Antimalarial agents

Abstract

To provide novel compounds that inhibit Plasmodium falciparum aspartic acid protease plasmepsin X and / or plasmepsin IX of a falciparum malaria parasite and enable treatment of a Plasmodium infection and / or malaria.SOLUTION: Provided are compounds of Formula (I) in the figure or a pharmaceutically acceptable salt thereof. Also provided are uses of the compounds of Formula (I) for inhibiting plasmepsin X activity, plasmepsin IX activity or plasmepsin X and IX activity, for treating a Plasmodium infection, and for treating malaria.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) or their derivatives which are useful for treating malaria parasite infections. More particularly, the present invention relates to a pharmaceutically acceptable salt of the compound of formula (I) for the treatment of malaria parasite infections. Compounds of formula (I) or their derivatives useful in the treatment of malaria, in particular It relates to physiologically acceptable salts. [Background technology]

[0002] Malaria is a major human disease, infecting hundreds of millions of people and killing more than 450,000 people each year. The most deadly form of malaria is caused by Plasmodium falciparum alciparum), a protozoan parasite that is responsible for almost all Plasmodium falciparum (P. falciparum) undergoes a complex life cycle that begins inside the body of the Anopheles mosquito vector. These sporozoites are injected into the human host during a blood meal. The virus migrates to the liver and invades hepatocytes, where it grows and forms thousands of liver merozoites, which then The liver merozoites leave the liver cells and enter the bloodstream, where they invade red blood cells and cause malaria. This initiates the asexual reproduction cycle of the parasite, which causes the symptoms of They grow in a protected niche and form 16-32 merozoites. Once mature, they leave the host cell and invade new red blood cells. Some of these parasites differentiate These produce gametocytes, the sexual form of the parasite. These are then ingested by the mosquito. There, male and female gametes form, fuse, and are deposited in the extracellular matrix of the mosquito's midgut. Sporozoites are formed within the oocyst and emerge from it. As the parasite travels, it migrates to the salivary glands and is delivered to the next host during a blood meal for persistence and survival of the parasite. will be done.

[0003] Another form of malaria is caused by Plasmodium vivax (P. vivax). There is a relapsing form of malaria that is associated with significant morbidity. It is the cause of the disease, which can cause a partially fatal pathological form of the disease, and is primarily It is a problem outside of Africa. It is a zoonotic parasite found in Asia, usually infecting cynomolgus monkeys, but in Malaysia It has been shown to infect humans on the island of Borneo.

[0004] Artemisinin in combination with partner drugs has become a mainstay in the treatment and control of malaria. However, there is a threat of drug resistance to artemisinin-based combination therapy (ACT). As a result of the increasing popularity of methicillin-resistant Staphylococcus aureus, new drugs that inhibit multiple stages in the parasite's life cycle are being developed. The development of novel targeted antimalarial drugs is an urgent priority for the field of malaria control. Such novel antimalarials (e.g., monotherapy or ACT partner drugs) may be Malaria is a rare disease, as it is unlikely that parasites with existing resistance mutations exist in the parasite population. This could be a step towards eradicating ria.

[0005] Currently, aspartic proteases are major targets for drug development: HIV Aspartic proteases have been successfully targeted with drugs in clinical use. Inhibitors targeting human renin, BACE1, and γ-secretase are already in clinical development. In the field of antimalarial drugs, Aspartic acid proteases plasmepsin X and plasmepsin IX (PMX and and PMIX) have been identified as potential targets, since inhibitors may be able to inhibit the parasite's host cells. It prevents escape from the vacuole and entry into the host cell, and some rhoptryta are required for this process. This is because it prevents the maturation of proteins and microneme proteins (Pino P , Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage a ntimalarial targets the plasmepsins IX a nd X essential for invasion and egress. Science. 2017;358(6362):522-8). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] 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 [Means for solving the problem]

[0007] The present invention relates to a compound of formula (I): [ka]

[0008] [In the formula, A, X, V, Y, Z, R a , R b , R 3 , R 4 , R 12 , R 13 , R 15 , m and and p are explained below. The present invention relates to compounds represented by the following formula:

[0009] Further, the present disclosure provides a method for administering to a subject in need of treatment for a malaria parasite infection, a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also described herein are methods for treating malaria infections. administering to a subject in need of treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It is written.

[0010] Further provided herein is a method for administering to a subject in need of treatment for malaria a compound of formula (I) and a method for treating malaria comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. It is written.

[0011] The present invention further provides compositions (including pharmaceutical compositions) for treating malaria. ), wherein the composition comprises one or more compounds of the invention (e.g., one or more compounds of the invention). or a tautomer thereof, or a pharmaceutical composition of said compound and / or said tautomer a commercially available commercially acceptable salt or solvate thereof, optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent. .

[0012] Furthermore, the present invention relates to a method for treating malaria, the method comprising administering to a subject a compound of formula (I) or (II) of the present invention. , for inhibiting plasmepsin X, or for inhibiting plasmepsin X and plasmepsin IX The present invention provides a method of using a pharmaceutical composition for dual inhibition of a steroid hormone, wherein the pharmaceutical composition comprises: one or more of the compounds in free form or in the form of a pharmaceutically acceptable salt thereof, in one or more conventional The compound or salt combination of the present invention may be administered in combination with one or more additional pharmaceutical excipients. Methods for use with other pharmaceutically active agents are also provided.

[0013] The present invention further relates to a method for inhibiting plasmepsin X or a method for inhibiting plasmepsin X and plasmepsin X. Method for dual inhibition of smepsin IX activity and plasmepsin X and / or plasmepsin X activity Diseases or disorders for which inhibition of smepsin IX has or could have a therapeutic effect (e.g., methods of treating, preventing, or ameliorating diseases (e.g., malaria) and / or methods of preventing or ameliorating such diseases; and a method for delaying the onset of a disease or disorder.

[0014] The present invention further provides a method for inhibiting Plasmodium falciparum aspartic protease. The present invention further provides a method for treating Plasmodium falciparum malaria by inhibiting plasmepsin X. The present invention further provides a method for inhibiting the growth of P. falciparum. , by inhibiting both PMX and plasmepsin IX, Plasmodium falciparum (P. The present invention provides a method for inhibiting the growth of F. falciparum.

[0015] The present invention further provides a method for treating malaria by inhibiting plasmepsin X. The present invention further provides a method for treating psoriasis by inhibiting both PMX and plasmepsin IX. This provides a method for treating malaria.

