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THE (40 mL) under N2 atmosphere.
The reaction was stirred at 0 "V for 30 min to make LDA. The resulting LDA (76 mL, 93 mmol) was dropped to a mixture at -78 C of ethyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3C1 (116 mL, 116 mmol) in anhydrous THF(90 mL). After 1 h, a solution of (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) in anhydrous THE (20 mL) was then added dropwise and the mixture was stirred at -78 C for 3h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with Et0Ac (200 mL) then filtered, rinsing with Et0Ac and water.
The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCOR; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford methyl 3-4(R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5).
MS (ESI) nilz 290.1 (M+H+) 'El NMR (500 MHz, CHLOROFORM-d) 6 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J=1.0, 10.0 Hz, 1H), 4.63 (br d, J=17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J=5.0, 16.0 Hz, 1H), 2.52 (dd, J=2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 114), 1.76-1.81 (m, 11-1), 1.71-1.75 (m, 1H), 1.26 (t, J=7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of Compound 3-6 \---\HNAK--' _______________________________ di 0 \
\ , HCI-oxane __________________________________________ I -µ Me0H * NH2 = HCI
,)\ tOOMe 00Me A solution of methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5) (9 g, 31.1 mmol) in 4N HC1-dioxane (20 mL) and Me0H (20.00 mL) at 25 C under atmosphere was stirred for 1 h. Solvent was evaporated under reduced pressure to give the crude product methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6) used crude for the next step directly.

MS (ESI) rn/z 186.2 (M+11 ) 'El NMR (500 MHz, CHLOROFORM-d) 6 5.75-5.80 (m, 1H), 5.08 (dd, J=1.0, 18.0 Hz, 1H), 4.98 (d, J=10.22 Hz, 11-1), 3.72-3.75 (m, 3H), 2.78-2.85 (m, 2H), 2.21-2.29 (m, 2H), 1.84-2.00 (m, 4H), 1.06 (t, J=7.5 Hz, 3H) Preparation of Compound 3-7 S
BocHNA N :40 Boc H 'N ----'µO
t., +ICI INT-1 *
0 o HN N

\coome EDCI, DIEA, ACN
1....00Me N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol) was added to a solution of EDC (9.08 g, 47.4 mmol), methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6) (3.5 g, 15.79 mmol) and methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6-carboxylate (INT-1) (5.78 g, 15.79 mmol) in ACN (30 mL). The reaction was stirred at 25 C for

12 h under N2 atmosphere. The mixture was quenched with water (50 mL), and extracted with Et0Ac (3 x 50 mL). The organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford methyl (4R)-4-((Z)-2-(tert-butoxycarbony1)-3-(3-ethyl-l-methoxy-l-oxohept-6-en-3-yl)guanidino)chromane-6-carboxylate (3-7) used crude for the next step directly.
MS (ESI) nilz 518.2 (M+H+) Preparation of Compound 3-8 Boc Boc 'N "'N'-(3 'N -,"=-0 II 7 ij,_ 7 DBU
/ -I.-00Me \

DBU (11.90 mL, 79 mmol) was added to a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl )-3-(3-ethyl-l-methoxy-1-oxohept-6-en-3 -yl )guani di no)chromane-6-carb oxyl ate (3-7) (8.17 g, 15.78 mmol) in THF (50 mL). The mixture was stirred at 50 C
for 16 h under N2 atmosphere. The mixture was quenched with water (50 mL), and extracted with Et0Ac (3 x 50 mL). The organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCOO; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @
40 mL/min) to afford methyl (4R)-4-((E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-8).
MS (ESI) in/z 486.2(M+1-1 ) 1H NMR (500 MHz, CHLOROFOR1VI-d) 6 7.77 (td, 12.0, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (dd, 1=2.0, 8.5 Hz, 1H), 6.33-6.42 (m, 1H), 5.76-5.90 (m, 1H), 5.00-5.14 (m, 2H), 4.42-4.49 (m, 1H), 4.22-4.23 (m, 1H), 3.81-3.86 (m, 3H), 2.70-2.81 (m, 1H), 2.51-2.60 (m, 2H), 2.03-2.16 (m, 4H), 1.75-1.84 (m, 2H), 1.65-1.73 (m, 4H), 1.52 (s, 9H), 0.98-1.04 (m, 3H) Preparation of Compounds 3-9A & 3-9B
Boc Bo 'N c'N
= =
HN N HN SFC
, N
/
TI
3-8 3-9A & 3-9B
Methyl (4R)-4-((E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-8) (4 g, 8.24 mmol) was separated by SFC (Column Boston Green ODS 150 x30mm, 5um Condition water(TFA)-ACN Begin End B 78 Gradient Time(min) 10 100%B Hold Time (min) 2 FlowRate (mL/min) 25 Injections 1) to give P1 methyl (4R)-4-((E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9A) (tR=2. 105 min, UV = 220 nm). P2 methyl (4R)-4-((E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9B) (tR=2.251 min, UV = 220 nm).
MS (ESI) rivZ 486.2 (M+11 ) 3-9A: NMR (500 MHz, CHLOROFORM-d) 37.77 (dd, J=1.5, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (d, 1=9.0 Hz, 1H), 6.37 (br dd, 1=7.0, 10.0 Hz, 1H), 5.81-5.86 (m, 1H), 5.00-5.12 (m, 2H), 4.42-4.45 (m, 2H), 4.21-4.24 (m, 1H), 3.83 (s, 3H), 2.68-2.78 (m, 1H), 2.07-2.16 (m, 3H), 1.66-1.83 (m, 5H), 1.51 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 3-9B: 11-1NMR (500 MHz, CHLOROFORM-d) 6 7.77 (br d, J=8.70 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.39 (hr dd, J=7.0, 10.0 Hz, 1H), 5.74-5.86 (m, 1H), 5.00-5.10 (m, 2H), 4.41-4.50 (m, 1H), 4.21-4.25 (m, 1H), 3.83 (s, 31-1), 2.73-2.81 (m, 1H), 2.06-2.12 (m, 3H), 1.68-1.83 (m, 5H), 1.52 (s, 9H), 0.98-1.04 (m, 3H) Preparation of Compound 3-10 Boc'N Boc HN N TMSOK HN N

Potassium trimethylsilanolate (872 mg, 6.80 mmol) was added to a solution of methyl (R)-4-((R,E)-4-(but-3-en-l-y1)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9A) (550 mg, 1.133 mmol) in TI-IF
(5 mL). The reaction was stirred at 25 C for 0.5 h. The solution of (R)-4-((R,E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-cthyl-6-oxotetrahydropyrimidin-1(2H)-y1)chromane-6-carboxylic acid (3-10) was used for next step directly without any further manipulation or purification.
MS (ESI) nilz 472.2 (M+H+).
Preparation of Compound 3-11 Boc BocN NH2 -HN N

EDCI, HOBt, 31' NH
OH DIEA, THF

DIEA (1.582 mL, 9.06 mmol) was added to a solution of (R)-44R,E)-4-(but-3-en-l-y1)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-y1)chromane-6-carboxylic acid (3-10) (534 mg, 1.132 mmol), EDC (1085 mg, 5.66 mmol), 1H-benzo[d][1,2,3]triazol-1-01 (765 mg, 5.66 mmol) and (S)-2,2-dimethy1-6-yinylchroman-4-amine (253 mg, 1.246 mmol) in THF (50 mL). The reaction was stirred at 25 C for 12 h. The mixture was quenched with water (20 mL), and extracted with Et0Ac (3 x 20 mL). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by prep-TLC (Pet. ether/Et0Ac=2:1) to afford tert-butyl ((R,E)-4-(but-3-en-1-y1)-1-((R)-6-(((S)-2,2-dimethy1-6-vinylchroman-4-yl)carbamoyl)chroman-4-y1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11).
MS (ESI) nilz 657.3 (M+H+) Preparation of Compound 3-12 Boc Boc `N `N
HN N HN N
Hoveyda 0 Grubbs 2nd 0 DCE

(1,3 -Bi s-(2,4,6-tri methyl phenyl)-2-imi dazoli di nyli dene)dichl oro(o-isopropoxyphenylmethylene)ruthenium (95 mg, 0.152 mmol) was added to a solution of tert-butyl ((R,E)-4-(but-3-en-1-y1)-14(R)-64(S)-2,2-dimethy1-6-vinylchroman-4-yl)carbamoyl)chroman-4-y1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11) (500 mg, 0.761 mmol) in DCE (500 mL). The reaction was stirred at 50 C for 5 h under N2 atmosphere. The mixture was concentrated in vacuo, and the crude was purified by flash column (Pet. ether/Et0Ac/Et0H=8:3:1) to afford tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethy1-17,17-dimethy1-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12).
MS (ESI) nilz 629.3 (M+H+) IHNMR (500 MHz, CHLOROFORM-d) 6 7.67 (dd, 1.5, 8.5 Hz, 1H), 7.36(s, 1H), 7.19(s, 1H), 7.05-7.10 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.37 (d, J=15.5 Hz, 1H), 6.09-6.22 (m, 2H), 5.92-5.93 (m, 1H), 5.40-5.42 (m, 1H), 4.49 (td, J=4.0, 11.5 Hz, 1H), 2.93-3.04 (m, 2H), 2.46-2.53 (m, 2H), 2.35-2.41 (m, 1H), 2.29 (dd, J=6.5, 13.0 Hz, 1H), 1.91-1.99 (m, 1H), 1.71-1.78 (m, 2H), 1.66-1.71 (m, 4H), 1.61-1.66 (m, 1H), 1.50-1.53 (m, 1H), 1.46-1.50 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.26 (s, 9H), 0.95 (t, J=7.48 Hz, 3H) Preparation of Compound 3-13 Boc Boc 'N 'N

HN--"N
0 Pd/C, H2 0 Jr$IçH

0 Me0H HN 0 Pd-C (50.8 mg, 0.048 mmol) was added to a solution of tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethy1-17,17-dimethy1-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12) (300 mg, 0.477 mmol) in Me0H (10 mL), under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 25 C for 0.5 h under H2 (15 psi). The catalyst was filtered off and filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethy1-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13) which was used for the next step directly.
MS (ESI) nilz 631.3(M+11) Preparation of Example 3A
Boc 'N NH
HN N HNAN
' 0 HCI-dioxane 0 A solution of tert-butyl ((4aR,8R,18aS,E)-8-ethy1-17,17-dimethy1-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13) (280 mg, 0.444 mmol) in HC1-dioxane(4N) (30 mL) was stirred at 25 C for 16 h. The solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HITE (Column Boston Green ODS 150 x 30mm, 5um Condition water (HC1)-ACN
Begin B 30 End B 50 Gradient Time (min) 10 100%B Hold Time (min) 2 FlowRate (mL/min) 25 Injections 6) to give (4aR,8R,18aS)-8-ethy1-28-imino-17,17-dimethyl-4,4a,7,8,9,10,11,12,17,18,18a,19-dodecahydro-3H,6H,20H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-6,20-dione Example 3A.
MS (ESI) nilz 531.2 (M+H+) 1-fl N1VIR (500 MHz, METHANOL-d4) 6 7.73 (dd, J=2.0, 8.5 Hz, 1H), 7.45 (s, 1f1), 7.02 (s, 1H), 6.92-6.99 (m, 2H), 6.70 (d, J=8.5 Hz, 1H), 5.37-5.44 (m, 2H), 4.44-4.47 (m, 1H), 4.12-4.17 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 2.55-2.70(m, 4H), 2.23-2.31 (m, 1H), 2.12 (dd, J=6.5, 13.0 Hz, 1H), 1.81-1.87 (m, 1H), 1.66-1.80 (m, 5H), 1.49-1.59 (m, 1H), 1.42 (s, 3H), 1.34-1.40 (m, 2H), 1.32 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) HNAN".

(1R,5R,18S)-5-ethy1-3-imino-16,16-dimethyl-10,15,25-trioxa-2,4,19-tri azahexacyclo [19.6.2.22,5.211,14.013,18.024,28]tritriaconta-11,13,21,23,28,30-hexaene-20,33-dione Preparation of Compound 4-2 MeONHMe=HCI, 0 EDCI, HOBt, DIEA 0 (bi I

DIEA (36.7 mL, 210 mmol) was added to a solution of hex-5-enoic acid (4-1) (8 g, 70.1 mmol), EDC (20.15 g, 105 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.21 g, 105 mmol) and N,0-dimethylhydroxylamine hydrochloride (7.52 g, 77 mmol) in THF (100 mL).
The reaction was stirred at 25 C for 5 h. The mixture was quenched with water (150 mL), and extracted with Et0Ac (3 x 50 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in yacuo. The crude product was purified by flash silica gel chromatography (ISCO(11); 80 g SepaFlashe Silica Flash Column, Fluent of 5%
Et0Ac/Pet.ether gradient @ 80 mL/min) to give N-methoxy-N-methylhex-5-enamide (4-2).
MS (ESI) in/z 157.7 (MAW) Preparation of compound 4-3 0 cb EtMgBr THF

Ethylmagnesium bromide (38.2 mL, 114 mmol), at 0 C, was added dropwise to a solution of N-methoxy-N-methylhex-5-enamide (4-2) (9 g, 57.2 mmol) in THE (120 mL) under N2 atmosphere. Then the mixture was stirred 20 C for 2 h. The mixture was quenched with saturated aqueous NH4C1 (25 mL). The mixture was quenched with water (150 ml) and extracted with Et0Ac (3 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered. Solvent was removed under reduced pressure to give crude product which was purified by column chromatography (SiO2, Pet.ether: Et0Ac=100:1-10:1) to afford oct-7-en-3-one (4-3).
NMR (500 MHz, CHLOROFORM-d) 6 5.76 (m, 1H), 4.93-5.04 (m, 2H), 2.38-2.44 (m, 4H), 2.05 (q, J=7.0 Hz, 2H), 1.68 (m, 2H), 1.04 (t, J=7.5 Hz, 3H).
Preparation of Compound 4-4 N--g?
\
Ti(OEt)4, THF, 2-methylpropane-2-sulfinamide (6.34 g, 52.3 mmol) was added to a solution oct-7-en-3-one (4-3) (5.5 g, 43.6 mmol) in THE (80 mL), followed by Ti(Et0)4 (18.31 ml, 87 mmol).
The reaction was stirred at 75 'V for 16 h under N2 atmosphere. The final mixture was cooled to 0 C, diluted with DCM (100 mL) and stirred for 15min. Ice cold-saturated aqueous sodium bicarbonate solution (15 mL) was added and the solution was filtered and concentrated in vacuo.
The crude was purified by flash column (SiO2, Pet. ether/Et0Ac = 100:1 to 5:1) to afford ((E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4-4).
MS (ESI) nilz 230.2 (MAW) 1H NMR (500 MHz, CHLOROFORM-d) 6 5.78-5.80 (m, 1H), 4.96-5.07 (m, 2H), 2.62-2.76 (m, 2H), 2.39-2.50 (m, 2H), 2.04-2.17 (m, 2H), 1.67-1.76 (m, 2H), 1.23 (s, 9H), 1.06-1.21 (m, 3H) Preparation of Compound 4-5 0 LiHMDS, N_e CH3COOMe HN
\ ?\THF, -78 C).' 00Me Methyl acetate (1.545 ml, 19.18 mmol) at -78 C was added to a solution of LiHMDS (22.67 ml, 22.67 mmol) in anhydrous THF (35 mL) under N2 atmosphere.
The reaction was stirred at -78 C for 15min. (E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4-4) (4 g, 17.44 mmol) in THY (15 mL) was then added dropwise and the mixture was stirred at -78 C for 3h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with Et0Ac (50 mL) then filtered, rinsing with Et0Ac and water. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (SiO2, Pet.
ether/Et0Ac=100:0 to 10:1) to afford methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5).
MS (ESI) nilz 304.3 (M+11 ).
1H NMIR (500 MHz, CHLOROFORM-d) 6 5 72-5 86 (m, 1H), 4.91-5_06 (m, 2H), 4.59-4.61 (m, 1H), 3.63-3.76 (m, 3H), 2.68-2.71 (m, 1H), 2.42-2.55 (m, 1H), 1.99-2.13 (m, 2H), 1.58-1.91 (m, 5H), 1.31-1.48 (m, 2H), 1.16-1.24 (m, 9H), 0.80-0.93 (m, 3H) Preparation of Compound 4-6 HN"gl< HCI-dioxane =HCI
Me0H
COOMe 00Me A solution of methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5) (2 g, 6.59 mmol) in HC1-dioxane (4N) (5 mL) and Me0H (5mL) at 15 C under N2 atmosphere was stirred at 15 C for 1 h. The solution was concentrated in vacuo to give the crude product methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6) which was used without any further purification.
1-E1 NMR (500 MHz, CHLOROFORM-d) 5.77 (m, 1H), 4.93-5.06 (m, 2H), 3.73 (s, 3H), 2.72-2.88 (m, 2H), 2.02-2.14 (m, 2H), 1.70-2.00 (m, 5H), 1.56 (m, 2H), 1.04 (t, J =
7.50 Hz, 3H) Preparation of compound 4-7 S -^0 /IL BocHN N 7 BOG 40 -N
=