[0016] These and other embodiments of the invention are described in detail below or are incorporated herein by reference. Such embodiments, as will be apparent to those skilled in the art, are included within the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] Described herein are compounds of structural formula (I): [ka]

[0018] [During the ceremony, A is a linear or branched, saturated or unsaturated ( C3-C 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl ( C3-C 10 ) alkylene, where one or more additional —CH2— groups in A are independently and selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR. and wherein one of the hydrogens along A is The above are hydroxyl, halogen and C 1-3 haloalkyl Can be replaced; X is a bond, C(R 14 )2, O, S, SO, SO2 or NH; Y is CR 9 or N, where when Y is N, Z is CR 11 and V is CR10 and; V is CR 10 or N, where when V is N, Z is CR 11 and , Y is CR 9 and; Z is CR 11 or N, where when Z is N, V ​​is CR 10 and , Y is CR 9 and; R is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C 1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl; R a is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )( R 8 ) or R b When combined with C3-C6 cycloalkyl or heteroalkyl wherein the C3-C6 cycloalkyl or heterocycloalkyl forms Alkyl is unsubstituted or substituted with halogen, CN, OH, C1-C6 alkoxy. , C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, Oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C 3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl -C1-C6 alkyl, -C1-C6 alkyl, -haloC1-C6 alkyl, -haloC1-C6 alkyl, C 1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 Rukill N(R 7 )(R 8 and substituted with one or two substituents selected from the group consisting of Cage; R b is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )( R 8 ) or R a When combined with C3-C6 cycloalkyl or heteroalkyl wherein the C3-C6 cycloalkyl or heterocycloalkyl forms Alkyl is unsubstituted or substituted with halogen, CN, OH, C1-C6 alkoxy. , C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, Oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C 3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl -C1-C6 alkyl, -C1-C6 alkyl, -haloC1-C6 alkyl, -haloC1-C6 alkyl, C 1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 Rukill N(R 7 )(R 8 ) is substituted with 1 to 3 substituents selected from the group consisting of: R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1- C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylO (b) C1-C6 alkyl, or R 4 When combined with forming a C3-C6 heterocycloalkyl or C3-C6 heterocycloalkyl; R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1- C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylO (b) C1-C6 alkyl, or R 3 When combined with forming a C3-C6 heterocycloalkyl or C3-C6 heterocycloalkyl; R 7 is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C 6 alkyl or COOC1-C6 alkyl; R 8 is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C 6 alkyl or COOC1-C6 alkyl; R 9 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and ; R 10 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 11 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 12 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 13 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 alkyl Chloroalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH , CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of: R 15 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 16 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 alkyl Chloroalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH , CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of: m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. It is a compound having the formula:

[0019] In the embodiments described herein, X is a bond, C(R 14 )2, O, S, S O, SO2, or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R 14 )2, where R 14 About are discussed in more detail below. In certain embodiments, X is a bond, CH, CH( CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In certain embodiments, X is CH, O, S, SO, SO, or NH. X is CH2. In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments, X is SO. In certain embodiments described herein, X is N It's H.

[0020] In the embodiments described herein, Y is CR 9 Or N. In this state, Y is CR 9 where R 9are discussed in more detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In the form, if Y is N, then Z is CR 11 and V is CR 10 is.

[0021] In the embodiments described herein, V is CR 10 Or N. In the form, V is CR 10 where R 10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In this embodiment, when V is N, Z is CR 11 and Y is CR 9 is.

[0022] In the embodiments described herein, Z is CR 11 Or N. In the form, Z is CR 11 where R 11 is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In this embodiment, when Z is N, V ​​is CR 10 and Y is CR 9 is.

[0023] In certain embodiments, X is O, Y and V are each CH, and Z is N In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O and V, Y and Z are all simultaneously It is CH.

[0024] In the compounds described herein, Ra are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC 1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 cycloa alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC 1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R b to be together with When C is substituted, it forms a C-C cycloalkyl or heterocycloalkyl, The 3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or Halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1 -C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1 -C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )( R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) from the group consisting of It is substituted with one or two selected substituents.

[0025] In certain embodiments described herein, R a is hydrogen.

[0026] In certain embodiments, R a is a halogen. Suitable examples of halogens include chlorine, These include bromine, fluorine and iodine.

[0027] In certain embodiments, R a is CN.

[0028] In certain embodiments, R a is OH.

[0029] In certain embodiments, R a is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0030] In certain embodiments, R a is C1-C6 alkylOC1-C6 alkyl.

[0031] In certain embodiments, R a is C1-C6 alkyl COOH.

[0032] In certain embodiments, R a is COOH.

[0033] In certain embodiments, R a is an oxo group.

[0034] In certain embodiments, R a is COOC1-C6 alkyl.

[0035] In certain embodiments, R a is C1-C6 alkylCOOC1-C6 alkyl.

[0036] In certain embodiments, R a is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0037] In certain embodiments, R a is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0038] etc.

[0039] In certain embodiments, R a is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R a teeth, It is methyl.

[0040] In certain embodiments, R ais C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0041] etc.

[0042] In certain embodiments, R a is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0043] In certain embodiments, R a is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0044] In certain embodiments, R a is CON(R 7 )(R 8 In certain embodiments, R a is N(R 7 )(R 8 In certain embodiments, R a is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0045] In certain embodiments, the compounds described herein have the formula (II): [ka]

[0046] It is expressed as:

[0047] In certain embodiments, R a is R b together with C3-C6 cycloalkyl or hexamethylcycloalkyl. forming a heterocycloalkyl, wherein said C3-C6 cycloalkyl or heterocycloalkyl Alkyl is unsubstituted or substituted with halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, o Xo, COOC1-C6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3 -C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1 -C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 Al Kill N(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of do.

[0048] In certain embodiments, R a is R b together to form a C3-C6 cycloalkyl wherein the cycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC 1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 cycloa alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC 1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) 1 or 2 selected from the group consisting of is substituted with the substituent

[0049] Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl ... cyclobutyl, cyclopentyl and cyclohexyl.

[0050] In certain embodiments, the cycloalkyl is unsubstituted. The heterocycloalkyl may be selected from halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, CO OC1-C6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cyclo cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C 1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy Kill OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0051] In certain embodiments, the cycloalkyl is selected from halogen, CN, OH, C1-C6 alkoxy. Oxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COO H, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl , C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C 6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C 6AlkylN(R 7 )(R 8 ) is substituted with one substituent selected from the group consisting of

[0052] In certain embodiments, the cycloalkyl is selected from halogen, CN, OH, C1-C6 alkoxy. Oxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COO H, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl , C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C 6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C 6AlkylN(R 7 )(R 8 ) is substituted with two substituents selected from the group consisting of

[0053] In certain embodiments, the cycloalkyl is substituted with OH.

[0054] In certain embodiments, R a is R b together with wherein the heterocycloalkyl is unsubstituted or substituted with halogen, CN, OH , C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkyl COO C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 cyclo Alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )( R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) or It is substituted with 2 substituents.

[0055] Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, Pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- Dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam lactams, delta lactams, beta lactones, gamma lactones, delta lactones and pyrrolidinones and Non-limiting examples of heterocycloalkyl groups include, but are not limited to, Although, [ka]

[0056] etc.

[0057] Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to: [ka]

[0058] etc.

[0059] In certain embodiments, R a is R b Together with [ka]

[0060] Form.

[0061] In certain embodiments, the heterocycloalkyl is unsubstituted. wherein the heterocycloalkyl is halogen, CN, OH, C1-C6 alkoxy, C1 -C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo , COOC1-C6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C 6 cycloalkyl, C1-C6 alkyl C3-C6 cycloalkyl, C1-C6 alkyl , -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C 6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkyl N(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0062] In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C1-C6 Alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C 1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1-C6 alkylN(R 7 )(R 8 ) substituted with one substituent selected from the group consisting of There are.

[0063] In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C1-C6 Alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C 1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1-C6 alkylN(R 7 )(R 8 and substituted with two substituents selected from the group consisting of There are.

[0064] In certain embodiments, the heterocycloalkyl is selected from the group consisting of C1-C6 alkyl. It is substituted with two selected substituents.

[0065] In the compounds described herein, R b are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC 1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 cycloa alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC 1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R a to be together with When C is substituted, it forms a C-C cycloalkyl or heterocycloalkyl, The 3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or Halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1 -C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1 -C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )( R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) from the group consisting of It is substituted with one or two selected substituents.