NH2HCI = Me EDCI, DIEA, ACN pOOMe N-ethyl-N-isopropylpropan-2-amine (4.37 ml, 24.56 mmol) was added to a solution of methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6-carboxylate (INT-1) (1.5 g, 4.09 mmol), methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6) (1.448 g, 6.14 mmol) and N-(3-Dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride (2.354 g, 12.28 mmol) in acetonitrile (30 mL). The mixture was stirred at 15 'V for 10 h. The mixture was quenched with water (50 mL), and extracted with Et0Ac (3 x 40 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl (4R)-4-((Z)-2-(tert-butoxyc arb ony1)-3-(3 -ethyl-l-methoxy-l-oxooct-7-en-3-yl)guanidino)chromane-6-carboxylate (4-7) which was used crude for the next step directly.
MS (ESI) nilz 532.3 (M+11 ).
Preparation of Compound 4-8 Boc -1\1 Boc 'N

1\1 1-11\r"
DBU
_________________________________________________ )1- 0 00Me THF

DBU (2.84 mL, 18.81 mmol) was added to a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbony1)-3-(3-ethy1-1-methoxy-1-oxooct-7-en-3-y1)guanidino)chromane-6-carboxylate (4-7) (2.0 g, 3.76 mmol) in THF (20 mL). The mixture was stirred at 50 C for 10 h.
The mixture was quenched with water (40 mL), and extracted with Et0Ac (3 x 40 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCOg; 20 g Agela Silica Flash Column, eluent of 15% ethyl acetate/pet. ether gradient @ 60 mL/min) to afford methyl (4R)-4-((E)-2-((tert-butoxycarbanyl)imino)-4-ethyl -6-ox o-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-8). MS (ES!) m/z:
500.6 (M+11 ).
'El NMR (400 MHz, CHLOROFORM-d) 10.10 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 6.83 (ddõI = 0.8, 8.8 Hz, 1H), 6.31-6.46 (m, 11-1), 5.77 (m, 1H), 4.97-5.10 (m, 2H), 4.43 (dõI =
11.2 Hz, 1H), 4.17-4.29 (m, 1H), 3.82 (s, 3H), 2.68-2.86 (m, 1H), 2.47-2.59 (m, 2H), 2.06-2.18 (m, 2H), 1.56-1.81 (m, 5H), 1.51 (s, 9H), 1.45 (s, 3H), 1.40 (s, 1H) Preparation of Compounds 4-9A & 4-9B
Boc Boc Boc 'N 'N
'N

HN HN N HN N
SFC

0 0,, _____________________________________________ 0 0..
0 0._ Methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-8) (1.8 g, 3.60 mmol) was separated by SFC (Instrument SFC-22 Method Column DAICEL CHIRALPAK AD (250mm x30mm, 10um) Condition 0.1%NH3H20 IPA Begin B 10% End B 10% Gradient Time (min) 100%B
Hold Time (min) FlowRate(mL/min) 50 Injections 60) to afford product (methyl (R)-44R,E)-2-((tert-but oxycarb onyl)imino)-4-ethy1-6-oxo-4-(pent-4-en-l-y1)t etrahydropyri mi din-1(2H)-yl)chromane-6-carboxylate (4-9A) (peak 1, Rt=0.816) and (methyl (E)-4-(2-((tert-butoxycarb onyl)imino)-4-ethyl -6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimi din-1(2H)-yl)chromane-6-carboxylate (4-9B) (peak2, Rt=0.879).
MS (ESI) m/z: 500.2 (M-F11 ) Preparation of Compound 4-10 Boc Boc"-N
'N 0 11 .
11 . 0s04, Na104 HN-- -"N`s HIV¨'N`' 2,6-lutidine, ________________________________________ /
Z

iiz ,0 0 dioxane, H20 )11- ,.... 0 I

2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium (VIII) oxide (5.09 mg, 0.020 mmol) were added to a solution of methyl (R)-44R,E)-2-((tert-butoxycarbonypimino)-4-ethy1-6-oxo-4-(pent-4-en-l-y1)tetrahydropyrimidin-1(2H)-y1)chromane-6-carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The resulting solution was stirred for 0.2 h at 25 'C. Sodium periodate (171 mg, 0.801 mmol) was added and the resulting solution was stirred for 2 h at 25 C. The mixture was quenched with Sat.
Na2S03 (10 mL) and water (5 mL), and extracted with Et0Ac (3 x 10 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxo-4-(4-oxobutyl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-10) which was used crude for the next step directly.
MS (E SI) nilz: 502.3 (M-FH+) Preparation of compound 4-11 Boc`N 0 Boc`N 0 Ii HN¨N`s.
HN-- ¨N`s NaBH4 I Me0H, 0 00 C

I
H

Nal3H4 (10.75 mg, 0.284 mmol) was added in portions to a solution of methyl (R)-4-((R, E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxo-4-(4-oxobutyl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-10) (95 mg, 0.189 mmol) in Me0H (2mL) at 0 C. The mixture was stirred at 0 C for 1 h. LCMS showed major desired product mass.
The mixture was quenched with water (5 mL), and extracted with Et0Ac (4 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuum, the crude was purified by prep-TLC (Pet. ether/Et0Ac=3:1) to afford methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-11).
MS (ESI) nilz: 504.4 (M-P1-1) 11-1 NMR (400 MHz, CHLOROFORM-d) 10.14 (s, 1H), 7.76 (dd, J= 2.0, 8.4 Hz, 1H), 7.65 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 7.2, 10.0 Hz, 1H), 4.43-4.46 (m, 1H), 4.22-4.26 (m, 1H), 3.84 (s, 3H), 3.68 (t, J= 6.4 Hz, 2H), 2.69-2.78 (m, 1H), 2.51-2.62 (m, 2H), 1.95-2.24 (m, 2H), 1.64-1.69 (m, 6H), 1.52 (s, 9H), 1.43-1.49 (m, 2H), 0.97 (t, J= 7.6 Hz, 3H) Preparation of Compound 4-12 Boc`N Boc`N 0 0 HN N"' HN N"
TMSOK
THF, r.t.

HO

Potassium trimethylsilanolate (81 mg, 0.631 mmol) was added to a solution of methyl (R)-4-0R,E)-2-((tert-butoxycarbonypimino)-4-ethyl-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-1(2H)-y1)chromane-6-carboxylate (4-11) (53 mg, 0.105 mmol) in THE' (1 mL). The reaction was stirred at 25 C for 0.5 h. LCMS showed major desired product mass.
The solution of (R)-4-((R, E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylic acid (4-12) was used in the next step without any further manipulation or purification.
MS (ESI) nilz: 490.2 (M-E11+) Preparation of Compound 4-13 Boc`N
Boc'N 0 Br ail HN N"
WI 0/IdJ
HN
" 0"
EDCI, HOBt, HO 0 DIEA, THF
Br HN 0 HO

DIEA (0.143 mL, 0.817 mmol) was added to a solution of (R)-44(R,E)-2-((tert-butoxycarbonyl)imino)-4-ethy1-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylic acid (4-12) (50 mg, 0.102 mmol), EDC (98 mg, 0.511 mmol), 1H-benzo[d][1,2,3]triazol-1-01 (69.0 mg, 0.511 mmol) and (S)-6-bromo-2,2-dimethylchroman-4-amine (28.8 mg, 0.112 mmol) in THE (5 mL). The reaction was stirred at 25 C
for 3 h. The mixture was quenched with water (5 mL), and extracted with Et0Ac (3 x 5 mL).
The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, the crude was purified by prep-TLC (Pet. ether/Et0Ac=3:1) to afford tert-butyl ((R,E)-1-((R)-6-(((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-y1)-4-ethyl-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13).
MS (ESI) rrilz: 727.2, 729.2 (M-41 ) Preparation of Compound 4-14 BocN Boc'N
JL, HN N". HN IV*
/II- 0 t-BuXphos G3, Cs2CO3 /I". 0 BrJ)ç dioxane, 70 C 0 In a glove box, [(2-Di-tert-butylphosphino-2',4',6'-triisopropy1-1,1'-bipheny1)-2-(2'-amino-1,11-bipheny1)] palladium(II) methanesulfonate (7.64 mg, 9.62 umol) and CsCO3 (37.1 mg, 0.192 mmol) was added to a mixture of tert-butyl ((R,E)-14(R)-6-(((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-y1)-4-ethyl-4-(4-hydroxybuty1)-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13) (70 mg, 0.096 mmol) in dioxane (3 mL). The mixture was stirred at 70 C for 3 h. The mixture was diluted with water (10 mL) and extracted with Et0Ac (3 x 10 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude was purified by prep-TLC (Pet.
ether/Et0Ac=2:1) to afford tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl -18,18-di m ethyl -6,21-di ox o-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-]][1]oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14).
MS (ESI) nilz: 647.3 (M-E11) NMIR (500 MHz, CHLOROFORM-d) 6 7.81 (dd, J= 2.0, 8.5 Hz, 1H), 7.01 (s, 1H), 6.93 (d, J
= 8.5 Hz, 1H), 6.88 (d, J= 1.0 Hz, 1H), 6.78 (s, 2H), 6.40 (dd, J= 7.0, 10.0Hz, 1H), 6.13 (d, J=
8.50 Hz, 1H), 5.37-5.44 (m, 1H), 4.44 (td, J= 3.5, 11.5 Hz, 1H), 4.17-4.23 (m, 2H), 3.82 (dt, J=
5.0, 9.5 Hz, 1H), 2.71-2.79 (m, 2H), 2.53 (d, J = 16.0 Hz, 1H), 2.35 (dd, J =
6.5, 13.0 Hz, 1H), 2.07-2.14 (m, 2H), 1.78 (dd, J= 7.50, 10.50 Hz, 4H), 1.52 (s, 2H), 1.49 (s, 9H), 1.42(s, 3H), 1.37 (s, 3H), 0.95 (t, J= 7.5 Hz, 3H) Preparation of Example 4 Boo, NH 0 HN N". HNAN".
rt-A0 ZoBr2 0 DC M, r.t 0 Zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14) (30 mg, 0.046 mmol) in DCM (3 mL) at 25 C were added to a solution of tert-butyl ((4aR,5R,8R,19aS,E)-8-ethy1-18,18-dimethy1-6,21-dioxo-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-]][1], under N2 atmosphere.
The mixture was stirred at 25 C for 16 h. The solvent was evaporated under reduced pressure to give the crude product and the residue was purified by reverse preparative HPLC
(Instrument e.g., Method Column Welch Xtimate C18 150 x 25mm, Sum; Condition water(TFA)-ACN
Begin B
25; End B 55 Gradient Time(min) 11; 100%B Hold Time(min) 2 FlowRate(mL/min) 25;
Injections 1) to give (4aR,5R,8R,19aS)-8-ethy1-29-imino-18,18-dimethyl-4,4a,7,8,9,10,11,12,18,19,19a,20-dodecahydro-3H,6H,21H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,121diazacyclononadecine-6,21-dione Example 4.
MS (ESI) nilz: 547.2 (M-Ell+) 1H NMR (500 MHz, METHANOL-d4) 6 8.55 (d, = 8.5 Hz, 1H), 7.73 (dd, .1 = 2.0, 8.5 Hz, 1H), 7.45 (d, J= 1.5 Hz, 1H), 6.94 (d, J= 8.50 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 6.76-6.82 (m, 1H), 6.70 (d, J= 9.0 Hz, 1H), 5.35-5.40 (m, 1H), 5.24-5.32 (m, 1H), 4.47 (td, J= 4.5, 11.50 Hz, 1H), 4.13-4.21 (m, 2H), 3.90-3.92 (m, 1H), 2.75-2.88 (m, 2H), 2.60-2.72 (m, 1H), 2.22-2.31 (m, 1H), 2.15 (dd, J= 6.5, 13.0 Hz, 1H), 1.66-1.85 (m, 7H), 1.47-1.60 (m, 2H), 1.40 (s, 3H), 1.33 (s, 3H), 0.97 (t, J= 7.5 Hz, 3H) NH rc HNANµ'µ
NH
(1 1R, 1 4R,14aR,21aS)-11-ethy1-16,16-di fluoro-24-imi n o-2,2-dim ethyl-1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-13,20(14aH)-dione Preparation of Compound 5-2 SH

Ts0H c\S
Toluene, Br Br 130 C, 16 h A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol), ethane-1,2-dithiol (5-1) (26.6 mL, 317 mmol) and 4-methylbenzenesulfonic acid (8.16 g, 47.4 mmol) in toluene (500 mL) was heated to 130 C for 16 h using a Dean-Stark apparatus.
TLC showed the reaction was complete. The cooled solution was washed with 10% NaOH (600 mL), and the aqueous layer extracted with DCM (3 x600 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO ; 330 g SepaFlash Silica Flash Column, Eluent of 10%
Et0Ac/Pet.ether gradient @ 60 mL/min) to give 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane] (5-2).
MS (ESI) in/z 286.9, 288.9 (M+H) NMR (500 MHz, CHLOROFORM-d) 6 7.40-7.44 (m, 1H), 7.31-7.38 (m, 2H), 3.50-3.56 (m, 2H), 3.40-3.47 (m, 2H), 2.96 (t, J= 6.5 Hz, 2H), 2.69 (t, J = 6.5 Hz, 2H) Preparation of Compound 5-3 C\S HF-Py, H (4 eq) Br F
DMDB
DCM, Br -70 C - RT Br 3 h A solution of 1,3-dibromo-5,5-dimethylhydantoin (194 g, 679 mmol) in anhydrous CH2C12 (700 mL) was cooled to -70 C in a dry ice-acetone bath.
Pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise at a temperature below -65 C under N2, and the mixture stirred at -70 C for 30 min. A solution of 5-bromo-2,3-dihydrospiro[indene-1,2'41,3]dithiolane] (5-2) (65 g, 226 mmol) in CH2C12 (200 mL) was added dropwise and the mixture was stirred at -70 C for 4 h, and then at 25 C overnight. TLC showed the reaction was complete. The mixture was poured into NaOH (2 M, 300 mL) containing 39% NaHS03 (600 mL) solution. The aqueous layer was extracted with CH2C12 (2Y600 mL) and the combined organic layer washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO(g); 220 g SepaFlash Silica Flash Column, Eluent of 100%
Pet.ether gradient @ 60 mL/min) to give 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3).
No LCMS signal.
NMR (500 MHz, CHLOROFORM-d) 6 7.52-7.58 (m, 1H), 7.47 (d, J= 6.5 Hz, 2H), 4.57 (tt, = 7.0, 10.5 Hz, 1H), 3.57 (ddd, J = 2.0, 7.5, 16.5 Hz, 1H), 3.27 (dd, J = 7.0, 16.5 Hz, 1H) Preparation of Compound 5-4 Br DBU
DCM, RT
Br Br To a solution of 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3) (60 g, mmol) in DCM (600 mL) was added DBU (43.5 mL, 289 mmol). The mixture was stirred at 25 C for 16 h. LCMS showed desired product mass. Water (600 mL) was added, the mixture was acidified with con.HC1 to pH=7. Filtered the mixture with diatomite, and the aqueous layer was extracted with CH2C12 (2><600 mL) and the combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO ; 330 g SepaFlash Silica Flash Column, Eluent of 100% Pet.ether gradient @ 50 mL/min) to give 5-bromo-1,1-difluoro-1H-indene (5-4).
No LCMS signal.
III NMR (500 MHz, CHLOROFORM-d) 6 7.41 (dd, J= 1.5, 8.0 Hz, 1H), 7.29-7.35 (m, 2H), 6.75 (d, J= 6.0 Hz, 1H), 6.22 (d, J 6.0 Hz, 1H) Preparation of Compound 5-5 F F
F F
HO
Mn(TMHD)3, PhSiH3' _______________________________________________ )1.
i-PrOH, 02, Br Br Br 5-4 5-5 5-5a To a solution of 5-bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mmol) in iPrOH (250 mL) which was bubble with 02 for 1 h, was added PHENYLSILANE (14.05 g, 130 mmol) and Mn(TM_HD)3 (3.93 g, 6.49 mmol) and stirred at 0 C for 2 h under 02(15 psi). TLC
showed the reaction was complete. The mixture was quenched with water (300 mL), and extracted with Et0Ac (3 x 300 mL). The organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (TSCO ; 40 g SepaFlash Silica Flash Column, Eluent of 17% Et0Ac/Pet.ether gradient @ 50 mL/min) to give a mixture of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (5-5a); (5-5: 5-5a =7:2).
IH NAIR (500 MHz, CHLOROFORM-d) 6 7.68 (s, 1H), 7.59-7.62 (m, 1H), 7.43-7.46 (m, 1H), 5.31 (q, J= 6.0 Hz, 1H), 3.01-3.12(m, 1H), 2.49 (dq, J= 5.0, 14.5 Hz, 1H) Preparation of Compound 5-6 F F F F F F F
F
HO Pd(dppOf)C12, HO
TEA, C
_______________________________________________ >
Br Me0H, Br DMSO, 80 C 00Me 00Me 5-5 5-5a 5-6 5-6a To a solution of mix of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (11.56 g, 47.3 mmol) (5-5: 5-5a =7:2) in Me0H

(150 mL) and DMSO (15 mL) was added [1,1'-Bis(diphenylphospino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) under Ar atmosphere at 20 C and the mixture was stirred at 80 C for 48 h under CO atmosphere (3.5 mbar). TLC showed the reaction was complete. After cooled, filtered the mixture with diatomite, and the mixture was diluted with H20 (200 mL), extracted with Et0Ac (3x200 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO(L); 120 g SepaFlash Silica Flash Column, Eluent of 17%
Et0Ac /
Pet. ether gradient @ 80 mL/min) to give a mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6) and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a); (5-6: 5-6a =3:1).
NMR (500 MHz, chloroform-d) 5 8.21 (s, 1H), 8.14 (d, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 5.37 (quin, J= 6.0 Hz, 1H), 3.96 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, .1= 5.0, 14.5 Hz, 1H) Preparation of Compound 5-7_P1 F F F F F F F F
HO SFC
HO H = 11. HO's' 00Me COOMe 00Me 00Me 5-6 5-6a 5-7 5-7_P2 The mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (8.3 g, 36.36 mmol) (5-6: 27-6a = 3:1) was separated by SFC (Column: Chiralpak AD-3 150 x 4.6mm ID., 3um, Mobile phase: A:CO2 B:iso-propanol (0.05% DEA), Gradient: from 5% to 40% of B
in 5 min and from 40% to 5% of B in 0.5 min, then hold at 5% of B for 1.5 min, Flow rate:
2.5mL/min, Column temp.: 35 C) to afford product methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7 Pl, desired) (peakl, Rt=2.577), methyl (R)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P2) (peak2, Rt=2.944) and a mixture of (5-7_132 and 5-6a) (2 g, 8.77 mmol). The mixture of (5-7_P2 and 5-6a) was separated by SFC
(Column: Cellulose 2 150 x 4.6mm ID., Sum, Mobile phase: A: CO2 B:Me0H (0.05%
DEA) Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, then hold 5% of B for 1.5 min, Column temp.: 35 C) to give methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a).

(5-7P1): 1H NMR (500 MHz, chloroform-d) 6 8.21 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 7.65 (d, J
= 8.0 Hz, 1H), 5.37 (q, J= 6.0 Hz, 1H), 3.96 (s, 3H), 3.06-3.17 (m, 1H), 2.54 (dq, J= 5.0, 14.5 Hz, 1H) (5-7_P2): NMR (500 MHz, chloroform-d) .3 8.20 (s, 1H), 8.13 (d, J=
8.0 Hz, 1H), 7.64 (d, J
= 8.0 Hz, 1H), 5.36 (q, J= 5.5 Hz, 1H), 3.95 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J= 5.0, 14.5 Hz, 1H) (5-6a): 1H NMR (500 MHz, chloroform-d) 6 8.05 (d, J= 8.0 Hz, 1H), 7.98 (s, 1H), 7.64 (d, J=
8.0 Hz, 1H), 4.53-4.68 (m, 1H), 3.95 (s, 3H), 3.40 (dd, J= 7.0, 16.0 Hz, 1H), 2.95 (dd, J= 5.0, 16.5 Hz, 1H) Preparation of Compound 5-8 Boc-N
HN NH
Boc'N F F

HN N".
ET
DIAD, PPh3 /"" 0 THF, RT 0 00Me 5-7_Pl 5-8 To a solution of methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7 _Pi) (585 mg, 2.56 mmol), tert-butyl (R,E)-(4-(but-3-en-1-y1)-4-ethy1-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT-2) (757 mg, 2.56 mmol) and Ph3P (1009 mg, 3.85 mmol) in TIFF (10 mL) was added DIAD (0.997 mL, 5.13 mmol) dropwise at 0 C
under N2 atmosphere, then the mixture was stirred at 18 C for 2 h. TLC showed no SM. The mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (ISCO ; 20 g SepaFlash Silica Flash Column, Eluent of 20%
Et0Ac/Pet.ether gradient @ 60 mL/min) to afford crude product. The crude product was re-purified by flash silica gel chromatography (ISC04); 20 g SepaFlash4) Silica Flash Column, Eluent of DCM gradient @
60 mL/min) to afford product methyl (R)-3-4R,E)-4-(but-3-en-l-y1)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-y1)-1,1-difluoro-2,3-dihydro-IH-indene-5-carboxylate (5-8).
MS (ESI) 111/Z 506.2 (M+H)+
1H NMR (400 MHz, chloroform-d) 6 10.08 (br s, 1H), 8.07 (d, J= 8.0 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 6.74 (q, J= 7.2 Hz, 1H), 5.80-5.87 (m, 1H), 4.95-5.21 (m, 2H), 4.05-4.19 (m, 1H), 3.91 (s, 3H), 2.92-3.14 (m, 2H), 2.58 (s, 2H), 2.07-2.19 (m, 2H), 1.63-1.78 (m, 4H), 1.52 (s, 9H), 0.97 (t, J= 7.6 Hz, 3H) Preparation of Compound 5-9 F F
F F
Boc`N Boc`N
HN N" TMSOK
THF, RTIP / 0 \
\ \

To a solution of methyl (R)-3-((R,E)-4-(but-3-en-1-y1)-2-((tert-b utoxy carb onyl)imino)-4-ethy1-6-oxotetrahy dropyrimi din-1(2H)-y1)-1,1-difluoro-2,3-dihy dro-1H-indene-5-carboxylate (5-8) (900 mg, 1.780 mmol) in THF (9 mL) was added potassium trimethylsilanolate (1370 mg, 10.68 mmol). The reaction was stirred at 18 C
for 0.5 h. LCMS
showed desired mass. Added H3PO4 (0.1 g/mL in H20) to adjust pH to about 6-7, and the mixture was quenched with water (10 mL), and extracted with Et0Ac (3 x 10 mL).
The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the product (R)-3-((R,E)-4-(but-3-en-1-y1)-2-((tert-butoxycarbonyl)imino)-4-ethy1-6-oxotetrahydropyrimidin-1(2H)-y1)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9).
MS (ESI) in/z 492.1 (M+H) 1H NIVIR (400 MHz, chloroform-d) 6 10.08 (br s, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J= 8.0 Hz, 1H), 6.72-6.77 (m, 1H), 5.80-5.89 (m, 1H), 4.99-5.16 (m, 2H), 2.98-3.14 (m, 2H), 2.59 (s, 2H), 2.11-2.13 (m, 2H), 1.64-1.83 (m, 4H), 1.53 (s, 9H), 0.98 (t, J= 7.6 Hz, 3H) Preparation of Compound 5-10 F
F Boc'N F
F
Boc`N NH2 Nr=
HN N"
OH EDCI, HOBt, DIEA, THF
I
\ /

To a solution of (R)-3-((R,E)-4-(but-3-en-l-y1)-2-((tert-butoxycarbonyl)imino)-ethy1-6-oxotetrahydropyrimidin-1(2H)-y1)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9) (0.87 g, 1.770 mmol), EDC (1.697 g, 8.85 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.718 g, 5.31 mmol) in THF (15 mL) was added DIEA (2.473 mL, 14.16 mmol) and (S)-2,2-dimethy1-6-vinylchroman-4-amine (0.396 g, 1.947 mmol). The reaction was stirred at 18 C
for 12 h. LCMS
showed desired mass. The mixture was quenched with water (15 mL), and extracted with Et0Ac (3 x 15 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO*; 12 g SepaFlash''' Silica Flash Column, Eluent of 17% Et0Ac/Pet.ether gradient @ 60 mL/min) to afford product tert-butyl ((R,E)-4-(but-3-en-l-y1)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbam oy1)-3 ,3 -di fluoro-2,3-di hydro-1H-i nden -1 -y1)-4-ethyl -6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10).
MS (ESI) nilz 677.4 (M+H)+
1H NMR (400 MHz, CHLOROFORM-d) 6 10.08 (br s, 1H), 7.72-7.78 (m, 1H), 7.61-7.69 (m, 2H), 7.28-7.34 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.76-6.77 (m, 1H), 6.58-6.62 (m, 1H), 6.22 (br d, J= 8.8 Hz, 1H), 5.72-5.77 (m, 1H), 5.46-5.61 (m, 2H), 5.11 (d, J= 11.2 Hz, 1H), 5.06-5.08 (m, 1H), 4.97-5.00 (m, 1H), 2.96-3.14 (m, 2H), 2.58 (s, 2H), 2.29-2.34 (m, 1H), 2.10 (br d, J=
6.0 Hz, 2H), 1.71-1.81 (m, 1H), 1.63-1.74 (m, 4H), 1.52 (s, 9H), 1.46 (s, 3H), 1.38 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H).
Preparation of Compound 5-11 Boc`N Boc`N Boc`N
NH HG-Il 0 0 NH
NH
DOE, 50 C
5-10 5-11 5-11a To a solution of tert-butyl ((R,E)-4-(but-3-en-1-y1)-1-((R)-6-(((S)-2,2-dimethy1-6-vi nyl chrom an-4-yl)carbam oy1)-3 ,3 -di fluoro-2,3 -di hydro-1H-i nden -1 -y1)-4-ethyl -6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10) (1 g, 1.478 mmol) in DCE
(500 mL) was added Dichloro[1,3-bis(2,6-isopropylpheny1)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol). The reaction was stirred at 50 C for 4 h with N2. LCMS showed desired mass. The mixture was concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCW; 12 g SepaFlash Silica Flash Column, Eluent of 15% Et0Ac/Petether gradient @ 60 mL/min) to afford tert-butyl ((7Z,11R,14R,14aR,21a S,24E)-11-ethy1-16,16-difluoro-2,2-dimethy1-13,20-di oxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:
17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11a, cis olefin; minor product) and tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethy1-16,16-difluoro-2,2-dimethy1-13,20-di oxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11, trans olefin; major product).
(5-11a, cis olefin): MS (ESI)in/z 649.3 (M-41)+
1H NMR (400 MHz, CHLOROFORM-d) 6 10.12 (s, 1H), 8.06 (d, J= 7.6 Hz, 1H), 7.73 (d, 1=
8.0 Hz, 1H), 7.17 (s, 1H), 6.99-7.01 (m, 1H), 6.84 (d, J= 8.4 Hz, 1H), 6.64-6.76 (m, 1H), 6.39 (d, J= 11.2 Hz, 1H), 6.28 (br d, J= 8.8 Hz, 1H), 5.58-5.61 (m, 1H), 5.41-5.45 (m, 1H), 3.01-3.13 (m, 2H), 2.66 (d, J= 16.4 Hz, 1H), 2.42-2.45 (m, 2H), 2.20-2.30 (m, 1H), 1.96-2.04(m, 1H), 1.63-1.86 (m, 5H), 1.51 (s, 9H), 1.46 (s, 3H), 1.39 (s, 3H), 1.02 (t, J=
7.2 Hz, 3H) (5-11, trans olefin): MS (ES!) in/z 649.3 (M+H) 1H NMR (400 MHz, CHLOROFORM-d) 6 10.15 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.70 (d, 1=
8.0 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.06 (dd, 1= 2.0, 8.4 Hz, 1H), 6.73 (d, J= 8.4 Hz, 1H), 6.61-6.70 (m, 1H), 6.39 (d, 1= 15.6 Hz, 1H), 6.06 (d, 1= 9.2 H7, 1H), 5.68-5.89 (m, 1H), 5.47-5.50 (m, 1H), 2.95-3.14 (m, 2H), 2.68 (d, J= 16.4 Hz, 1H), 2.55 (d, J = 16.4 Hz, 1H), 2.32-2.35 (m, 3H), 1.85-1.97 (m, 1H), 1.64-1.76 (m, 4H), 1.47 (s, 3H), 1.41 (s, 9H), 1.40 (br s, 3H), 0.97 (t, 1= 7.6 Hz, 3H) Preparation of Compound 5-12 Boc'N Boc'N Boc'N
HN
HN N"
Pd/C, H2 NH NH
NH
Me0H
5-11 5-11a 5-12 To a solution of tert-butyl ((7E, 11R,14R,14aR,21aS,24E)-11-ethy1-16,16-difluoro-2,2-dimethy1-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11) (780 mg, 1.202 mmol) in Me0H (10 mL) was added 10%Pd-C (128 mg, 0.120 mmol) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 18 C for 10 min under H2 (15 psi) atmosphere.
LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl ((11R,14R,14aR,21aS,E)-11-ethy1-16,16-di fluoro-2,2-di m ethyl - 13,20-di oxo-1,2,8,9,10, 11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14 -(epiminomethano)-4, 6:17,19-di ethenocyclopenta[b]pyrano[4,3 -h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-12), which was used as is directly in next step.
MS (ESI) nilz 651.4 (M+H)+
Preparation of Example 5 Boc NH
H NI`s=
HN N`s=
HCI-dioxane NH NH

A solution of tert-butyl ((11R,14R,14aR,21aS,E)-11-ethy1-16,16-difluoro-2,2-dimethy1-13,20-dioxo-1,2,8,9, 10,11,12,13, 14a,15,16,20,21,21 a-tetradecahydro-7H-11,14-(epi mi nometh ano)-4,6 :17,19-di ethenocycl openta[b]pyrano[4,3-h ] [1, 7] di azacycl ooctadeci n-24-ylidene)carbamate (5-12) (700 mg, 1.076 mmol) in HC1-dioxane (4N) (10 mL) was stirred at 18 C for 12 h. LCMS showed the reaction was complete. Solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC
(Instrument 3-101(EK) Method Phase separation Column Boston Uni C18 150 x 40mm, 5um Condition water (0.04%HC1)-ACN Begin B 33 End B 63 Gradient Time(min) 10 100%B
Hold Time 2 Flow Rate(mL/min) 60 Injections 2) to afford (11R,14R,14aR,21aS)-11-ethy1-16,16-difluoro-24-imino-2,2-dimethyl- 1,2,7,8,9,10,11,12, 15,16,21,21a-dodecahydro-13H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-

13,20(14aH)-dione Example 5.
MS (ESI) nilz 551.3 (M+H) 1-H NAIR (400 MHz, METHANOL-d4) 6 7.98 (d, J= 8.0 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.62 (s, 1H), 7.03 (s, 1H), 6.97-7.00 (m, 1H), 6.70 (d, J= 8.0 Hz, 1H), 5.72 (hr d, J= 6.4 Hz, 1H), 5.42 (dd, J= 6.4, 11.6 Hz, 1H), 3.22-3.31 (m, 1H), 2.95-3.15 (m, 2H), 2.46-2.63 (m, 3H), 2.14-2.17 (m, 1H), 1.73-1.91 (m, 5H), 1.55-1.72 (m, 2H), 1.39-1.51 (m, 5H), 1.33 (s, 3H), 0.98 (t, J=
7.2 Hz, 3H) The compounds in Table 1 were prepared in an analogous fashion to that described for Example 1 and/or Example 5. The isomers were separated by preparative HPLC
or/and preparative chiral SFC.
An asterisk (*) may be used in a chemical structure drawing that indicates the location of a chiral center.