[0066] In certain embodiments described herein, R b is hydrogen.

[0067] In certain embodiments, R b is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0068] In certain embodiments, R b is CN.

[0069] In certain embodiments, R b is OH.

[0070] In certain embodiments, R b is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0071] In certain embodiments, R b is C1-C6 alkylOC1-C6 alkyl.

[0072] In certain embodiments, R b is C1-C6 alkyl COOH.

[0073] In certain embodiments, R b is COOH.

[0074] In certain embodiments, R b is an oxo group.

[0075] In certain embodiments, R b is COOC1-C6 alkyl.

[0076] In certain embodiments, R bis C1-C6 alkylCOOC1-C6 alkyl.

[0077] In certain embodiments, R b is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0078] In certain embodiments, R b is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0079] etc.

[0080] In certain embodiments, R b is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R b teeth, It is methyl.

[0081] In certain embodiments, R b is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0082] etc.

[0083] In certain embodiments, R b is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0084] In certain embodiments, R b is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0085] In certain embodiments, R b is CON(R 7 )(R 8 In certain embodiments, R b is N(R 7 )(R 8 In certain embodiments, R b is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0086] In certain embodiments, R b is R a together with a cycloalkyl or heterocyclo alkyl, wherein the cycloalkyl or heterocycloalkyl is substituted No or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

[0087] In certain embodiments, R b is R a together with The cycloalkyl may be unsubstituted or may be substituted with halogen, CN, OH, C1-C6 Alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C 1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R8 ), N(R 7 )(R 8 ) and C 1-C6 alkylN(R 7 )(R 8 and one or two substituents selected from the group consisting of It has been replaced.

[0088] Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl ... cyclobutyl, cyclopentyl and cyclohexyl.

[0089] In certain embodiments, the cycloalkyl is unsubstituted. The heterocycloalkyl may be selected from halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, CO OC1-C6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cyclo cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C 1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy Kill OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0090] In certain embodiments, the cycloalkyl is selected from halogen, CN, OH, C1-C6 alkoxy. Oxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COO H, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl , C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C 6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C 6AlkylN(R 7 )(R 8 ) is substituted with one substituent selected from the group consisting of

[0091] In certain embodiments, the cycloalkyl is selected from halogen, CN, OH, C1-C6 alkoxy. Oxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COO H, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl , C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C 6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C 6AlkylN(R 7 )(R 8 ) is substituted with two substituents selected from the group consisting of

[0092] In certain embodiments, the cycloalkyl is substituted with OH.

[0093] In certain embodiments, R b is R a together with wherein the heterocycloalkyl is unsubstituted or substituted with halogen, CN, OH , C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkyl COO C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 cyclo Alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )( R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) or It is substituted with 2 substituents.

[0094] Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, Pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- Dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam lactams, delta lactams, beta lactones, gamma lactones, delta lactones and pyrrolidinones and Non-limiting examples of heterocycloalkyl groups include, but are not limited to, Although, [ka]

[0095] etc.

[0096] Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to: [ka]

[0097] etc.

[0098] In certain embodiments, R b is R a Together with [ka]

[0099] Form.

[0100] In certain embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is selected from the group consisting of halogen, C N, OH, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl, C1-C 6 alkyl COOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkyl COO-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl C3-C 6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl HaloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N( R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 1 selected from the group consisting of or 2 substituents. In certain embodiments, the cycloalkyl or heterocycloalkyl Chloroalkyl is halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 In certain embodiments, the cycloalkyl group is substituted with one substituent selected from the group consisting of: The cycloalkyl or heterocycloalkyl is selected from halogen, CN, OH, C1-C6 alkoxy, , C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, Oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C 3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl -C1-C6 alkyl, -C1-C6 alkyl, -haloC1-C6 alkyl, -haloC1-C6 alkyl, C 1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 Rukill N(R 7 )(R 8 ) is substituted with two substituents selected from the group consisting of

[0101] In certain embodiments, the heterocycloalkyl is selected from the group consisting of C1-C6 alkyl. In certain embodiments, the cycloalkyl is substituted with two selected substituents. and substituted with two substituents selected from the group consisting of 1-C6 alkyl. In some embodiments, the cycloalkyl is unsubstituted.

[0102] In the embodiments described herein, R3 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1 -C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4 When taken together, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl Form.

[0103] In certain embodiments of the compounds described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1- C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 ) (R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 4 together When the aryl group is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a halogen Suitable halogens include fluorine, chlorine, bromine and iodine. In the embodiment, R 3 is CN. In certain embodiments, R 3 is OH.

[0104] In certain embodiments, R 3 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 3 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 3 is COOH. is R 3 is C1-C6 alkylCOOH. In certain embodiments, R 3 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 3 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 3 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 3 is CON(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of CONH2 and CON(CH3) include, but are not limited to, CONH2 and CON(CH3) In certain embodiments, R 3 is N(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 3 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0105] R7 and R 8 is discussed in more detail below.

[0106] In certain embodiments, R 3 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, [ka]

[0107] etc.

[0108] In certain embodiments, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )( R 8 ) R 7 , R 8 and n are discussed in detail below. Kill (OCH2CH2) n N(R 7 )(R 8 Suitable examples of But, [ka]

[0109] etc.

[0110] For the compounds described herein, n is 1, 2, 3, or 4. In embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0111] In certain embodiments, R 3 is R 4 together with C3-C6 cycloalkyl or C In certain embodiments, R 3 is R 4 together and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include the following: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is R 4 Together with C3-C6 hetero Suitable examples of heterocycloalkyl include, but are not limited to, However, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomo thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrofuranyl Dorothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ These include lactones and pyrrolidinones and their oxides.

[0112] In certain embodiments, R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0113] is.

[0114] In certain embodiments, R 3 is hydrogen, methyl, ethyl or [ka]

[0115] is.

[0116] In certain embodiments, R 3 is R 4 together to form oxetanyl.

[0117] In certain embodiments described herein, R 4 are hydrogen, halogens, CN, O H, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkoxy COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1- C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) , C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N (R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or , R 3 When taken together with In certain embodiments of the compounds described herein, R 4 teeth, Hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 Alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1- C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or is R 3 When taken together with C3-C6 cycloalkyl or C3-C6 heterocyclo In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is a halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 OH is.

[0118] In certain embodiments, R 4 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 4 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 4 is COOH. is R 4 is C1-C6 alkylCOOH. In certain embodiments, R 4 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 4 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 4 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 4 is CON(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of CONH2 and CON(CH3) include, but are not limited to, CONH2 and CON(CH3) In certain embodiments, R 4 is N(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 4 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0119] R 7 and R 8 is discussed in more detail below.

[0120] In certain embodiments, R 4 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, [ka]

[0121] etc.

[0122] In certain embodiments, R 4 is C1-C6 alkyl (OCH2CH2) n N(R 7 )( R 8 ) R 7 , R 8 is discussed in detail below, and n is discussed above. C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) suitable Suitable examples include, but are not limited to: [ka]

[0123] etc.

[0124] In certain embodiments, R 4 is R 3 together with C3-C6 cycloalkyl or C In certain embodiments, R 4 is R 3 together and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include the following: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 4 is R 3 Together with C3-C6 hetero Suitable examples of heterocycloalkyl include, but are not limited to, However, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomo thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrofuranyl Dorothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ These include lactones and pyrrolidinones and their oxides.