Example Structure MS Observed Chemical Name (1R,5S,17S)-5-ethy1-3-imino-N H
15,15-dimethyl-

14,24-dioxa-HN N
=2,4,18-3B 531.2 triazahexacyclo[18 HN 0 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,9E,16R,17 R)-5-ethy1-16-NH hydroxy-3-imino-HN A N 24-oxa-2,4,18-/".' 0 triazahexacyclo[18 5a 515.3 .6.2.22,5.211,14.0 13,17.023,27]dotri aconta-9,11,13,20,22,27,2 9-heptaene-19,32-dione (1R,5R,9Z,16R,17 R)-5-ethy1-16-NH hydroxy-3-i mi no-H N N
24-oxa-2,4,18-/"L ....,___.L0 triazahexacyclo[18 HN
6 515.2 .6.2.22,5.211,14.0 13,17.023,27]dotri õOH
aconta-9,11,13,20,22,27,2 9-heptaene-19,32-dione (1R,5R,9E,18S)-5-ethy1-3-imino-NH
16,16-dimethyl-HNAN

15,25-di oxa-2,4,19-/" 0 triazahexacyclo[19 7 543.3 HN
.6.2.22,5.211,14.0 13,18 .024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33-di on e (1R,5R,18S)-5-ethy1-3-imino-NH 16,16-dimethyl-HNNL 15,25-dioxa-2,4,19-8 545.3 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18 .024,28]tritri LJLJç
aconta-11,13,21,23,28,30-hexaene-20,33 -dione (1R,5S,18S)-5-ethy1-3-imi no-NH

16,16-dimethyl-HN
15,25-dioxa-2,4,19-triazahexacyclo[19 9 545.3 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33 -dione (1R,5R,9Z,19S)-5-ethy1-3-imino-

17,17-dimethyl-NH
16,26-dioxa-HN -2,4,20-"" 0 triazahexacyclo[20 557.3 .6.2.22,5.212,15.0 NH
14,19.025,29]tetrat riaconta-9,12,14,22(30),23, 25(29),31-heptaene-21,34-dione (1R,5R,9E,20S)-5-ethy1-3-imino-

18,18-dimethyl-NH
HN,11-,N 17,27-dioxa-2,4,21-triazahexacyclo[21 11 557.3 .6.2.22,5.112,16.0 15,20.026,30]tetrat riaconta-9,12(32),13,15,23, 25,30-heptaene-22,34-dione (1R,5R,19S)-5-ethy1-3-imino-NH
17,17-dimethyl-HN.A.N
16,26-dioxa-2,4,20-" " 0 triazahexacyclo[20 12 559.3 .6.2.22,5.212,15.0 14,19.025,29]tetrat riaconta-12,14,22(30),23,2 5(29),31-hexaene-21,34-dione (1R,5S,20S)-5-ethy1-3-imi no-18,18-dimethyl-N H
HN)1,N -17,27-dioxa-17.
2,4,21-triazahexacyclo[21 HN 559.3 .6.2.22,5.112,16.0 15,20.026,30]tetrat riaconta-12(32),13,15,23,2 5,30-hexaene-22,34-dione (1R,5R,20S)-5-ethy1-3-i mi no-18,18-dimethyl-N H
HN
17,27-dioxa-2,4,21-" 0 triazahexacyclo[21 14 559.3 .6.2.22,5.112,16.0 15,20.026,30]tetrat riaconta-12(32),13,15,23,2 5,30-hexaene-22,34-di one (1R,16R,17R,26R) -5-ethy1-16-hydroxy-3-imino-NH '= 0 (methoxymethy1)-HN.-2.c`s.
24-oxa-2,4,18-15A 561.2 triazahexacyclo[18 .6.2.22,5.211,14.0 OH
13,17.023,27]dotri aconta-11,13,20,22,27,29-hexaene-19,32-dione (1R,16R,17R,26R) -5-ethyl-16-hydroxy-3-imino-1, 26-NH "O
(methoxymethyl)-HNN`s.
24-oxa-2,4,18-15B 0 561.2 triazahexacyclo[18 .6.2.22,5.211,14.0 OH
13,17.023,27]dotri aconta-11,13,20,22,27,29-hexaene-19,32-dione (1R,18S,27R)-5-ethy1-3-imino-27-CY" (methoxymethyl)-1 16,16-dimethyl-NH
15,25-dioxa-2,4,19-16A 0 589.3 triazahexacyclo[19 HN 0 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33 -dione rae-(1R,18S,27R)-5-ethy1-3-imino-(methoxymethyl)-NH 16,16-dimethyl-HNN's.
15,25-dioxa-16B 0 589.3 2,4,19-triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri 0 aconta-11,13,21,23,28,30-hexaene-20,33 -dione rac-(12R,13R,22S)-8-ethy1-10-imino-1, (methoxymethy1)-NH 0 24,24-dimethyl-15,25-dioxa-0 601.3 9,11,21-* "HO

triazaheptacyclo[2 0.6.2.28,11.216,19 .02,4.012,17.026,3 0]tetratriaconta-1(29),16(32),17,19 (31),26(30),27-hexaene-20,33-dione rac-(1R,5R,9E,18S)-5-ethy1-3-imino-H NN"=
15,25-dioxa-2,4,19-triazahexacyclo[19 18 515.2 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33-dione rac-(1R,5R,18S)-5-ethy1-3-imino-NH
15,25-dioxa-HNAN".
2,4,19-/II "
triazahexacyclo[19

19 517.2 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33 -dione rac-(1R,8E,17S)-5-ethy1-3-imino-NH
15,15-dim ethyl -14,24-dioxa-LJHN N
2,4,18-triazahexacyclo[18

20 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione rac-(8R,12R,22S)-8-ethyl- 1 0-imino-15,25-di oxa-NH
HNAN".
9,11,21-

21 triazaheptacyclo[2 /" " 0 0.6.2.28,11.216,19 529.2 * HN 0 .02,4.012,17.026,3 O]tetratriaconta-1(29),16(32),17,19 (31),26(30),27-hexaene-20,33-di on e rac-(1R,5R,19S)-5-ethy1-3-imino-N H
17,17-dimethyl-HN N
16,26-dioxa-2,4,20-/I'1._..0 triazahexacyclo[20

22 545.2 H N 0 .6.2.22,5.111,15.0 14,19.025,29]tritri aconta-11(31),12,14,22,2 4,29-hexaene-21,33-dione rac-(1R,11Z,21S)-5-ethy1-3-imino-N H
19,19-dimethyl-HN N
18,28-dioxa-2,4,22-0 triazahexacyclo[22

23 571.3 H N 0 .6.2.22,5.113,17.0 16,21.027,31Thent atriaconta-11,13(33),14,16,2 4,26,31-heptaene-23,35-dione rac-(1R,21S)-5-ethy1-3-imino-N H
19,19-dimethyl-H N* N
18,28-dioxa-2,4,22-0 triazahexacyc1o[22 24A 573.3 H N .6.2.22,5.113,17.0 16,21.027,31]pent atriaconta-13(33),14,16,24,2 6,31-hexaene-23,35-dione rac-(1R,21S)-5-ethy1-3-imino-N H
19,19-dimethyl-A -H N* N 18,28-dioxa-2,4,22-triazahexacyclo[22 24B 573.3 .6.2.22,5.113,17.0 16,21.027,31Thent atriaconta-13(33),14,16,24,2 6,31-hexaene-23,35-dione rac-(1R,18S,27R)-3-i mino-27-(methoxymethyl)-5,16,16-trim ethyl-N H
15,25-dioxa-H N`'.
2,4,19-25A 0 575.4 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33 -dione rac-(1R,18S,27R)-3 -imino-27-(methoxymethyl)-5,16,16-trim ethyl-15,25-dioxa-2,4,19-25B 0 575.3 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33 -dione rac-(1R,9E,185,27R)-5-ethy1-3 -imino-(methoxymethy1)-NH
16,16-dimethyl-HKjc". 15,25-dioxa-26A 0 587.5 2,4,19-triazahexacyclo[19 .6.2.22,5.211,14.0 LJJcç 13,18.024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33-dione rac-(1R,9E,18S,27R)-5-ethy1-3-imino-(methoxymethy1)-NH -=
15,25-dioxa-26B 0 587.3 2,4,19-HN a triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33-dione (1R,5R,8E,15S)-5-ethy1-3-imino-15-NH
HN N`s= methy1-22-oxa-2,4,16-""0 triazapentacyclo[l 28 473.2 6.6.2.22,5.110,14.
/
021,25]nonacosa-8,10,12,14(27),18, 20,25-heptaene-17,29-dione (1R,5R,16S)-5-ethy1-3 -imino-16-NH methy1-23-oxa-HN N= 2,4,17-triazahexacyc1o[17 29 HN 0 487.2 .6.2.22,5.111,15.0 *
8,10.022,26]triaco 1110 nta-11,13,15(28),19,2 1,26-hexaene-18,30-di one (1R,5R,15R,16R)-5-ethyl-IS-H hydroxy-3-imino-HNANN%µ= 2,4,17-" 0 triazahexacyclo[17 30 0 NH 487.2 .5.2.22,5.210,13.0 12,16.022,25]triac ,,,OH
onta-10,12,19,21,25,27-hexaene-18,30-dione (1R,15R,16R)-15-hydroxy-3-imino-NH 5-methy1-23-oxa-H N*A 2,4,17-triazahexacyclo[17 31 489.2 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr .õ
iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,8Z,14S,16 S)-5-ethy1-3-NH 0 imino-14-methyl-HN 23-oxa-2,4,17-/"- 0 triazahexacyclo[17 32 HN 499.2 .6.2.22,5.210,13.0 12,16.022,26]hentr 8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,14S,16S)-5-ethy1-3-imino-methy1-23-oxa-HNAN' 2,4,17-triazahexacyclo[17 33 HN 501.2 .6.2.22,5.210,13.0 12,16.022,26]hentr 10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,14R,16S)-5-ethy1-3-imino-methy1-23-oxa-2,4,17-""
triazahexacyclo[17 34 HN 501.3 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,15R,16R)-5-ethyl-I5-NH hydroxy-3-imino-HNANN'' 2,4,17-triazahexacyclo[17 HN
35 501.2 .6.2.22,5.210,13.0 12,16.022,26]hentr .,,OH
iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,8Z,17S)-5-ethy1-3-imino-NH 14,24-dioxa-2,4,11,18-tetrazahexacyclo[l '.

36 502.3 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-0"
8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,15R,16R)-5-ethyl-IS-NH hydroxy-3-imino-HNAN 23-oxa-2,4,17-triazahexacyclo[17 37 503.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,8Z,14R,16 S)-5,14-diethy1-3-NH imino-23-oxa-HNWs. 2,4,17-/1¶. a triazahexacyclo[17 38 513.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8Z,14S,16 S)-5,14-diethy1-3 -NH 0 imino-23-oxa-HNANS. 2,4,17-a TLJ
triazahexacyclo[17 39 HN 513.3 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-':
8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8E,14S,16 S)-5,14-diethy1-3 -NH imino-23-oxa-HNANN'' 2,4,17-a triazahexacyclo[17 40 HN 513.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-":
8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8E,14R,16 S)-5,14-diethy1-3 -NH imino-23-oxa-HN 2,4,17-/11-a triazahexacyclo[17 41 HN 513.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-':
8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8Z,15R,17 S)-5-ethy1-3-NH
imino-15-methyl-HNAN
14,24-dioxa-2,4,18-/1" 0 triazahexacyclo[18 42 515.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8Z,16S,17 S)-5-ethyl-3-NH
imino-16-methyl-HN N`' 0 14,24-dioxa-A.
2,4,18-triazahexacyclo[18 43 515.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8Z,15R,16 R)-5-ethyl -15-hydroxy-3 -imino-15-methy1-23-oxa-2,4,17-triazahexacyclo[17 44 515.2 .6.2.22,5.210,13.0 .,,OH
12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaen e-18,31-di on e (1R,5R,7E,16S)-5-ethy1-3-imino-NH
14,14-dimethyl-13,23-dioxa-HN N".
2,4,17-/I'= = 0 triazahexacyclo[17 45 515.2 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-7,9,11,19,21,26,28 -heptaene-18,31-dione (1R,5R,8E,15R,17 S)-5-ethyl-3-NH
imino-15-methyl-HN N
14,24-dioxa-2,4,18-triazahexacyclo[18 46 515.3 .6.2.22,5.210,13.0 12,17.023,27]dotri S
aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,16R,17R)-5-ethyl-I 6-NH hydroxy-3-imino-HN 24-oxa-2,4,18-triazaheptacyclo[l 47 515.2 8.6.2.22,5.211,14.
* * HN 0 08,10.013,17.023, .,,OH
27]dotriaconta-11,13,20,22,27,29-hexaene-19,32-di on e 1R,5R,9E,18S)-5-ethy1-3-imino-NH 15,25-dioxa-HNAN". 2,4,19-/"triazahexacyclo[19 ..
48 515.2 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33-dione (1R,5R,8E,15R,16 R)-5-ethy1-15-hydroxy-3-imino-HNAN`'. 15-methy1-23-oxa-2,4,17-/II'. 0 triazahexacyclo[17 49 515.2 .6.2.22,5.210,13.0 .õOH
12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8E,16R,17 S)-5-ethy1-3-NH
imino-16-methyl-HNN`'= 14,24-dioxa-2,4,18-triazahexacyclo[18 50 515.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8E,16S,17 S)-5-ethy1-3-NH
imino-16-methyl-HN N`' 0 14,24-dioxa-2,4,18-"
triazahexacyclo[18 51 515.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8E,16R)-5-ethy1-3-imino-15,15-dimethyl-NH
HNAN`'.
14,23-dioxa-ftJ 2,4,17-" " 0 triazahexacyclo[17 52 515.3 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,14R,16S)-5,14-di ethy1-3-NH imino-23-oxa-HNAN' 2,4,17-/".. 0 triazahexacyclo[17 53 515.3 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-di on e (1R,SR,14S,16S)-5,14-diethy1-3-NH imino-23-oxa-HNANN'. 2,4,17-triazahexacyclo[17 54 HN 515.3 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,15R,16R)-5-ethyl-IS-NH hydroxy-3-imino-methy1-2,4,17-triazahexacyclo[17 55 /....
515.3 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,15R,17S)-5-ethy1-3-imino-methy1-14,24-HNAN dioxa-2,4,18-/"" 0 triazahexacyclo[18 56 HN 517.3 .6.2.22,5.210,13.0 12,17.023,27]dotri 101 0 aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,16S)-5-ethy1-3-imino-NH
14,14-dimethyl-HNAN", 13,23-dioxa-2,4,17-" "
triazahexacyclo[17 57 517.2 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione (1R,5R,15S,17S)-5-ethy1-3-imino-methyl-14,24-HNAN dioxa-2,4,18-triazahexacyclo[18 58 517.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,15R,16R)-5-ethyl-I5-hydroxy-3-i mi no-NH
HNAN'. 15-methy1-23-oxa-µ
2,4,17-" 0 triazahexacyclo[17 59 517.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-di on e (1R,5R)-5-ethyl-15-hydroxy-3-NH imino-14-methyl-HNANN' 23-oxa-2,4,17-triazahexacyclo[17 /"..
60 517.3 .6.2.22,5.210,13.0 12,16.022,26]hentr O
AP.H iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,15R,16R)-15-hydroxy-3-NH imino-5-isopropyl-HNANN' 23-oxa-2,4,17-)11"o triazahexacyclo[17 61 HN 517.3 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr .õ
iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R)-5-ethyl-15-hydroxy-3-NH 0 imino-14-methyl-HNA IV= 23-oxa-2,4,17-/"" 0 triazahexacyclo[17 62 N 517.2 .6.2.22,5.210,13.0 kI 0 OH
12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,16S)-5-ethy1-3-imino-15,15-dimethyl-NH
HNAN 13,23-dioxa-2,4,17-/""
triazahexacyclo[17 63 517.2 HN 0 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione (1R,5R,16R)-5-ethy1-3-imino-15,15-dimethyl-HN N`' 14,23-dioxa-A.
2,4,17-triazahexacyclo[17 64 517.3 HN 0 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,16R,17S)-5-ethy1-3-imino-methy1-14,24-HNANV dioxa-2,4,18-/"" 0 1LJ
triazahexacyclo[18 65 517.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-0 10,12,20,22,27,29-hexaene-19,32-dione (1R,5R)-5¨ethyl-15-hydroxy-3 ¨
NH 0 imino-14-methyl-H 23-oxa-2,4,17-a triazahexacyclo[17 66 517.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-di one (1R,5R,16S,17S)-5-ethy1-3-imino-methyl-I 4,24-HN 1\l`s. dioxa-2,4,18-a triazahexacyclo[18 67 517.3 .6.2.22,5.210,13.0 12,17. 023,27]dotri Si .ssµµ
aconta-10,12,20,22,27,29-hexaene-19,32-di one (1R,5R,18S)-5-ethy1-3 NH 0 15,25-dioxa-HNAN`s. 2,4,19-" " 0 triazahexacyclo[19 68 517.2 .6.2.22,5.211,14.0 13,18. 024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33-di one (1R,5R,15R,16R,2 3S)-5-ethy1-15-0¨

hydroxy-3-imino-methoxy-HNN's= 2,4,17-/".L..__0 triazahexacyclo[17 69 517.3 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione (1S,8E,15S,23R)-5-ethy1-3-imino-NH o (methoxymethyl)-HN N'' 15,23-dimethyl-irA
22-oxa-2,4,16-70 0 517.2 triazapentacyclo[l HN
6.5.2.22,5.110,14.
021,24]octacosa-8,10,12,14(26),18, 20,24-heptaene-17,28-dione (1R,5R,14S,16S)-5-ethy1-3-imino-methoxy-23-HN oxa-2,4,17-triazahexacyclo[17 71 517.2 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,16S)-5-ethy1-3-imino-NH
14,14-dimethyl-HN N
8,13,23-trioxa-2,4,17-/"0 triazahexacyclo[17 72 519.2 .6.2.22,5.29,12.01 1,16.022,26]hentri 0 aconta-9,11,19,21,26,28-hexaene-18,31-dione (1R,5R,16S,17R)-5-ethyl-I 6-NH
hydroxy-3 -imino-14,24-dioxa-2,4,18-" 0 triazahexacyclo[18 73 519.2 HN 0 .6.2.22,5.210,13.0 12,17.023,27]dotri SO.