[0125] In certain embodiments, R 4 is hydrogen or methyl. In certain embodiments, R 4 teeth, Hydrogen, methyl, ethyl or [ka]

[0126] In certain embodiments, R 4 is R 3 together to form oxetanyl. In certain embodiments, R 3 and R 4 are both hydrogen, methyl or ethyl.

[0127] In certain embodiments, R 3 is hydrogen, and R 4 is hydrogen.

[0128] In certain embodiments, R 3 and R 4 are both halogens, In certain embodiments, R is selected from fluorine, chlorine, bromine, and iodine.3 and R 4 are both fluorine atoms.

[0129] In the embodiments described herein, R 5 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0130] In certain embodiments described herein, R 5 is hydrogen.

[0131] In certain embodiments, R 5 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0132] In certain embodiments, R 5 is CN.

[0133] In certain embodiments, R 5 is OH.

[0134] In certain embodiments, R 5 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0135] In certain embodiments, R 5 is C1-C6 alkylOC1-C6 alkyl.

[0136] In certain embodiments, R 5 is C1-C6 alkyl COOH.

[0137] In certain embodiments, R 5 is COOH.

[0138] In certain embodiments, R 5 is an oxo group.

[0139] In certain embodiments, R 5 is COOC1-C6 alkyl.

[0140] In certain embodiments, R 5 is C1-C6 alkylCOOC1-C6 alkyl.

[0141] In certain embodiments, R 5 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0142] In certain embodiments, R 5 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0143] etc.

[0144] In certain embodiments, R 5 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R 5 teeth, It is methyl.

[0145] In certain embodiments, R 5 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0146] etc.

[0147] In certain embodiments, R 5 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0148] In certain embodiments, R 5 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0149] In certain embodiments, R 5 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 5 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0150] In certain embodiments, R 5 is hydrogen, methyl, ethyl or t-butyl.

[0151] In the embodiments described herein, R 6 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0152] In certain embodiments described herein, R 6 is hydrogen.

[0153] In certain embodiments, R 6 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0154] In certain embodiments, R 6 is CN.

[0155] In certain embodiments, R 6 is OH.

[0156] In certain embodiments, R 6 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0157] In certain embodiments, R 6 is C1-C6 alkylOC1-C6 alkyl.

[0158] In certain embodiments, R 6 is C1-C6 alkyl COOH.

[0159] In certain embodiments, R 6 is COOH.

[0160] In certain embodiments, R 6 is an oxo group.

[0161] In certain embodiments, R 6 is COOC1-C6 alkyl.

[0162] In certain embodiments, R 6 is C1-C6 alkylCOOC1-C6 alkyl.

[0163] In certain embodiments, R 6 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0164] In certain embodiments, R 6 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0165] etc.

[0166] In certain embodiments, R 6 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R6 teeth, It is methyl.

[0167] In certain embodiments, R 6 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0168] etc.

[0169] In certain embodiments, R 6 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0170] In certain embodiments, R 6 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0171] In certain embodiments, R 6 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 6 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8is explained in detail below. .

[0172] In certain embodiments, R 6 is hydrogen, methyl, ethyl or t-butyl.

[0173] In the embodiments described herein, R 7 is hydrogen, C1-C6 alkyl COO H, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R 7 is hydrogen, C1-C6 alkyl COOH, COOH, C 3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 It is alkyl-OH.

[0174] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C6 In certain embodiments, R 7 is COOH. In this state, R 7 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include , including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclo hexyl, etc. In certain embodiments, R 7 is C1-C6 alkyl. Examples of C6 alkyl groups include, but are not limited to, methyl, ethyl, and n-propyl. , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl ethylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl Silyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methyl Examples of propyl esters include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. In terms of form, R 7 is haloC1-C6 alkyl. Suitable examples of haloalkyl include: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 is C1-C6 alkylOH. Examples of suitable alcohols Examples of the alcohol include, but are not limited to, methanol, ethanol, propanol, and butanol. Examples include alcohol and isobutanol.

[0175] In certain embodiments, R 7 is COC1-C6 alkyl. Suitable examples include Examples include, but are not limited to, COCH3. In certain embodiments, R 7 COOC Suitable examples include, but are not limited to, COOCH3. There are some.

[0176] In the embodiments described herein, R 8 is hydrogen, C1-C6 alkyl COO H, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R 8 is hydrogen, C1-C6 alkyl COOH, COOH, C 3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 It is alkyl-OH.

[0177] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C1-C6 In certain embodiments, R 8 is COOH. In this state, R 8 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include , including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclo hexyl, etc. In certain embodiments, R 8 is C1-C6 alkyl. Examples of C6 alkyl groups include, but are not limited to, methyl, ethyl, and n-propyl. , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl ethylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl Silyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methyl Examples of propyl esters include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. In terms of form, R 8 is haloC1-C6 alkyl. Suitable examples of haloalkyl include: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8 is C1-C6 alkylOH. Examples of suitable alcohols Examples of the alcohol include, but are not limited to, methanol, ethanol, propanol, and butanol. Examples include alcohol and isobutanol.

[0178] In certain embodiments, R 8 is COC1-C6 alkyl. Suitable examples include Examples include, but are not limited to, COCH3. In certain embodiments, R 8 COOC Suitable examples include, but are not limited to, COOCH3. There are some.

[0179] In the embodiments described herein, R 9 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is a halogen Suitable halogens include fluorine, chlorine, bromine or iodine. In the embodiment, R 9 is CN. In certain embodiments, R 9 is OH.

[0180] In certain embodiments, R 9 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 9 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 9 is COOH. is R 9 is C1-C6 alkylCOOH. In certain embodiments, R 9 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 9 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 9 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 9 is CON(R 7 )(R 8 ) in a particular implementation In terms of form, R 9 is N(R 7 )(R 8 In certain embodiments, R 9 is C1-C 6AlkylN(R 7 )(R 8 )

[0181] With respect to the compounds described herein, R 10 are hydrogen, halogens, CN, OH , C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C 6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 teeth, Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 10 is CN. In certain embodiments, R 10 is OH do.

[0182] In certain embodiments, R 10 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 10 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 10 is COOH. In terms of form, R 10 is C1-C6 alkylCOOH. In certain embodiments, R 10 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 10 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: Although not specified, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include 1,2-difluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In embodiments, R 10 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol, etc. In certain embodiments, R 10 is CON(R 7 )(R 8 ) In certain embodiments, R 10 is N(R 7 )(R 8 ) In certain embodiments, is R 10 is C1-C6 alkylN(R 7 )(R 8 )

[0183] In the embodiments described herein, R 11 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 11 is CN. In certain embodiments, R 11 is OH .

[0184] In certain embodiments, R 11 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 11 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 11 is COOH. In terms of form, R 11 is C1-C6 alkylCOOH. In certain embodiments, R 11 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 11 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: Although not specified, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include 1,2-difluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In embodiments, R 11 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol, etc. In certain embodiments, R 11 is CON(R 7 )(R 8 ) In certain embodiments, R 11 is N(R 7 )(R 8 ) In certain embodiments, is R 11 is C1-C6 alkylN(R 7 )(R 8 )

[0185] In the embodiments described herein, R 12 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R 12 is hydrogen In certain embodiments, R 12 is a halogen. Suitable halogens include fluorine, In certain embodiments, R 12 is CN. In certain embodiments, R12 is OH.