10,12,20,22,27,29-hexaene-19,32-dione (1S,15S,23R)-5-ethy1-3-imi no-23-(methoxymethyl)-NH 15,23-dimethyl-H N*A N`s. 22-oxa-2,4,16-74 0 519.2 triazapentacyclo[l 6.5.2.22,5.110,14.
021, 24]octacosa-10,12,14(26),18,2 0,24-hexaene-17,28-di one (1R,15R,16R)-5-ethy1-23,23-F difluoro-15-F
NH hydroxy-3-imino-HN*ANs' 2,4,17-triazahexacyclo[17 75A 523.2 0 .5.2.22,5.210,13.0 HN
12,16.022,25]triac onta-10,12,19(26),20,2 2(25),27-hexaene-18,30-dione (1R,15R,16R)-5-ethy1-23,23-difluoro-15-F
ANH HN* hydroxy-3-imino-N's = 2,4,17-triazahexacyclo[17 0 .5.2.22,5.210,13.0 HN 523.2 12,16.022,25]triac cPonta-10,12,19(26),20,2 2(25),27-hexaene-18,30-dione (1R,5R,8Z)-5-ethy1-15-hydroxy-NH
3-imino-spiro[23---".0 HN N 7 oxa-2,4,17-/""
ftJ
triazahexacyclo[17 .6.2.22,5.210,13.0 76 527.2 14.1\1 12,16.022,26]hentr Ala. OH iaconta-WIF
8,10,12,19,21,26,2 8-heptaene-14,1'-cyclopropane]-18,31-di one (1R,5R,8E)-5-ethy1-15-hydroxy-NH 3-imino-spiro[23-oxa-2,4,17-/""
triazahexacyclo[17 .6.2.22,5.210,13.0 77 527.3 12,16.022,26]hentr * OH iaconta-8,10,12,19,21,26,2 8-heptaene-14,1'-cyclopropane]-18,31-dione (1R,5R)-5-ethyl-15-hydroxy-3-NH
imino-spiro[23-HN N
oxa-2,4,17-/""
triazahexacyclo[17 .6.2.22,5.210,13.0 78 529.2 14.N 0 12,16.022,26]hentr OH iaconta-10,12,19,21,26,28-hexaene-14,1'-cyclopropane]-18,31-dione (1R,5R,8Z,15S,17 S)-5,15-di ethyl-3-NH imino-14,24-HNN = dioxa-2,4,18-/"" 0 triazahexacyclo[l 8 79 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di on e (7R,11R,21S,23R) -7-ethy1-9-imino-23-methy1-14,24-NH
H N N
dioxa-8,10,20-triazaheptacyclo[l 9.6.2.27,10.215,18 80 529.3 * * HN 0 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (1R,5R,17S)-5-ethy1-3-imi no-spiro[14,24-dioxa-NH 0 2,4,18-triazahexacyclo[ 1 8 .6.2.22,5.210,13.0 81 529.3 12,17.023,27]dotri aconta-10(30),11,13(29),2 0 0,22,27-hexaene-15,1'-cyclopropane]-19,32-dione (6R,10R,20S)-6-ethy1-8-imino-22,22-dimethyl-NH 13,23-dioxa-HN N 7,9,19-I'== *
triazaheptacyclo[l 82 529.2 8.6.2.26,9.214,17.

02,4.010,15.024,2 8]dotriaconta-0 1(27),14(30),15,17 (29),24(28),25-hexaene-18,31-dione (1R,5R,8Z,17R)-5-ethy1-3-imino-14,14-dimethyl-NH
HN Nv-15,24-dioxa-2,4,18-triazahexacyclo[18 83 HN o 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10(30),11,13(29) ,20,22,27-heptaene-19,32-dione (7R,11R,21S,23S) -7-ethy1-9-imino-NH
23-methyl-14,24-dioxa-8,10,20-HNAN
triazaheptacyclo[l 9.6.2.27,10.215,18 84 529.3 * * HN 0 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (1R,5R,8E,17R)-5-ethy1-3-imino-14,14-dimethyl-NH
HNN`s 15,24-dioxa-=
2,4,18-/I". 0 triazahexacyclo[18 85 HN 0 529.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10(30),11,13(29) ,20,22,27-heptaene-19,32-dione (1R,5R,8E,15R,17 S)-5,15-diethy1-3-NH imino-14,24-dioxa-2,4,18-triazahexacyc1o[18 86 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-0 8,10,12,20,22,27,2 9-heptaene-19,32-dione (7R,11R,21S,22S) -7-ethy1-9-imino-NH
22-methyl-14,24-dioxa-8,10,20-HNAW.
triazaheptacyclo[l o 9.6.2.27,10.215,18 87 529.2 * * HN 0 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (1R,8E,17S)-5-ethy1-3-imi no-15,15-dimethyl-NH
14,24-dioxa-o HN*AN
2,4,18-triazahexacyclo[18 88 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (8R,12R,22S)-8-ethy1-10-imino-15,25-dioxa-NH
HNAN`s.
9,11,21-triazaheptacyclo[2 /1". 0 0.6.2.28,11.216,19 89 529.2 * HN 0 .02,4.012,17.026,3 O]tetratriaconta-1(29),16(32),17,19 (31),26(30),27-hexaene-20,33-di on e (1R,5R,8E,15S,17 S)-5,15-diethy1-3-NH imino-14,24-HN dioxa-2,4,18-LL/"" 0 triazahexacyclo[18 90 529.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-0 8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8Z)-5,14-diethyl-15-NH
HNAN".
hydroxy-3-imino-23-oxa-2,4,17-/"" 0 triazahexacyclo[17 91 WN 0 529.2 .6.2.22,5.210,13.0 ofp OH
12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione (1R,5R,8E)-5,14-diethyl-15-HNN's= hydroxy-3-imino-23-oxa-2,4,17-/"" 0 triazahexacyclo[17 92 I4N NO 529.2 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione NH
(1R,5R,8Z,17S)-5-HNAN ethy1-3-imino-/"" 0 S 15,15-dimethyl-14,24-dioxa-2,4,18,29-93 530.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,8E,17S)-5-HNAN ethy1-3-imino-/".= 0 15,15-dimethyl-14,24-dioxa-2,4,18,29-530.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,8Z,15R,16R,2 NH ", 0 5R)-15-hydroxy-HN*
,A.N" 3-imino-25-(methoxymethyl)-5-methy1-23-oxa-2,4,17-.00H
95 531.3 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione NH
(1R,8Z,165,17R)-HNIõAN\s. 16-hydroxy-3-0 imino-5,15,15-trimethy1-14,24-so0H dioxa-2,4,18-96 531.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(7R,11R,21R,22S) HNAN". -7-ethyl-/ hydroxy-9-imino-* HN 0 14,24-dioxa-OH
8,10,20-triazaheptacyclo[l 97 531.2 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (13 (1S,8E,15R,16R,2 NH 7 4R)-5-ethyl-15-HN,(1-LN0' hydroxy-3-imino-

24-methy1-23-oxa-(methoxymethyl)-2,4,17-.õ OH
98 531.2 triazahexacyclo[17 .5.2.210,13.12,5.0 12,16.022,25]nona cosa-8,10,12,19,21,25,2 7-heptaene-18,29-dione NH (1R,5R,8E,16S,17 H N N"= R)-5-ethy1-16-/".= hydroxy-3-imino-HN 0 16-methyl-14,24-OH dioxa-2,4,18-99 1110 0 531.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one (1R,8E,16S,17R)-HNõAN" 16-hydroxy-3 -0 imino-5,15,15-trimethy1-14,24-OH dioxa-2,4,18-100 531.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one (1R,5R,7E,14R,15 NH ="- 0 R,24R)-5-ethyl-hydroxy-3-/I'= 0 imino-24-(methoxymethyl)-22-oxa-2,4,16-101 1410. ,,,OH
531.3 triazahexacyclo[16 .6.2.22,5.29,12.01 1,15 .021,25]triaco nta-7,9,11,18,20,25,27 -heptaene-17,30-dione (1R,5R,8Z)-5-HNANNs. ethy1-16-hydroxy-/" 0 3-imino-methyl-14,24-* OH dioxa-2,4,18-102 0 531.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,8E)-5-HNAN". ethy1-16-hydroxy-/'" 0 3-imino-methyl-14,24-OH
dioxa-2,4,18-103 0 531.2 *
LJL
L.
triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one NH
(1S,10R,14R,17Z) HNANNs' ¨14¨ethyl-30¨
/ 0 fluoro-12-imino-NH
0 24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 104 531.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH (1R,5R)-5,14-HN A N'- diethyl-/ I" 0 hydroxy-3-imino-23-oxa-2,4,17-I4.
triazahexacyclo[17 105 dok 531.2 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-di on e (1R,5R,17R)-5-HN)LN`s. ethy1-3-imino-"" 14,14-dimethyl-15,24-dioxa-2,4,18-triazahexacyclo[18 106 531.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione NH
(1R,10R,14R,25S) HN No = -14-ethyl-25-hydroxy-12-imino-24,24-0H dimethy1-23-oxa-.0 2,11,13-triazahexacyclo[17 107 531.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione NH
(1R,5R,15S,17S)-HN AN 7 5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18 108 531.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,15R,17S)-HNN 5,15-diethy1-3-/"" 0 imino-14,24-dioxa-2,4,18-triazahexacyclo[18 109 531.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,17S)-5-HN)-(N"- ethy1-3-imino-16,16-dimethyl-14,24-dioxa-2,4,18-110 531.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e NH 0 (1R,5R)-5,14-HN kl. diethyl-o hydroxy-3-imino-N
23-oxa-2,4,17-14.
triazahexacyclo[17 111 op 531.3 .6.2.22,5.210,13.0 OH
12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione NH 0 (1R,5R,17S)-5-"
H N N'''f--) ethy1-3-imino-"
15,15-dimethyl-HNO 14,24-dioxa-2,4,18,28-112 532.2 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione 1IINH 0 (1R,5R,17S)-5-HN'It'N` ethy1-3-imino-"
I N
15,15-dimethyl-"
HN 14,24-dioxa-2,4,18,21-113 532.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-di on e NH
(1R,5R,17S)-5-HNAN ethy1-3-imino-/ 0 S 15,15-dimethyl-HN
14,24-dioxa-2,4,18,29-114 532.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,17S)-5-HNAN ethy1-3-imi no-" 0 15,15-dimethyl-14,24-dioxa-2,4,18,30-115 532.2 tetrazahexacyclo[l N., I

8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,16S,17R)-HNAN". 5-ethyl-/ I" 0 hydroxy-3-imino-16-methyl-14,24-dioxa-2,4,18-116 533.2 triazahexacyc1o[18 OH
.6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e NH (1R,5R,17S)-5-HN r ethy1-3-imino-15,15-dimethyl-HN
8,14,24-trioxa-0 2,4,18-triazahexacyclo[18 0 533.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH (1R,5R,17S)-5-H - ethy1-3-imi no-15,15-dimethyl-9,14,24-trioxa-0 2,4,18-triazahexacyclo[18 118 0 533.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,16S,17R)-16-., =
HN1*11 N" hydroxy-3-i mi no-0 5,15,15-trimethyl-HN 0 14,24-dioxa-OH2,4,18-119 533.3 triazahexacyc1o[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e NH
(1R,5R,15S,16R)-(hydroxymethyl)-3-imino-15-methyl-14,23-dioxa-2,4,17-120 533.2 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione NH (1R,5R)-5-ethyl-HNAN\'' 16-hydroxy-3-/"" 0 imino-15-methyl-14,24-dioxa-* OH 2,4,18-triazahexacyclo[18 0 533.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH 0 (1R,5R)-5-ethyl-hydroxy-3 -"" 0 imino-15-methyl-14,24-dioxa-FiN 0 * OH
2,4,18-*
triazahexacyclo[18 0 533.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH (1R,5R)-5-ethyl-HNAN" 16-hydroxy-3 -"" 0 imino-15-methyl-14,24-dioxa-FiN 0 * OH
2,4,18-triazahexacyclo[18 0 533.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH (1R,5R)-5-ethyl-HN N`'. 16-hydroxy-3 -imino-15-methyl-14,24-dioxa-FiN 0 * OH
2,4,18-121D LjL0..J.533.3 triazahexacyc1o[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e NH
(1R,5R,15S,16R)-H N N"= 5-ethyl-/I" 0 hydroxy-3-imino-14-dimethyl-OH
13,23-dioxa-2,4,17-122 533.2 triazahexacyclo[17 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione (1S,14R,15R,23R) ethyl -14-- o hydroxy-3-imino-methy1-22-oxa-(methoxymethyl)-2,4,16-123 533.2 triazahexacyclo[16 .5.2.22,5.29,12.01 1,15.021,24]nonac osa-9,11,18,20,24,26-hexaene-17,29-dione (1 S,15R,16R,24R) ethyl -15-H N*A N hydroxy-3-imino-(methoxymethyl)-24-methy1-23-oxa-, õOH
2,4,17-124 533.2 triazahexacyclo[17 .5.2.210,13.12,5.0 12,16.022,25]nona cosa-10,12,19,21,25,27-hexaene-18,29-dione CY' (1R,15R,16R,25R) -15-hydroxy-3-HAN%. = imino-25-(methoxymethyl)-5-methy1-23-oxa-OH
2,4,17-, 125 õ 533.2 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione NH
(1R,5R,17S)-5-HN Nµs'CrLi. ethy1-3 -imino-1\1 N
/ o N 15,15-dimethyl-14,24-dioxa-2,4,18,21,28-pentazahexacyclo[
0 533.3 18.6.2.22,5.210,13 .012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-di one (1S,10R,14R)-14-ethy1-30-fluoro-12-imino-24,24-NH
dimethy1-23-oxa-H N N". 2,11,13-".. 0 triazahexacyclo[17 127 NH 533.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione (1S,10R,14R,17Z, NH
HN.A.N". 24R)-14-ethyl -8,8-difluoro-12-imino-methy1-23-oxa-NH
2,11,13-triazahexacyclo[17 128 535.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-di one NH
(1R,5R,8Z,15R,16 H N N R)-5-ethyl-23,23-/"Lo difluoro-15-..
hydroxy-3 -imino-H N 0 2,4,17-129 535.2 .õOH
triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-dione NH
(1R,9Z,16R,17R)-HN*ANµµ= 5-ethyl-24,24-ftJ difluoro-hydroxy-3 -imino-0 NH 2,4,18-triazahexacyclo[18 535.3 .5.2.22,5.211,14.0 13,17.023,26]hentr iaconta-9,11,13,20,22,26,2 8-heptaene-19,31-dione (1R, 9E,16R,17R)-NH
HN* N, 5-ethyl-24,24--difluoro-16-hydroxy-3 -imino-0 NH 2,4,18-triazahexacyclo[18 535.3 .5.2.22,5.211,14.0 13,17.023,26]hentr iaconta-9,11,13,20,22,26,2 8-heptaene-19,31-di on e (1 S,14R,15R,23R) - 0 J-t -5-ethyl-, hydroxy-3-imino-(methoxymethyl)-23-methyl-8,22-, õOH
dioxa-2,4,16-132 535.4 triazahexacyclo[16 .5.2.22,5.29,12.01 1,15 .021,24]nonac osa-9,11,18,20,24,26-hexaene-17,29-dione (1 S,10R)-14-ethyl-NH
8,8-difluoro-12-H N". imino-23,23-0 dimethy1-22-oxa-NH
2,11,13-triazahexacyclo[16 133 537.4 .6.2.24,7.211,14.0 6,10.021,25]triaco nta-4,6,18(26),19,21(2 5),29-hexaene-3,28-dione ( 1 S,10R,14R,24R) NH
-14-ethy1-8,8-H N N".
difluoro-12-imino-24-methy1-23-oxa-NH
2,11,13-triazahexacyclo[17 134 537.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione (1S,10R,14R,24S) NH
HNJ-L.N \s=
¨14¨ethyl-8,8¨
difluoro-12-imino-".. 0 24-methy1-23-oxa-NH
2,11,13-triazahexacyclo[17 135 "", 537.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione NH
(1R,16R,17R)-5-ethyl-24,24-HN* =
difluoro-16-hydroxy-3 -imino-0 NH 2,4,18-õOH
triazahexacyclo[18 136 537.3 .5.2.22,5.211,14.0 13,17.023,26]hentr iaconta-11,13,20,22,26,28-hexaene-19,31-di on e NH
(1R,5R,15R,16R)-HNAN''. 5-ethyl-23,23-/
difluoro-15-...