[0186] In certain embodiments, R 12 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 12 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R 12 is COOH. In the embodiment, R 12 is C1-C6 alkylCOOH. In certain embodiments, R 1 2 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 12is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 12 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 12 is CON(R 7 )(R 8 In certain embodiments, R 12 is N(R 7 )(R 8 ) Specific embodiments So, R 12 is C1-C6 alkylN(R 7 )(R 8 )

[0187] In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0188] is.

[0189] In certain embodiments, R 12 is hydrogen or [ka]

[0190] is In the embodiments described herein, R 13 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R 13 is hydrogen In certain embodiments, R 13 is a halogen. Suitable halogens include fluorine, In certain embodiments, R 13 is CN. In certain embodiments, R 13 is OH.

[0191] In certain embodiments, R 13 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 13 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R 13 is COOH. In the embodiment, R 13 is C1-C6 alkylCOOH. In certain embodiments, R 1 3 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 13 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 13 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 13 is CON(R 7 )(R 8 In certain embodiments, R 13 is N(R 7 )(R 8 ) Specific embodiments So, R 13 is C1-C6 alkylN(R 7 )(R 8 )

[0192] In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0193] is.

[0194] In certain embodiments, R 13 is hydrogen or [ka]

[0195] is.

[0196] In certain embodiments, R 12 and R 13 are independently hydrogen and C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl.

[0197] In certain embodiments described herein, R 14 Each occurrence of is hydrogen, halogen , CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1 -C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, HaloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 Ha, Hello Suitable halogens include fluorine, chlorine, bromine or iodine. In an embodiment of the present invention, R 14 is CN. In certain embodiments, R 14 is OH.

[0198] In certain embodiments, R 14 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 14 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R 14 is COOH. In the embodiment, R 14 is C1-C6 alkylCOOH. In certain embodiments, R 1 4 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 14 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 14 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 14 is CON(R 7 )(R 8 In certain embodiments, R 14 is N(R 7 )(R 8 ) Specific embodiments So, R 14 is C1-C6 alkylN(R 7 )(R 8 )

[0199] In certain embodiments, X is C(R 14 )2, then R 14 is hydrogen, halogen, O H, C1-C6 alkyl OH, C1-C6 alkyl alkoxy, C1-C6 alkyl OC Independently selected from the group consisting of 1-C6 alkyl and C1-C6 alkyl.

[0200] In certain embodiments, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0201] is.

[0202] In the embodiments described herein, R 15 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 15 is hydrogen. In certain embodiments, R 15 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 15 is CN. In certain embodiments, R 15 is OH .

[0203] In certain embodiments, R 15 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 15 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 15 is COOH. In terms of form, R 15 is C1-C6 alkylCOOH. In certain embodiments, R 15 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 15 is ethyl.

[0204] In certain embodiments, R 15 is haloC1-C6 alkyl. Suitable haloalkyl groups are: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl In certain embodiments, R 15 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propane, alcohol, butanol, and isobutanol. In certain embodiments, R 15 teeth, CON(R 7 )(R 8 In certain embodiments, R 15 is N(R 7 )(R 8 )in In certain embodiments, R15 is C1-C6 alkylN(R 7 )(R 8 )

[0205] In certain embodiments, R 15 is methyl or ethyl.

[0206] In the embodiments described herein, R 16 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 16 is hydrogen. In certain embodiments, R 16 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 16 is CN. In certain embodiments, R 16 is OH .

[0207] In certain embodiments, R 16 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 16 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 16 is COOH. In terms of form, R 16 is C1-C6 alkylCOOH. In certain embodiments, R 16 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 16 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 16 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: Although not specified, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include 1,2-difluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In embodiments, R 16 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol, etc. In certain embodiments, R 16 is CON(R 7 )(R 8 ) In certain embodiments, R16 is N(R 7 )(R 8 ) In certain embodiments, is R 16 is C1-C6 alkylN(R 7 )(R 8 )

[0208] In embodiments of the compounds described herein, m is 0 or 1. In embodiments, m is 0. In certain embodiments, m is 1.

[0209] In embodiments of the compounds described herein, p is 0 or 1. In embodiments, p is 0. In certain embodiments, p is 1.

[0210] In the embodiments described herein, A contains at least one -CH2- group. Straight or branched chain saturated or unsaturated (C3-C 10 ) alkylene, phenyl (C3 -C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, where The one or more additional -CH2- groups in A are independently selected from O, S, NR, CONR, NRCO , SO2 and SO2NR. and wherein one or more of the hydrogens along A are selected from hydroxyl, halogen, and C 1- 3 haloalkyl. In this embodiment, A is a linear or branched, saturated or unsaturated (C3-C 10 ) alkylene or cyclo alkyl(C3-C 10 ) alkylene, where one or more -CH2- groups in A are , independently replaced by a moiety selected from the group consisting of O, S, and NH In certain embodiments, A always has at least one -CH2- group.

[0211] In certain embodiments, A is a straight chain (C3-C 10 ) alkylene. Straight chain (C3-C 10 ) Examples of alkylenes are: [ka]

[0212] etc.

[0213] In certain embodiments, A is a branched chain (C3-C 10 ) alkylene. Suitable branched chain (C3-C 10 ) Alkylene includes, but is not limited to, [ka]

[0214] etc.

[0215] In certain embodiments, A is saturated (C3-C 10 ) alkylene. Examples include , [ka]

[0216] etc.

[0217] In certain embodiments, A is an unsaturated (C3-C 10 ) alkylene. Suitable unsaturated (C3-C 10 ) alkylene, the saturated (C3-C 10 ) alkylene In which hydrogen has been removed and there are one or more double covalent bonds between adjacent carbon atoms or triple covalent bonds exist. 10 ) alkylene Examples include, but are not limited to: [ka]

[0218] etc.

[0219] In another embodiment, A is a straight chain cycloalkyl (C-C 10 ) alkylene. Suitable linear cycloalkyl (C3-C 10 ) alkylene, two carbons in the chain are (C 3-C 10 ) Cycloalkyl (C3-C 10 ) alkylene etc. Straight-chain cycloalkyl (C3-C 10 Examples of alkylene include, but are not limited to, Although, [ka]

[0220] etc.

[0221] In certain embodiments, A is a branched cycloalkyl (C-C 10 ) alkylene Suitable branched cycloalkyl (C3-C 10 ) For alkylene, two carbon atoms in the chain (C3-C 10 ) Cycloalkyl contains branched chain (C3-C 10 ) alkylene Cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to, However, [ka]

[0222] etc.

[0223] In certain embodiments, A is saturated cycloalkyl (C-C 10 ) alkylene. Saturated cycloalkyl (C3-C 10 Examples of alkylene include, but are not limited to: , [ka]

[0224] etc.

[0225] In certain embodiments, A is an unsaturated cycloalkyl (C-C 10 ) alkylene Unsaturated cyclo(C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0226] etc.

[0227] In certain embodiments, A is an unsaturated or saturated phenyl (C3-C 10 ) alkylene Unsaturated and saturated phenyl (C3-C 10 ) Examples of alkylene include, but are not limited to: There is no, [ka]

[0228] etc.

[0229] In another embodiment, one or more -CH2- groups in A are independently selected from O, S, NR, CON R, NRCO, SO2, and SO2NR. In another embodiment, one or more -CH2- groups in A are independently selected from O, S and and NH. In some embodiments, one or more -CH2- groups in A may be independently replaced by O. In embodiments, one or more -CH2- groups in A may be independently replaced with S. In another embodiment, one or more -CH2- groups in A are independently replaced with NR. In another embodiment, one or more -CH2- groups in A are independently CONR. In another embodiment, one or more -CH2- groups in A are independently In another embodiment, one or more -CH2 in A may be replaced by NRCO. In another embodiment, one or more of the - groups in A may be independently replaced by SO2. The -CH2- groups above may be independently replaced by SO2NR. , which are described in more detail below.