hydroxy-3-imino-HN 0 2,4,17-137 537.2 .õOH triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione NH F
(1R,5R)-5-ethyl-HNAN0' "
14,14,23,23-tetrafluoro-3-" 0 imino-2,4,17-0 NH triazahexacyclo[17 138 543.2 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione NH
(7R,11R,21S)-7-HWIL'N ethy1-9-imino-t..
23,23-dimethyl-14,24-dioxa-* * HN 0 8,10,20-triazaheptacyclo[l 139A 543.2 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-di on e NH
(7R,11R,21S)-7-HNAN ethy1-9-imino-/I". 23,23-dimethyl-14,24-dioxa-* * HN 0 8,10,20-triazaheptacyclo[l 139B 543.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione NH
(1R,5S,8Z,17S)-5-J-L ' \ HN N 01/ ethy1-3-imino-HN
6,15,15-trimethyl-14,24-dioxa-2,4,18-543.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH (1R,5S,8Z,17S)-5--µ HNA N (1110 ethy1-3-imino-1,.. 6,15,15-trimethyl-HN
14,24-dioxa-2,4,18-543.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5S,8E,17S)-5-HNAN ethy1-3-imino-\ it.. 0 6,15,15-trimethyl-HN
14,24-dioxa-2,4,18-141"tZJtIIIIJ 543.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,8Z,15R,17 HN)I,N 7 S)-5-ethyl-3-imino-15-isopropyl-14,24-dioxa-2,4,18-triazahexacyc1o[18 543.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8E,15R,17 S)-5-ethy1-3-NH imino-15-HN,11..N
isopropyl-14,24-/"L _J.0 LtJ dioxa-2,4,18-143 HN 0 543.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH (7R,11R,21S)-7-HN N ethy1-9-imino-N
/".. 23,23-dimethyl-14,24-dioxa-* * H N
8,10,17,20-tetrazaheptacyclo[

144 544.2 19.6.2.27,10.215,1 8.02,4.011,16.025, 29]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (1S,8E,15R,16R,2 4R)-5-ethy1-15-hydroxy-3-imino-HN*

(methoxymethyl)-methy1-23-oxa-2,4,17-545.2 triazahexacyclo[17 .5.2.22,5.210,13.0 12,16.022,25]triac onta-8,10,12,19,21,25,2 7-heptaene-18,30-dione NH
(1R,5R,8Z,16R,17 HNAN".
imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-146 545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8Z,16S,17 HNAN". S)-5-ethyl-3-/'oimino-16-(methoxymethyl)-14,24-dioxa-2,4,18-147 545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,17S)-5-HNAN". ethy1-3-imino-/"" 0 15,15-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18 148 0 545.2 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-9,19,32-trione (7R,11R,21R,22S) HN)L N`s. -7-ethyl-/II hydroxy-9-imino-22-methy1-14 * * HN 0 dioxa-8,10,20-triazaheptacyclo[l 149 545.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione (1R,16R,17R,26R) hydroxy-3---IL = imino-26-H Nk (methoxymethyl)-* * HN
5-methy1-24-oxa-2,4,18-.õ
150 OH 545.3 triazaheptacyclo[l 8.6.2.22,5.211,14.
08,10.013,17.023, 27]dotriaconta-11,13,20,22,27,29-hexaene-19,32-dione (1R,5R,8Z,15R,16 R,25S)-5-ethy1-15-) hydroxy-3 -imino-

25-(methoxymethyl)-HN 23-oxa-2,4,17-151 /"" 0 545.4 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr .,,OH
iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-di one Cr"
(1R,5R,8Z,15R,16 NH 0 R,25R)-5-ethyl-HN.A.N"= 15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17-, õOH
152 545.3 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-di one NH
(1R,5R,8E,16S,17 HNAN". R)-5-ethyl-16-/'o hydroxy-3-imino-HN
15,15-dimethyl-14,24-dioxa-2,4,18-153 545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,8E,16S,17 HNAN`s. S)-5-ethyl-3-/ ".. 0 imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-LjL0J
154 545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,5R,8E,16R,17 HNAN". S)-5-ethy1-3-/ = imino-16-HN
(methoxymethyl)-14,24-dioxa-=s"0-2,4,18-155 545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one Cr" (1R,5R,8E,15R,16 NH '''= 0 R,25R)-5-ethyl-HN)k.. N`s= 15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17-õ,OH
156 545.2 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-8,10,12,19,21,26,2 8-heptaene-18,31-di one NH
(7R,11R,20S)-7-HN AN . ethyl-30-fluoro-9-/ II0 imino-22,22-NH
dimethy1-23-oxa-8,10,19-triazaheptacyclo[l 157 545.2 8.6.2.27,10.214,17 .02,4.011,15.024,2 8]dotriaconta-1(27),14,16,24(28) ,25,29-hexaene-18,31-dione C( (1S,9S,10S,14R)-NH
ià 14-ethyl HNN " imino-9-methoxy-24,24-dimethyl-23-oxa-2,11,13-HN
triazahexacyclo[17 158 545.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione NH
(1R,5R,16S,17R)-HNAN". 5-ethyl-/1 " 0 hydroxy-3-imino-15,15-dimethyl-14-oxa-2,4,18-OH

triazahexacyclo[18 0 545.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH "-""O
(1R,5R,17S,26S)-HN N= 5-ethy1-3-imino-" "
15,15,26-trimethy1-14,24-dioxa-2,4,18-160 545.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH --"0 (1R,5R,15R,17S)-HN.JI,N 7 5-ethy1-3-imino-15-isopropyl-14,24-dioxa-2,4,18-161 545.3 triazahexacyc1o[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e NH
(1R,5S,17S)-5-HN N
\ 1... ethy1-3-imino-0 6,15,15-trimethyl-HN
14,24-dioxa-2,4,18-545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5S,17S)-5-HNAN ethy1-3-imi no-\
HN
0 1101 6,15,15-trimethyl-14,24-dioxa-2,4,18-545.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,15S,17S)-HN--11,N 5-ethy1-3-imino-15-isopropyl-14,24-dioxa-2,4,18-163 545.3 triazahexacyc1o[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di on e C( (1S,9R,10S,14R)-HN N"' imino-9-methoxy-NH 14-ethyl-12-/l'. 0 24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 164 545.3 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione NH (5R,17S)-5-ethyl-HNAN 3 -imino-15,15,26-/
trimethy1-14,24-". H y"
dioxa-2,4,18,28-NO
tetrazahexacyclo[l 165 546.3 8.6.2.22,5.210,13.

012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione (1 S,15R,16R,24R) -5-ethyl-IS -A = hydroxy-3-imino-HN* N"

(methoxymethyl)-methy1-23-oxa-..,OH 2,4,17-166 547.2 triazahexacyclo[17 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione NH
(1R,5R,16S,17R)-HN A N"= 5-ethy1-16-/...
hydroxy-3-imino-HN
15,15-dimethyl-14,24-dioxa-2,4,18-OH

167 547.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,16S,17S)-HNAN"' 5-ethy1-3-imino-(methoxymethyl)-14,24-dioxa-Cr' 2,4,18-168 547.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,16R,17S)-HNANNs. 5-ethy1-3-imino-(methoxymethyl)-14,24-dioxa-2,4,18-169 547.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,5R,17S)-5-HN AN". ethy1-8-hydroxy-/ " 3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18 170 0 547.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione NH
(1R,5R,15S,16R)-HN A N 5-ethy1-3-imino-o 15-(methoxymethyl)-15-methy1-14,23-dioxa-2,4,17-171 547.2 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione O
(1R,5R,15R,16R,2 NH ''= 0 5R)-5-ethy1-15-NW-11'N". hydroxy-3-imino-/"== 0 25-HN
(methoxymethyl)-23-oxa-2,4,17-OH
172 547.3 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,15R,16R,2 5S)-5-ethyl-15-HN N"µ
hydroxy-3-imino-(methoxymethyl)-HN 0 23-oxa-2,4,17-173 ,,,OH 547.3 triazahexacyclo[17 .6.2.22,5.210,13.0 12,16.022,26]hentr iaconta-10,12,19,21,26,28-hexaene-18,31-dione (1R,5R,18S)-5-HNAN`s. ethy1-3-imino-/"== o 16,16-dimethyl-9,15,25-trioxa-2,4,19-174 547.2 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33-dione (1R,5R,17S)-5-HN.11,,N.
ethy1-9-hydroxy-3-imino-15,15-dimethy1-14,24-*
dioxa-2,4,18-H 175 547.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione (1R,18S)-5-ethy1-3-imino-16,16-NH 0 dimethy1-8,15,25-HAN`s. trioxa-2,4,19-V
triazahexacyclo[19 176 547.2 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33-dione NH 0 (1R,5R)-5-ethyl-HNAN"' 16-hydroxy-3-/"" imino-15,16-dimethyl-14,24-1\1 0 * OH dioxa-2,4,18-177 547.2 *
triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1S,10R,14R)-14-NH
HNAN"= ethy1-8,8-di fl uoro-12-imino-/"'. 0 spiro[23-oxa-NH
2,11,13-triazahexacyclo[17 .6.2.24,7.211,14.0 178 549.2 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-24,1'-cyclopropane]-3,29-dione F F
(1S,10R,14R,17Z) HN
-14-ethy1-8,8-HWILW

0 24,24-dimethyl-HN 23-oxa-2,11,13-triazahexacyclo[17 179 === 549.4 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione (1S,10R,14R,17E) NH
-14-ethy1-8,8-HNAN".
0 24,24-dimethyl-NH
23-oxa-2,11,13-180 549.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH
(1R,5R)-5-ethyl-HNAN"= 23,23-difluoro-15-hydroxy-3-hnino-/"'. spiro[2,4,17-OH
.5.2.22,5.210,13.0 triazahexacyclo[17 181 549.2 12,16.022,25]triac onta-10,12,19(26),20,2 2(25),27-hexaene-14,1'-cyclopropane]-18,30-dione (1S,15R,16R,24R) NH
-5-ethyl-IS-hydroxy-3-imino-HN*1 24-0 (methoxymethyl)-methyl-9,23-dioxa-2,4,17-182 549.

triazahexacyclo[17 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione (1 S,15R,16R,24R) NH
-5-ethyl-IS -HN'"NV
hydroxy-3-imino-O
(methoxymethyl)-methyl-8,23-dioxa-2,4,17-183 549.3 triazahexacyclo[17 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione NH
(1S,14R,17Z)-14-ethy1-8,8-difluoro-HNAN 12-imino-24,24-/1" 0 dimethy1-23-oxa-HN
2,5,11,13-tetrazahexacyclo[l 184 550.2 7.6.2.24,7.211,14.
06,10.022,26]hentr iaconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH
(1S,14R,17E)-14-ethy1-8,8-difluoro-HNAN \ 12-imino-24,24-/1" 0 dimethy1-23-oxa-HN
2,5,11,13-tetrazahexacyclo[l 185 550.2 7.6.2.24,7.21 L14.
06,10.022,26]hentr iaconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH
(1 S,14R)-14-ethyl-8,8-difluoro-12-HNAN imino-24,24-".. 0 dimethy1-23-oxa-HN
2,5,11,13-tetrazahexacyclo[l 186 552.2 7.6.2.24,7.211,14.
06,10.022,26]hentr iaconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione (1R,10R,14R,25S) NH
-14-ethy1-8,8-HNANV difluoro-25-hydroxy-12-HN imino-25-methyl-..10H 23-oxa-2,11,13-187 553.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione (1R,10R,24S)-14-NH
A = ethy1-8,8-difluoro-HNõ N" 24-hydroxy-12-0 imino-23,23-NH
dimethy1-22-oxa-.
2,11,13-188 553.2 triazahexacyclo[16 .6.2.24,7.211,14.0 6,10.021,25]triaco nta-4,6,18(26),19,21(2 5),29-hexaene-3,28-dione (1 S,14R)-14-ethyl-NH
8,8,29-trifluoro-H NAN 12-imino-23,23-dimethy1-22-oxa-NH
2,11,13-triazahexacyclo[16 189 555.2 .6.2.24,7.211,14.0 6,10.021,25]triaco nta-4,6,18(26),19,21(2 5),29-hexaene-3,28-dione NH
(1R,5R,14R,16S)-HNAN 5-ethy1-3-imino-/1" 0 14-H N
(trifluoromethyl)-13,23-dioxa-2,4,17-. F
SI 0 'F
190557.3 triazahexacyclo[17 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione (1S,9S,10R,14R,1 NH mik 7Z)-14-ethyl-12-HN
.11,N = iipP imino-9-"
o (methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 557.3 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),17,1 9(27),20,22(26)-heptaene-3,29-dione 0¨

(1S,9R,10R,14R,1 NH 7Z)-14-ethyl-I2-HNN"= imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 557.3 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),17,1 9(27),20,22(26)-heptaene-3,29-dione NH (1R,5R)-5-ethyl-HN1Nµµ ' 14,14,23,23-LLJ
tetrafluoro-15-/"" 0 hydroxy-3-imino-0 õNH 2,4,17-OH triazahexacyclo[17 193 559.2 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione (1S,9Z,16R,17R,2 NH 5R)-5-ethy1-16-HN* Nµµ
hydroxy-3-imino-' (methoxymethyl)-methy1-24-oxa-\ ,õOH
194 559.2 triazahexacyclo[18 2,4,18-.5.2.22,5.211,14.0 13,17.023,26]hentr iaconta-9,11,13,20,22,26,2 8-heptaene-19,31-dione CY-(1R,5R,7E,16S,25 NH 0 R)-5-ethy1-3-HNN`s= imino-25-(methoxymethyl)-14,14-dimethyl-13,23-dioxa-195 559.3 2,4,17-triazahexacyclo[17 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-7,9,11,19,21,26,28 -heptaene-18,31-dione 0¨

(1R,8R,10R,14R,1 NH
HN)-N 7Z,25S)-14-ethy1-25-hydroxy-12-/"" 0 imino-8-methoxy-HN 0 24,24-dimethyl-.00H 23-oxa-2,11,13-triazahexacyclo[17 0 559.4 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),17,1 9(27),20,22(26)-heptaene-3,29-dione (1R,8R,10R,14R,1 NH _ HNAN 7E,25S)-14-ethy1-25-hydroxy-12-/"" 0 imino-8-methoxy-HN 0 24,24-dimethyl-OH
23-oxa-2,11,13-triazahexacyclo[17 0 559.4 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),17,1 9(27),20,22(26)-heptaene-3,29-dione 0¨

(1S,9S,10R,14R)-NH ma I4-ethyl-12-HN
AN = 111, imino-9-"

(methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 559.3 0 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione 0¨
/ (1S,9R,10R,14R)---NH 14-ethyl-HNN" imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 559.3 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione NH
(1R,5R,16S,17R)-HN N's= 16-hydroxy-3->1" imino-5-i sopropyl-15,15-dimethyl-14,24-dioxa-2,4,18¨

200 561.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1S,5R,16R,17R,2 5R)-5-ethy1-16-hydroxy-3-imino-(b, 25-(methoxymethyl)-HNANo= 25-methy1-24-oxa-2,4,18-201 /,561.2 ...
triazahexacyclo[18 .5.2.22,5.211,14.0 13,17.023,26]hentr iaconta-11,13,20,22,26,28-hexaene-19,31-dione (1S,9R,10S)-14-ethy1-12-imino-9-(methoxymethyl)-(I) 9,23,23-trimethyl-NH = 8,22-dioxa-HN, 2,11,13-triazahexacyclo[16 561.4 .6.2.24,7.211,14.0 6,10.021,25]triaco nta-4(30),5,7(29),18(2 6),19,21(25)-hexaene-3,28-dione (1R,8S,10R,14R,2 NH
HNN`s= 5S)-14-ethyl-25-hydroxy-12-/"" 0 imino-8-methoxy-HN 0 24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17 0 .3 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-di one (1R,5R,16S,25R)-NH
5-ethy1-3-imino-HNAN`s.