[0230] In the embodiments described herein, R is hydrogen, C1-C6 alkylCOOH , COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R is hydrogen, C1-C6 alkylCOOH, COOH, C3- C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 ar Kill OH.

[0231] In certain embodiments, R is hydrogen. In certain embodiments, R is C1-C6 alkyl. In certain embodiments, R is COOH. In certain embodiments, R is COOH. and R is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl In certain embodiments, R is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxymethyl Examples include ethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In the form, R is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, However, methanol, ethanol, propanol, butanol and isobutanol are not Tanol, etc.

[0232] In certain embodiments, R is COC1-C6 alkyl. Suitable examples include those having the following limitations: In certain embodiments, R is COOC1- C alkyl. Suitable examples include, but are not limited to, COOCH3. be.

[0233] Examples of such embodiments include, but are not limited to: [ka]

[0234] etc.

[0235] In certain embodiments, A is [ka]

[0236] is.

[0237] In certain embodiments, one or more of the hydrogens along A can be selected from hydroxyl, halogen, and C 1-3 and haloalkyl. Examples of halogens include chlorine, bromine, fluorine, and iodine. ,A is, [ka]

[0238] is.

[0239] Further described herein are compounds of structural formula (III): [ka]

[0240] [During the ceremony, A is a linear or branched, saturated or unsaturated ( C3-C 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl ( C3-C 10 ) alkylene, where one or more additional —CH2— groups in A are independently and selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR. and wherein one of the hydrogens along A is The above are hydroxyl, halogen and C 1-3 haloalkyl Can be replaced; Q is C(R 16 )2, O, S, SO, SO2 or NH; X is a bond, C(R 14 )2, O, S, SO, SO2 or NH; Y is CR 9 or N, where when Y is N, Z is CR 11 and V is CR 10 and; V is CR 10 or N, where when V is N, Z is CR 11 and , Y is CR 9 and; Z is CR 11 or N, where when Z is N, V ​​is CR 10 and , Y is CR 9 and; R is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C 1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl; R 1is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 2 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, oxo, COOC1-C 6 alkyl, C1-C6 alkyl COOC1-C6 alkyl, C3-C6 cycloalkyl , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 a HaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1- C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylO (b) C1-C6 alkyl, or R 4 When combined with forming a C3-C6 heterocycloalkyl or C3-C6 heterocycloalkyl; R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1- C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylO (b) C1-C6 alkyl, or R 3 When combined with forming a C3-C6 heterocycloalkyl or C3-C6 heterocycloalkyl; R 5 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and ; R 6 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and ; R 7 is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C 6 alkyl or COOC1-C6 alkyl; R 8 is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C 6 alkyl or COOC1-C6 alkyl; R 9 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON( R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8) and ; R 10 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 11 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 12 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 13is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 alkyl Chloroalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH , CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of: R 15 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkenyl Chyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON (R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) the law of nature; R 16 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 Alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 alkyl Chloroalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH , CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of: l is 0 or 1; m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. It is a compound having the formula:

[0241] In the embodiments described herein, Q is C(R 16 )2, O, S, SO, S O or NH. In certain embodiments, Q is C(R 16 )2, where R 1 6 are discussed in more detail below. In certain embodiments, Q is CH, C H(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In embodiments, Q is CH, O, S, SO, SO, or NH. In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In another embodiment described herein, Q is SO. In embodiments, Q is SO. Certain embodiments described herein include: Q is NH. In another embodiment described herein, Q is O or SO. In still other embodiments described herein, Q is O or CH2. do.

[0242] In the embodiments described herein, X is a bond, C(R 14 )2, O, S, S O, SO2, or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R 14 )2, where R 14 About are discussed in more detail below. In certain embodiments, X is a bond, CH, CH( CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In certain embodiments, X is CH, O, S, SO, SO, or NH. X is CH2. In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments, X is SO. In certain embodiments described herein, X is N It's H.

[0243] In the embodiments described herein, Y is CR 9 Or N. In this state, Y is CR 9 where R 9 are discussed in more detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In the form, if Y is N, then Z is CR 11 and V is CR 10 is.

[0244] In the embodiments described herein, V is CR 10 Or N. In the form, V is CR 10 where R 10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In this embodiment, when V is N, Z is CR 11 and Y is CR 9 is.

[0245] In the embodiments described herein, Z is CR 11 Or N. In the form, Z is CR 11 where R 11 is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In this embodiment, when Z is N, V ​​is CR 10 and Y is CR 9 is.

[0246] In certain embodiments, X is O, Y and V are each CH, and Z is N In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O and V, Y and Z are all simultaneously It is CH.

[0247] 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.

[0248] Further described herein are compounds of structural formula (IIIA): [ka]

[0249] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described herein As stated] An embodiment of the present invention is a compound represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described in Formula III. Another embodiment of IIIA is R 3 and R 4 are both hydrogen, methyl, ethyl or halogen Another embodiment of Formula IIIA is realized when R 3 and R 4 Both are chlorine and and fluorine. Another embodiment of formula IIIA is , Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or C F2. In another embodiment described herein, the compound of formula III Q in A is O or SO2. In yet another embodiment described herein In formula IIIA, Q is O or CH2. Another embodiment of formula IIIA is a compound in which A is at least Straight or branched chain saturated or unsaturated (C3-C1 0) alkylene, where one or more additional —CH— groups in A are independently selected from O a moiety selected from the group consisting of S, NR, CONR, NRCO, SO2 and SO2NR and wherein one or more of the hydrogens along A is replaced by the structure Hydroxyl, halogen and C 1-3 substituted with a group independently selected from haloalkyl This is realized when it is possible to

[0250] Further described herein are compounds of structural formula (IIIB): [ka]

[0251] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described herein As stated] An embodiment of the present invention is a compound represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described in Formula III. Another embodiment of IIIB is R 3 and R 4 are both hydrogen, methyl, ethyl or halogen Another embodiment of formula IIIB is realized when R 3 and R 4 Both are chlorine and and fluorine. Another embodiment of formula IIIB is , Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or C F2. In another embodiment described herein, the compound of formula III Q in B is O or SO2. In yet another embodiment described herein In formula IIIB, Q is O or CH2. Another embodiment of formula IIIB is a compound in which A is at least Straight or branched chain saturated or unsaturated (C3-C1 0) alkylene, where one or more additional —CH— groups in A are independently selected from O a moiety selected from the group consisting of S, NR, CONR, NRCO, SO2 and SO2NR and wherein one or more of the hydrogens along A is replaced by the structure Hydroxyl, halogen and C 1-3 substituted with a group independently selected from haloalkyl This is realized when it is possible to

[0252] Particular embodiments are: Formulas IV-VI: [ka]

[0253] It is expressed as:

[0254] In the embodiments described herein, R 1 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0255] In certain embodiments described herein, R 1 is hydrogen.

[0256] In certain embodiments, R 1 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0257] In certain embodiments, R 1 is CN.

[0258] In certain embodiments, R 1 is OH.

[0259] In certain embodiments, R 1 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0260] In certain embodiments, R 1 is C1-C6 alkylOC1-C6 alkyl.