/".. 0 (methoxymethyl)-HN 0 14,14-dimethyl-.00H 13,23-dioxa-204 0 561.3 2,4,17-triazahexacyclo[17 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione (7R,11R,20S)-7-NH
ethyl-13,13 -HN NIµs.
difluoro-9-imino-" = 0 22,22-dimethyl-NH
23-oxa-8,10,19-*
triazaheptacyclo[l 205 563.3 8.6.2.27,10.214,17 .02,4.011,15.024,2 8] dotri ac onta-1(27),14,16,24(28) ,25,29-hexaene-18,31-dione NH
(1R,5R,8Z,17S)-5-HNANN' ethyl-24,24-/' difluoro-3-imino-"
15,15-dimethyl-HN 0 14-oxa-2,4,18-triazahexacyclo[18 206 563.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,10R,14R,17E, NH
25 S)-14-ethy1-8,8-HNAN`s. difluoro-0 hydroxy-12-NH
0 spH imino-24,24-=
dimethy1-23-oxa-2,11,13-207 565.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH
(1R,5R,17S)-5-HNAN".
ethyl-24,24-/11LJ difluoro-3-imino--15,15-dimethyl-HN 0 14-oxa-2,4,18-triazahexacyclo[18 208 565.3 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,17S)-5-HNAN`s. ethy1-9,9-difluoro-/"" 0 3-imino-15,15-dimethy1-14,24-dioxa-2,4,18-F
209 0 567.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione (1R,10R,14R,25S) NH
HNAN`s= -14-ethyl-8,8-difluoro-25-/"'= hydroxy-0 imino-24,24-NH
dimethy1-23-oxa-2,11,13-210 567.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione NH
(1R,5R,17S)-5-HNAN". ethy1-8,8-difluoro-/"" 0 3-imino-15,15-211 567.3 dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione NH (1R,5R,16S)-8-HN A N (di fluorom ethyl)-o 5-ethy1-3-imino-H N 0 14,14-dimethyl-13,23-dioxa-2,4,17-212 567.5 triazahexacyclo[17 .6.2.22,5.29,12.01 1,16.022,26]hentri aconta-9,11,19,21,26,28-hexaene-18,31-dione NH
(1R,5R,8Z,15S,17 HNAN S)-5-ethyl-3-/ 0 imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-F

213 569.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,8Z,15R,17 H N S)-5-ethyl-3-/1 ". 0 imino-15-HN
(trifluoromethyl)-14,24-dioxa-F
2,4,18-, 214 0 "irF 569.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NHFF
(1 S,14R)-14-ethyl-8,8,30-trifluoro-HN N 12-imino-24,24-/"' 0 dimethy1-23-oxa-NH
2,11,13-triazahexacyclo[17 215 569.2 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione NH
(1R,5R,15R,17S)-HN N 5-ethy1-3-imino-" 0 15-(trifluoromethyl)-14,24-dioxa-2,4,18-. F
0 "ir F
216 571.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,15S,17S)-HN N (110 5-ethy1-3-imino-o 15-HN
(trifluoromethyl)-14,24-dioxa-2,4,18-217 571.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,11Z,21S)-5-ethy1-3-imino-19,19-dimethyl-N H /-**-"0 HIA N 18,28-dioxa-t 2,4,22-triazahexacyclo[22 218 571.3 .6.2.22,5.113,17.0 16,21.027,31]pent ¨
atriaconta-11,13(33),14,16,2 4,26,31-heptaene-23,35-dione (7R,11R,12R,20S) NH -7-ethy1-9-imino-HNAN

/l. 0 (methoxymethyl)-* HN
22,22-dimethyl-*
23-oxa-8,10,19-triazaheptacyclo[l .3 0 8.6.2.27,10.214,17 .02,4.011,15.024,2 8]dotriaconta-1(27),14(30),15,17 (29),24(28),25-hexaene-18,31-di one (7R,11R,12R,20S) NH -7-ethy1-9-imino-H N N"= 12-(methoxymethyl)-22,22-dimethyl-* * HN 0 23-oxa-8,10,19-triazaheptacyclo[l .3 0 8.6.2.27,10.214,17 .02,4.011,15.024,2 8]dotriaconta-1(27),14(30),15,17 (29),24(28),25-hexaene-18,31-dione NH
(1R,5R,15R,17S)-H N N 5-ethy1-3-imino-/1" 0 y' (tri fluorom ethyl)-14,24-dioxa-2,4,18,28-, F
220 0 F 572.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione NH ,.."O (1R,21 S)-5-ethyl -HN, N 3-imino-19,19-o dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[22 221A 573.3 .6.2.22,5.113,17.0 16,21.027,31]pent atriaconta-13(33),14,16,24,2 6,31-hexaene-23,35-dione NH (1R,21 S)-5-ethyl-HN* N 3-i mino-19,19-o dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[22 221B 573.3 .6.2.22,5.113,17.0 16,21.027,31]pent atriaconta-13(33),14,16,24,2 6,31-hexaene-23,35-di one (5R,8Z,17S)-5-NH : 0 ethy1-3-imino-26-(methoxymethyl)-HNAN \
y-15,15-dimethyl-14,24-dioxa-2,4,18,28-\
222 574.2 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,8Z,165,17R,2 NH 0 6R)-16-hydroxy-,K. = 3-imino-

26-(methoxymethyl)-5,15,15-trimethyl-14,24-dioxa-.0 223 575.4 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,8E,16S,17R,2 NH"= 0 6R)-16-hydroxy-.11, = 3-imino-HN* N`s (methoxymethyl)-5,15,15-trimethyl-õOH
14,24-dioxa-224 575.3 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one (1S,9R,10S,14R)-N40,. 14-ethyl-12-H N`s= imino-9-/1... 0 HN

(methoxymethyl)-9,24,24-trimethyl-8,23 -dioxa-2,11,13-225 575.4 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-di one (1R,18S,27R)-3-imino-27-(methoxymethyl)-5,16,16-trimethyl-NH
A = 15,25-dioxa-HN* NV' 2,4,19-226 0 575.3 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18.024,28]tritri aconta-11,13,21,23,28,30-hexaene-20,33-dione O (1R,5R,17S,26R)-NH 0 5-ethy1-3-imino-HNN`s= 26-(methoxymethyl)-15,15-dimethyl-HN 0 14,24-dioxa-2,4,18-227 575.4 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione O (5R,17S)-5-ethyl-3-imino-26-HW N (methoxymethyl)-IL''Th-"-L., 15,15-dimethyl-..

HN-0 14,24-dioxa-/1.
2,4,18,28-228 576.3 tetrazahexacyclo[l 0 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione O (5R,16S)-5-ethyl-NH 3-imino-(methoxymethyl)-HN N
==-= 8,14,14-trimethyl-/"" 0 HN 13,23-dioxa-2,4,17,27-229 576.3 tetrazahexacyclo[l o 7.6.2.22,5.29,12.0 11,16.022,26]hentr iaconta-9,11,19,21,26,28-hexaene-18,31-dione NH
(7R,11R,21S)-7-HNAN".
ethyl-14,14-/I difluoro-9-imino-". 0 23,23-dimethyl-* * HN 0 24-oxa-8,10,20-triazaheptacyclo[l 230A 0 577.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione NH
(7R,11R,21S)-7-HN N"= ethyl-14,14-difluoro-9-imino-23,23-dimethyl-* * HN 0 24-oxa-8,10,20-triazaheptacyclo[l 230B 0 577.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione NH
(7R,11R,21S)-7-HNANµs. ethyl-14,14-difluoro-9-imino-23,23-dimethyl-HN 0 24-oxa-8,10,20-triazaheptacyclo[l 231 0 577.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione \O (1R,5R,16S,17R,2 NH 6R)-5-ethy1-16-HN N"= hydroxy-3-imino-/". 0 ' HN
(methoxymethyl)-16-methyl-14,24-ss dioxa-2,4,18-OH
232 577.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1R,16S,17R,26R) NH "= 0 -16-hydroxy-3-..K. = imino-26-fti (methoxymethyl)-5,15,15-trimethyl-OH
14,24-dioxa-233 577.3 .õ
2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(1R,5R,8Z,16S,17 H N N"= R)-5-ethy1-24,24-difluoro-16-hydroxy-3-imino-HN OH 0 15,15-dimethyl-14-oxa-2,4,18-0<1ZIIIi11IIIJccT579.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione (1R,9R,10S,25S)-14-ethy1-25-A = hydroxy-HN* N"
imino-9-0 (methoxymethyl)-HN9,25 -dimethyl-8,18,23-trioxa-2,11,13-235 579.2 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4(31),5,7(30),19(2 7),20,22(26)-hexaene-3,29-dione F F
(1S,8R,10R,14R,1 NH
7Z)-14-ethyl-12-mik = MI
imino-24,24-HN N"
dimethy1-8-NH
(trifluoromethyl)-4, 236 581.2 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH
(1R,5R,16S,17R)-HNANµs.
5-ethyl-24,24-difluoro-16-/I" = 0 hydroxy-3-imino-HN 0 15,15-dimethyl-14-oxa-2,4,18-237 0 581.3 triazahexacyclo[18 OH
.6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
(7R,11R,21S,23S) HNAN -7-ethy1-9-imino-*
(trifluoromethyl)-* HN 0 14,24-dioxa-8,10,20-triazaheptacyclo[l 583.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione F F
(1S,8S,10R,14R)-NH
\L-F
14-ethyl-12-HNAN imino-24,24-dimethy1-8-/"'. 0 (trifluoromethyl)-NH
23-oxa-2,11,13-239 583.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione F F
F
(1S,8R,10R,14R)-14-ethyl-12-NH
HN N"' imino-24,24-dim ethyl-8-(trifluoromethyl)-NH
=
23-oxa-2,11,13-240 583.2 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione F F
F
(1S,9R,10R,14R)-NH 14-ethyl-H NAN"' imino-24,24-/".. 0 dimethy1-NH
(trifluoromethyl)-23-oxa-2,11,13-241 583.2 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione F F
F
(1S,9S,10R,14R)-NH 14-ethyl-HN
AN" = 411. imino-24,24-dimethy1-9-NH
(trifluoromethyl)-=
23-oxa-2,11,13-242 583.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione NH
(1R,5R,8Z)-5-HNAN = ethy1-16-hydroxy-/"" 3-imino-(trifluoromethyl)-* OH 14,24-dioxa-2,4,18-F

243 585.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-di one (5R,15R,17S)-5-HNAN ethyl-3-imino-26-I 0HN 1\1 methyl-y' (trifluoromethyl)-O
14,24-dioxa-2,4,18,28-. F
244 0 586.3 tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-di one NH (1R,5R)-5-ethyl-hydroxy-3 -"" imino-15-(tri fluorom ethyl)-* OH 14,24-dioxa-2,4,18-F

245 587.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-di one (1R,9E,185,27R)-NH '=a 5-ethy1-3-imino-)1.N`s = 27-(methoxymethyl)-16,16-dimethyl-HN 0 15,25-dioxa-2,4,19-246 587.3 triazahexacyclo[19 .6.2.22,5.211,14.0 13,18. 024,28]tritri aconta-9,11,13,21,23,28,3 0-heptaene-20,33 -di one O
(1R,5R,8Z,16S,17 NH 0 R,26S)-5-ethy1-16-H N". hydroxy-3-imino-(methoxymethyl)-.s.PH 15,15-dimethyl-14,24-dioxa-247 0 589.6 2,4,18¨

triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NO
(7R,11R,12R,21R, NH 0 22 S)-7-ethy1-22-HNN's= hydroxy-9-imino-/" LJ 12-' (methoxymethy1)-22-methyl-14 24-OH
dioxa-8,10,20-248 0 589.3 triazaheptacyclo[l 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione O
(1R,5R,8E,16S,17 NH 0 R,26R)-5-ethyl-HN.A..N`s= 16-hydroxy-3-imino-26-"
HN
(methoxymethyl)-15,15-dimethyl-OH
14,24-dioxa-249 0 589.3 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione [(1R,5R,16S,17R)-5-ethy1-3-imino-0 15,15-dimethyl-19,32-dioxo-o 's% 14,24-dioxa-2,4,18-250 589.2 triazahexacyclo[ 1 8 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaen-16-yl]
acetate (1S,9R,10S,14R)-14-ethyl-12-imino-9-(methoxymethyl)-NH
---9,25,25-trimethyl-H N N ' :
8,24-dioxa-r 2,11,13-251 589.4 triazahexacyclo[18 .6.2.24,7.211,14.0 6,10.023,27]clotria conta-4(32),5,7(31),20(2 8),21,23(27)-hexaene-3,30-dione (1 S,14R,17Z,24R) NH
HNAN
-14-ethyl-8,8-difluoro-12-imino-" " 0 24-HN
(trifluoromethyl)-\ 23-oxa-2,5,11,13-252 590.2 tetrazahexacyclo[l 7.6.2.24,7.211,14.
06,10.022,26]hentr iaconta-4,6,17,19(27),20,2 2(26),30-heptaene-3,29-dione NH (1 S,10R,14R,24R) -14-ethyl-8,8-HN
difluoro-12-imino-/ = 0 24-NH

(trifluoromethyl)-F 23-oxa-2,11,13-253 591.3 triazahexacyclo[17 .6.2.24,7.211,14.0 6,10.022,26]hentri aconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione CY" (1R,5R,16S,17R,2 NH = 0 6R)-5-ethy1-16-HN N"= hydroxy-3 -imino-HN

(methoxymethyl)-15,15-dimethyl-14,24-dioxa-254 0 591.3 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione O
(1R,5R,16S,17R,2 NH 0 6S)-5-ethy1-16-HNAN". 26-HN
hydroxy-3-imino-/".. 110/
(methoxymethyl)-15,15-dimethyl-14,24-dioxa-255 0 591.3 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione (1 S,14R,24R)-14-NH
ethy1-8,8-difluoro-HN N 12-imino-(trifluoromethyl)-HN 23-oxa-2,5,11,13-tetrazahexacyclo[l 256 592.2 ""
7.6.2.24,7.211,14.
06,10.022,26]hentr iaconta-4,6,19(27),20,22(2 6),30-hexaene-3,29-dione F F
(7R,11R,13R,20S) -7-ethy1-9-imino-NH
HNANµ'. 22,22-dimethyl-/"..
(trifluoromethyl)-* NH
=
23-oxa-8,10,19-257 595.3 triazaheptacyclo[l 8.6.2.27,10.214,17 .02,4.011,15.024,2 8]dotriaconta-1(27),14,16,24(28) ,25,29-hexaene-18,31-dione 0.
(1S,15R,16R,24R) hydroxy-3-.A. = imino-24-HN* N"
(methoxymethyl)-methyl-5-HN
.õOH pheny1-23-oxa-595.2 2,4,17-triazahexacyclo[17 .5.2.22,5.210,13.0 12,16.022,25]triac onta-10,12,19,21,25,27-hexaene-18,30-dione NH
(1R,5R,17S)-8-HNAN`s. (di 5-ethyl-8-HN 0 5-ethy1-hydroxy-3-imino-HO
15,15-dimethyl-14,24-dioxa-0 2,4,18-259A 597.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione NH
(1R,5R,17S)-8-HN)L-N`s.
(difluoromethy1)-/...