[0261] In certain embodiments, R 1 is C1-C6 alkyl COOH.

[0262] In certain embodiments, R 1 is COOH.

[0263] In certain embodiments, R 1 is an oxo group.

[0264] In certain embodiments, R 1 is COOC1-C6 alkyl.

[0265] In certain embodiments, R 1 is C1-C6 alkylCOOC1-C6 alkyl.

[0266] In certain embodiments, R 1 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0267] In certain embodiments, R 1 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0268] etc.

[0269] In certain embodiments, R 1 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- Examples include ethyl-1-methylpropyl.

[0270] In certain embodiments, R 1 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0271] etc.

[0272] In certain embodiments, R 1 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0273] In certain embodiments, R 1 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0274] In certain embodiments, R 1 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 1 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0275] In certain embodiments, R 1 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN is oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.

[0276] In the embodiments described herein, R 2 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0277] In certain embodiments described herein, R 2 is hydrogen.

[0278] In certain embodiments, R 2 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0279] In certain embodiments, R 2 is CN.

[0280] In certain embodiments, R 2 is OH.

[0281] In certain embodiments, R 2is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0282] In certain embodiments, R 2 is C1-C6 alkylOC1-C6 alkyl.

[0283] In certain embodiments, R 2 is C1-C6 alkyl COOH.

[0284] In certain embodiments, R 2 is COOH.

[0285] In certain embodiments, R 2 is an oxo group.

[0286] In certain embodiments, R 2 is COOC1-C6 alkyl.

[0287] In certain embodiments, R 2 is C1-C6 alkylCOOC1-C6 alkyl.

[0288] In certain embodiments, R 2 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0289] In certain embodiments, R 2 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0290] etc.

[0291] In certain embodiments, R 2 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- Examples include ethyl-1-methylpropyl.

[0292] In certain embodiments, R 2 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0293] etc.

[0294] In certain embodiments, R 2 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0295] In certain embodiments, R 2 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0296] In certain embodiments, R 2 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 2 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0297] In certain embodiments, R 2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN is oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.

[0298] In certain embodiments, R 1 and R 2 and are both hydrogen. In certain embodiments, R 1 is OH, and R 2 is hydrogen.

[0299] In the embodiments described herein, R 3 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1 -C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4 When taken together, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl Form.

[0300] In certain embodiments of the compounds described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1- C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 ) (R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 4 together When the aryl group is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a halogen Suitable halogens include fluorine, chlorine, bromine and iodine. In the embodiment, R 3is CN. In certain embodiments, R 3 is OH.

[0301] In certain embodiments, R 3 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 3 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 3 is COOH. is R 3 is C1-C6 alkylCOOH. In certain embodiments, R 3 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 3 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 3 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 3 is CON(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of CONH2 and CON(CH3) include, but are not limited to, CONH2 and CON(CH3) In certain embodiments, R 3 is N(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 3 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0302] R 7 and R 8 is discussed in more detail below.

[0303] In certain embodiments, R 3is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, [ka]

[0304] etc.

[0305] In certain embodiments, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )( R 8 ) R 7 , R 8 and n are discussed in detail below. Kill (OCH2CH2) n N(R 7 )(R 8 Suitable examples of But, [ka]

[0306] etc.

[0307] For the compounds described herein, n is 1, 2, 3, or 4. In embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0308] In certain embodiments, R 3 is R 4 together with C3-C6 cycloalkyl or C In certain embodiments, R 3 is R 4 together and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include the following: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is R 4 Together with C3-C6 hetero Suitable examples of heterocycloalkyl include, but are not limited to, However, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomo thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrofuranyl Dorothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ These include lactones and pyrrolidinones and their oxides.

[0309] In certain embodiments, R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0310] is.

[0311] In certain embodiments, R 3 is hydrogen, methyl, ethyl or [ka]

[0312] is.

[0313] In certain embodiments, R 3 is R 4 together to form oxetanyl.

[0314] In certain embodiments described herein, R 4 are hydrogen, halogens, CN, O H, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkoxy COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1- C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) , C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N (R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or , R 3 When taken together with In certain embodiments of the compounds described herein, R 4 teeth, Hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 Alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1- C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or is R 3 When taken together with C3-C6 cycloalkyl or C3-C6 heterocyclo In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is a halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 OH is.

[0315] In certain embodiments, R 4 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 4 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 4 is COOH. is R 4 is C1-C6 alkylCOOH. In certain embodiments, R 4 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 4 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 4 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 4 is CON(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of CONH2 and CON(CH3) include, but are not limited to, CONH2 and CON(CH3) In certain embodiments, R 4 is N(R 7 )(R 8 ). N(R 7 ) (R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 4 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0316] R 7 and R 8 is discussed in more detail below.

[0317] In certain embodiments, R 4 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, [ka]

[0318] etc.

[0319] In certain embodiments, R 4 is C1-C6 alkyl (OCH2CH2) n N(R 7 )( R 8 ) R 7 , R 8 is discussed in detail below, and n is discussed above. C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) suitable Suitable examples include, but are not limited to: [ka]

[0320] etc.

[0321] In certain embodiments, R 4 is R 3 together with C3-C6 cycloalkyl or C In certain embodiments, R 4 is R 3 together and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include the following: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is R 3 Together with C3-C6 hetero Suitable examples of heterocycloalkyl include, but are not limited to, However, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomo thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrofuranyl Dorothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ These include lactones and pyrrolidinones and their oxides.

[0322] In certain embodiments, R 4 is hydrogen or methyl. In certain embodiments, R 4 teeth, Hydrogen, methyl, ethyl or [ka]

[0323] In certain embodiments, R 4 is R 3 together to form oxetanyl. In certain embodiments, R 3 and R 4 are both hydrogen, methyl or ethyl.

[0324] In certain embodiments, R 3 is hydrogen, and R 4 is hydrogen.

[0325] In the embodiments described herein, R 5 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0326] In certain embodiments described herein, R 5 is hydrogen.

[0327] In certain embodiments, R 5 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0328] In certain embodiments, R 5 is CN.

[0329] In certain embodiments, R 5 is OH.

[0330] In certain embodiments, R 5 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0331] In certain embodiments, R 5 is C1-C6 alkylOC1-C6 alkyl.

[0332] In certain embodiments, R 5 is C1-C6 alkyl COOH.

[0333] In certain embodiments, R5 is COOH.

[0334] In certain embodiments, R 5 is an oxo group.

[0335] In certain embodiments, R 5 is COOC1-C6 alkyl.

[0336] In certain embodiments, R 5 is C1-C6 alkylCOOC1-C6 alkyl.

[0337] In certain embodiments, R 5 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0338] In certain embodiments, R 5 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0339] etc.

[0340] In certain embodiments, R 5 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R 5 teeth, It is methyl.

[0341] In certain embodiments, R 5 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0342] etc.

[0343] In certain embodiments, R 5 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0344] In certain embodiments, R 5 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0345] In certain embodiments, R 5 is CON(R 7 )(R 8In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 5 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0346] In certain embodiments, R 5 is hydrogen, methyl, ethyl or t-butyl.

[0347] In the embodiments described herein, R 6 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1 -C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl, C3-C6 cycloalkyi alkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1 -C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

[0348] In certain embodiments described herein, R 6 is hydrogen.

[0349] In certain embodiments, R 6 is a halogen. Examples of suitable halogens include chlorine, These include bromine, fluorine and iodine.