5-ethyl-8-hydroxy-3-imino-HO
15,15-dimethyl-14,24-dioxa-0 2,4,18-259B 597.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione NH (7R,11R)-7-ethyl-hydroxy-9-/' 0 = imino-23-* *
(trifluoromethyl)-* OH 14,24-dioxa-8,10,20-triazaheptacyclo[l 599.3 9.6.2.27,10.215,18 .02,4.011,16.025,2 9]tritriaconta-1(28),15(31),16,18 (30),25(29),26-hexaene-19,32-dione F F
(1R,5R,17S,26S)-NH 5-ethy1-3-imino-HN,Jt.N`s. 15,15-dimethyl-/I''. 26-HN
(trifluoromethyl)-14,24-dioxa-261 599.3 triazahexacyclo[18 2,4,18¨
.6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione F F
(1R,5R,17S,26R)-NH 0 5-ethy1-3-imino-HN)LN" 15,15-dimethyl-,.. = 26-(trifluoromethyl)-HN 0 14,24-dioxa-2,4,18-262 599.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione NH
[(1R,5R,16S,17R)-HN N 's= 5-ethy1-3-imino-/"" 15,15-dimethyl-H N
19,32-dioxo-0 14,24-dioxa-2,4,18-263 603.3 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaen-16-yl]
propanoate (1R,5R,8Z,15R,17 NH 0 S,26R)-5-ethy1-3-HN-jc`s. imino-26-(methoxymethyl)-"

(trifluoromethyl)-14,24-dioxa-F
264 "ir F 613.2 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione O
(5R,8Z,15R,17S)-NH 5-ethy1-3-imino-H N \
(methoxymethyl)-/

(trifluoromethyl)-\
14,24-dioxa-, F
265 0 F 614.2 2,4,18,28-tetrazahexacyclo[1 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-8,10,12,20,22,27,2 9-heptaene-19,32-dione NH
(1R,5R,17S)-5-ethy1-9-hydroxy-/"" 0 3-imino-15,15-F
HN dimethy1-*
(trifluoromethyl)-F
14,24-dioxa-0 2,4,18-266 615.2 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10(30),11,13(29),2 0,22,27-hexaene-19,32-dione O
(1R,5R,15R,17S,2 NH "O 6R)-5-ethy1-3-HNAN`s. imino-26-/
(methoxymethyl)-F

(trifluoromethyl)-14,24-dioxa-267 0 F 615.2 2,4,18-triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaene-19,32-dione CY- (5R,15R,17S)-5-NH 0 ethy1-3-imino-26-HNN (methoxymethyl)-..., `-r 15-(trifluoromethyl)-HN 0 14,24-dioxa-2,4,18,28-268 616.2 0 rF
tetrazahexacyclo[l 8.6.2.22,5.210,13.
012,17.023,27]dot riaconta-10,12,20,22,27,29-hexaene-19,32-dione [(1R,5R,16S,17R)-HN.1t.N`s. 5-ethy1-3-imino-0 15,15-dimethyl-19,32-dioxo-14,24-dioxa-2,4,18-269 617.4 triazahexacyclo[18 .6.2.22,5.210,13.0 12,17.023,27]dotri aconta-10,12,20,22,27,29-hexaen-16-yl] 2-methylpropanoate Assessing antiparasite potency in a parasite LDH growth assay (Parasite Assay) The parasite stock was maintained at 4% haematocrit in RPMI-Hepes media 30 buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5% albumax.
Approximately 42 hours prior to the potency assay being set up, parasites were synchronized with 5% sorbitol to select for ring stage parasites. On the day of assay set up, a blood smear of the parasite culture was Giemsa stained and counted. The parasitemia was 35 adjusted to 0.7%
rings and the haematocrit was diluted to 2% in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5%
albumax. 30u1 of diluted parasites are then added into lOul of media + compound in pre-prepared Greiner TC
assay plates. Parasite assay plates were placed in gassed humidified boxes in single layer and allowed to incubate at 37 C for 72 hours. After 72 hours growth, assay plates are sealed with parafilm and frozen flat, in single file at -80 C overnight. On the following day, assay plates are allowed to thaw at room temperature for 4 hours to which an LDH assay is performed to measure parasite growth.
Assay EC50 results are shown in Table 2.
Table 2 Example EC50 (nM) 1 2.7 2 11.0 3A 0.2 3B 269.8 4 2.0 5 0.2 5a 0.9 6 2.8 7 0.9 8 1.1 9 76.5 10 2.5 11 4.6 12 1.0 13 22.0 14 34.0 15A 9.2 15B 81.0 16A 61.5 16B 3.4 17 18.9 18 6.0 19 4.8 3.6 21 5.1 22 57.4 23 7.5 24A 5.4 24B 2.0 25A 23.0 25B 0.7 26A 189.7 26B 7.4 28 19.4 29 6.3 30 11.3 31 7.8 32 0.7 33 1.0 34 1.6 35 2.5 36 7.0 37 6.2 38 0.7 39 1.7 40 7.0 41 8.8 42 0.7 43 0.7 44 0.8 45 1.5 46 2.6 47 4.2 48 6.0 49 7.3 50 7.7 51 9.1 52 19.5 53 0.7 54 0.7 55 3.1 56 0.2 57 0.3 58 0.4 59 0.6 60 0.9 61 1.0 62 1.0 63 1.8 64 1.9 65 2.0 66 2.2 67 2.6 68 4.8 69 12.0 70 18.0 71 0.7 72 0.7 73 2.1 74 5.2 75A 0.8 75B 1.3 76 0.3 77 7.0 78 0.5 79 0.6 80 0.6 81 0.6 82 0.6 83 0.7 84 1.4 85 2.1 86 2.4 87 3.4 88 3.6 89 5.1 90 6.8 91 0.5 92 6.5 93 3.0 94 8.8 95 1.0 96 1.2 97 1.5 98 2.6 99 3.3 100 7.7 101 8.3 102 0.8 103 6.7 104 0.3 105 0.7 106 0.7 107 0.7 108 0.8 109 1.0 110 1.8 111 0.6 112 0.3 113 0.7 114 1.5 115 3.4 116 0.3 117 0.4 118 0.6 119 1.4 120 1.5 121A 1.6 121B 0.5 121C 0.6 121D 5.7 122 1.9 123 2.3 124 3.8 125 6.0 126 0.8 127 0.6 128 0.3 129 1.1 130 1.9 131 2.1 132 10.6 133 0.3 134 0.3 135 0.5 136 0.9 137 2.0 138 1.6 139A 0.3 139B 0.8 140A 1.0 140B 1.4 141 7.3 142 1.4 143 7.3 144 0.3 145 0.2 146 0.6 147 0.7 148 0.7 149 0.8 150 0.9 151 1.0 152 1.2 153 5.9 154 6.2 155 6.2 156 9.6 157 1.0 158 0.3 159 0.6 160 0.6 161 0.7 162A 1.4 162B 1.1 163 1.1 164 2.1 165 2.4 166 0.4 167 0.4 168 1.2 169 1.4 170 2.5 171 2.9 172 3.1 173 3.2 174 3.4 175 5.0 176 5.3 177 0.7 178 0.4 179 0.8 180 6.7 181 0.6 182 0.8 183 2.4 184 0.9 185 19.5 186 0.8 187 0.6 188 0.6 189 19.4 190 0.5 191 1.0 192 0.9 193 1.7 194 0.9 195 1.1 196 3.6 197 6.6 198 0.7 199 1.9 200 0.4 201 0.6 202 1.1 203 1.8 204 3.2 205 0.3 206 0.9 207 1.9 208 0.7 209 0.4 210 0.7 211 0.7 212 0.9 213 1.2 214 1.9 215 0.6 216 0.2 217 5.6 218 7.5 219A 2.5 219B 6.4 220 1.0 221A 5.4 221B 2.0 222 2.7 223 0.7 224 2.7 225 0.4 226 0.7 227 0.8 228 0.4 229 19.0 230A 0.9 230B 0.8 231 1.1 232 0.2 233 0.8 234 3.1 235 0.4 236 0.8 237 0.7 238 0.8 239 0.2 240 0.6 241 0.7 242 1.2 243 0.4 244 2.4 245 1.4 246 7.4 247 0.3 248 0.7 249 1.2 250 1.3 251 1.0 252 2.1 253 1.0 254 0.3 255 1.2 256 0.7 257 0.6 258 2.4 259A 9.9 259B 2.3 260 0.8 261 2.3 262 6.7 263 0.9 264 0.8 265 1.0 266 16.0 267 1.0 268 1.9 269 1.1

Claims

WHAT IS CLAIMED:

1. A compound having the structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3-C1o)alkylene or cycloalkyl(C3-C1o)alkylene comprising at least one ¨CH2- group, wherein one or more additional ¨CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of 0, S, NR, CONR, NRCO, S02, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl;
X is a bond, C(R")2, 0, S, SO, SO2 or NH;
Y is CR9 or N, wherein when Y is N, Z is CR" and V is CR10;
V is CR' or N, wherein when V is N, Z is CR" and Y is CR9;
Z is CR" or N, wherein when Z is N, V is CR1- and Y is CR9;
R is hydrogen, C1-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Ci-C6a1ky1OH, COC1-C6alkyl or COOC1-C6alkyl;
Ra is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky10C1-C6alkyl, C1-C6a1ky1COOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cyc1oalkyl, C1-C6alkyl C6cycloalkyl, C1-C6alkyl, -C1-C6a1ky1Oha1oC1-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(10), N(R7)(1e) or C1-C6a1ky1N(R7)(1e) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky10C1-C6alkyl, C1-C6a1ky1COOH, COOH, oxo, COOCI-C6alkyl, Ci-C6a1ky1COOCI-C6alkyl, C3-C6cycloalkyl, CI-C6alkylC3-C6cycloalkyl, CI-C6alkyl, -CI-C6alkylOhaloCi-C6alkyl, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(R8), N(R7)(R8) and Ci-C6a1ky1N(R7)(R8);
Rb is hydrogen, halogen, CN, OH, Cl-C6a1koxy, CI-C6alkylOCi-C6alkyl, Ci-C6a1ky1COOH, COOH, oxo, COOC1-C6alkyl, C1-C6a1ky1COOC1-C6alkyl, C3-C6cycloalkyl, Ci-C6a1ky1C3-C6cycloalkyl, Ci-C6alkyl, -C1-C6a1ky1Oha1oC1-C6alkyl, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(R8), N(R7)(R8) or C1-C6a1ky1N(R7)(R8) or when taken with Ra forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or three substituents selected from the group consisting of halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, oxo, COOCI-C6alkyl, Ci-C6a1ky1COOC1-C6alkyl, C3-C6cycloalkyl, C1-C6a1ky1C3-C6cycloalkyl, -Ci-C6alkylOhaloC1-C6alkyl, haloCi-C6alkyl, C1-C6a1kylOH, CON(R7)(R8), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
R3 is hydrogen, halogen, CN, OH, C1-C6a1koxy, CI-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, C3 -C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8), Cl-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2)nN(R7)(R8) or Ci-C6alkylOhaloCi-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;
R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, CI-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, C3-C6cycloalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8), Ci-C6alkylN(R7)(R8), Ci-C6alkyl(OCH2CH2)11N(R7)(R8) or C1-C6a1ky1Oha1oC1-C6alkyl or when taken with R3 forms a C3-C6cyc1oa1ky1 or C3-C6beterocyc1oa1ky1;
R7 is hydrogen, Ci-C6a1ky1COOH, COOH, C3-C6cycloalkyl, Cl-C6alkyl, ha1oC1-C6alkyl, Ci-C6a1ky1OH, COC1-C6alkyl or COOCI-C6alkyl;
R8 is hydrogen, Ci-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Ci-C6a1ky1OH, COC1-C6alkyl or COOC1-C6alkyl;
R9 is hydrogen, halogen, CN, OH, C1-C6a1koxy, CI-C6alkylOCi-C6alkyl, C1-C6a1ky1COOH, COOH, C3 -C6cycloalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6a1ky1N(R7)(R8);
R1 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, C3 -C6cycloalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
Rll is hydrogen, halogen, CN, OH, Ci-C6alkoxy, C1-C6a1ky1OC1-C6alkyl, Ci-C6a1ky1COOH, COOH, C3 -C6cycloalkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6a1ky1N(R7)(R8);

R12 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, C3-C6cycloalkyl, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkylOH, CON(R7)(R8), N(R7)(R8) or Ci-C6a1ky1N(R7)(R8);
R13 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky1OC1-C6alkyl, C1-C6a1ky1COOH, COOH, C3 -C6CyClOalkyl, Cl-C6alkyl, hal0C1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6a1ky1N(R7)(R8);
each occurrence of Rt4 is independently selected from the group consisting of hydrogen, halogen, CN, OH, CI-CGalkoxy, C1-C6alkylOCi-C6alkyl, Ci-C6a1ky1COOH, COON, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(R8), N(R7)(1V) and Ci-C6a1ky1N(R7)(R8);
Ri5 is hydrogen, halogen, CN, OH, C1-C6a1koxy, C1-C6a1ky1OC1-C6alkyl, C1-C6a1ky1C0OH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(R8), N(R7)(R8) or Ci-C6alkylN(R7)(R8);
each occurrence of Rt6 is independently selected from the group consisting of hydrogen, halogen, CN, 011, Ci-C6a1koxy, Ci-C6a1ky1OCI-C6alkyl, CI-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, C1-C6a1ky1OH, CON(R7)(118), N(R7)(R8) and Ci-C6alkylN(R7)(R8);
m is 0 or 1, n is 1, 2, 3 or 4; and pisOor 1

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, p is 1 and X is O.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, p is 1 and X is a bond.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a heterocycloalkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a heterocycloalkyl, wherein the heterocycloalkyl is , and wherein the heterocycloalkyl is substituted with two Ci-C6alkyl groups.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a C3-C6cycloalkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a C3-C6cycloalkyl, wherein the heterocycloalkyl is , and wherein the C3-C6cycloalkyl is unsubstituted or substituted with OH.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, C1-C6a1ky1OC1-C6alkyl or Ci-C6alkyl or when taken with R4 forms a C3-C6heterocycloalkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen or C1-C6alkyl or when taken with R4 forms a C3-C6heterocycloalkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein le and R4 are both halogen.

1 1 . The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R15 is hydrogen or Ci-C6alkyl.

1 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from the group consisting of hydrogen, halogen, OH, Ci-C6a1ky1OH, Ci-C6alkylalkoxy, Ci-C6alkyl0Cl-C6alkyl, C1-C6alkyl, C1-C6alkylOhaloCl-C6alkyl, CON(C1-C6alky1)2, C1-C6alkylN(R7)(R8) and C1-C6alkyl(OCH2CH*N(R7)(12.8);
R7 is hydrogen, C1-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCi-C6alkyl, Ci-C6a1ky1OH, COC1-C6alkyl or COOC1-C6alkyl;
R8 is hydrogen, C1-C6a1ky1COOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloCl-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6a1kyl; and n is 3 .

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R12 and R" are independently selected from the group consisting of hydrogen, halogen, OH, CI-C6a1ky1OH, Ci-C6alkylalkoxy and Ci-C6alkylOCl-C6alkyl, Ci-C6alkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C(R")2, R" is independently selected from the group consisting of hydrogen, halogen, OH, Ci-C6alkylOH, C1-C6alkylalkoxy, C1-C6alkylOC1-C6alkyl and C1-C6alkyl.

15. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

16. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

17. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein V is CH.

18. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is a straight, saturated or unsaturated (C3-C1o)alkylene.

19. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is a branched, saturated or unsaturated (C3-C1o)alkylene.

20. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is

21. A compound selected from the group consisting of , or a pharmaceutically acceptable salt thereof.

22. A compound having the formula or a pharmaceutically acceptable salt thereof.

23. A compound having the formula , or a pharmaceutically acceptable salt thereof.

24. A compound having the formula:

, or a pharmaceutically acceptable salt thereof.

25. A method for treating a Plasmodium infection, or for treating malaria, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof.

26. A method for inhibiting plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof.

27. A method for inhibiting plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof.

28. A method for dual inhibition of plasmepsin X and plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof.

29. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to treat a Plasmodium infection, or malaria in a patient in need thereof

30. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to inhibit plasmepsin X in a patient in need thereof.

31. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to inhibit plasmepsin IX in a patient in need thereof

32. The use of a compound, or pharmaceutically acceptable salt thereof, of claim 1 to inhibit plasmepsin IX and plasmepsin X, in a patient in need thereof.

33. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

35. A method for treating a Plasmodium infection, or for treating malaria, comprising administration of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an effective amount of one or more additional anti-malarial agents.

36. A method for the treatment of malaria by inhibition of plasmepsin X, IX
and at least one other mechanism, comprising administration of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an effective amount of one additional anti-malarial agent, wherein the additional anti-malarial agent acts through a different mechanism than inhibiting plasmepsin IX or plasmepsin X.