[0350] In certain embodiments, R 6 is CN.

[0351] In certain embodiments, R 6 is OH.

[0352] In certain embodiments, R 6 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and Examples include n-butoxy.

[0353] In certain embodiments, R 6 is C1-C6 alkylOC1-C6 alkyl.

[0354] In certain embodiments, R 6 is C1-C6 alkyl COOH.

[0355] In certain embodiments, R 6 is COOH.

[0356] In certain embodiments, R 6 is an oxo group.

[0357] In certain embodiments, R 6 is COOC1-C6 alkyl.

[0358] In certain embodiments, R 6 is C1-C6 alkylCOOC1-C6 alkyl.

[0359] In certain embodiments, R 6 is C3-C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Examples include ethyl and cyclohexyl.

[0360] In certain embodiments, R 6 is C1-C6 alkyl C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, [ka]

[0361] etc.

[0362] In certain embodiments, R 6 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups Examples of aryl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl butyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1- ethyl-1-methylpropyl, etc. In certain embodiments, R 6 teeth, It is methyl.

[0363] In certain embodiments, R 6 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to, But, [ka]

[0364] etc.

[0365] In certain embodiments, R 6 is haloC1-C6 alkyl. Suitable haloalkyl groups include Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl Examples include:

[0366] In certain embodiments, R 6 is C1-C6 alkylOH. Suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol.

[0367] In certain embodiments, R 6 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 6 is C1-C6 alkyl N(R 7 )(R 8 ), where R 7 and R 8 is explained in detail below. .

[0368] In certain embodiments, R 6 is hydrogen, methyl, ethyl or t-butyl.

[0369] In the embodiments described herein, R 7 is hydrogen, C1-C6 alkyl COO H, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R 7 is hydrogen, C1-C6 alkyl COOH, COOH, C 3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 It is alkyl-OH.

[0370] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C6 In certain embodiments, R 7 is COOH. In this state, R 7 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include , including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclo hexyl, etc. In certain embodiments, R 7 is C1-C6 alkyl. Examples of C6 alkyl groups include, but are not limited to, methyl, ethyl, and n-propyl. , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl ethylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl Silyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methyl Examples of propyl esters include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. In terms of form, R 7is haloC1-C6 alkyl. Suitable examples of haloalkyl include: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 is C1-C6 alkylOH. Examples of suitable alcohols Examples of the alcohol include, but are not limited to, methanol, ethanol, propanol, and butanol. Examples include alcohol and isobutanol.

[0371] In certain embodiments, R 7 is COC1-C6 alkyl. Suitable examples include Examples include, but are not limited to, COCH3. In certain embodiments, R 7 COOC Suitable examples include, but are not limited to, COOCH3. There are some.

[0372] In the embodiments described herein, R 8 is hydrogen, C1-C6 alkyl COO H, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R 8 is hydrogen, C1-C6 alkyl COOH, COOH, C 3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 It is alkyl-OH.

[0373] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C1-C6 In certain embodiments, R 8is COOH. In this state, R 8 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include , including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclo hexyl, etc. In certain embodiments, R 8 is C1-C6 alkyl. Examples of C6 alkyl groups include, but are not limited to, methyl, ethyl, and n-propyl. , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl ethylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl Silyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methyl Examples of propyl esters include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. In terms of form, R 8 is haloC1-C6 alkyl. Suitable examples of haloalkyl include: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8 is C1-C6 alkylOH. Examples of suitable alcohols Examples of the alcohol include, but are not limited to, methanol, ethanol, propanol, and butanol. Examples include alcohol and isobutanol.

[0374] In certain embodiments, R8 is COC1-C6 alkyl. Suitable examples include Examples include, but are not limited to, COCH3. In certain embodiments, R 8 COOC Suitable examples include, but are not limited to, COOCH3. There are some.

[0375] In the embodiments described herein, R 9 are hydrogen, halogens, CN, OH, C 1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylC OOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is a halogen Suitable halogens include fluorine, chlorine, bromine or iodine.

[0376] In certain embodiments, R 9 is CN. In certain embodiments, R 9 is OH .

[0377] In certain embodiments, R 9 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and and n-butoxy. In certain embodiments, R 9 is C1-C6 alkyl OC1- C alkyl. In certain embodiments, R 9 is COOH. is R 9 is C1-C6 alkylCOOH. In certain embodiments, R 9 is C3- Suitable examples of cycloalkyl include, but are not limited to, C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9 is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-di Methylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpropyl 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl butylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl In certain embodiments, R 9 Ha, Hello Suitable examples of haloalkyl include, but are not limited to, C1-C6 alkyl. , fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1, In certain embodiments, 2-difluoroethyl and 2,2-difluoroethyl are included. R 9 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to: but not methanol, ethanol, propanol, butanol and isobutanol In certain embodiments, R 9 is CON(R7 )(R 8 ) in a particular implementation In terms of form, R 9 is N(R 7 )(R 8 In certain embodiments, R 9 is C1-C 6AlkylN(R 7 )(R 8 )

[0378] With respect to the compounds described herein, R 10 are hydrogen, halogens, CN, OH , C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C 6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 teeth, Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 10 is CN. In certain embodiments, R 10 is OH do.

[0379] In certain embodiments, R 10 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 10 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 10 is COOH. In terms of form, R10 is C1-C6 alkylCOOH. In certain embodiments, R 10 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 10 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: Although not specified, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include 1,2-difluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In embodiments, R 10 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol, etc. In certain embodiments, R 10 is CON(R7 )(R 8 ) In certain embodiments, R 10 is N(R 7 )(R 8 ) In certain embodiments, is R 10 is C1-C6 alkylN(R 7 )(R 8 )

[0380] In the embodiments described herein, R 11 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 11 is CN. In certain embodiments, R 11 is OH .

[0381] In certain embodiments, R 11 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 11 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 11 is COOH. In terms of form, R11 is C1-C6 alkylCOOH. In certain embodiments, R 11 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 11 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: Although not specified, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include 1,2-difluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In embodiments, R 11 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol, etc. In certain embodiments, R 11 is CON(R7 )(R 8 ) In certain embodiments, R 11 is N(R 7 )(R 8 ) In certain embodiments, is R 11 is C1-C6 alkylN(R 7 )(R 8 )

[0382] In the embodiments described herein, R 12 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R 12 is hydrogen In certain embodiments, R 12 is a halogen. Suitable halogens include fluorine, In certain embodiments, R 12 is CN. In certain embodiments, R 12 is OH.

[0383] In certain embodiments, R 12 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 12 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R12 is COOH. In the embodiment, R 12 is C1-C6 alkylCOOH. In certain embodiments, R 1 2 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 12 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 12 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 12 is CON(R 7 )(R 8 In certain embodiments, R 12 is N(R 7 )(R 8 ) Specific embodiments So, R 12 is C1-C6 alkylN(R 7 )(R 8 )

[0384] In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0385] is.

[0386] In certain embodiments, R 12 is hydrogen or [ka]

[0387] is.

[0388] In the embodiments described herein, R 13 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R13 is hydrogen In certain embodiments, R 13 is a halogen. Suitable halogens include fluorine, In certain embodiments, R 13 is CN. In certain embodiments, R 13 is OH.

[0389] In certain embodiments, R 13 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 13 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R 13 is COOH. In the embodiment, R 13 is C1-C6 alkylCOOH. In certain embodiments, R 1 3 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 13 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 13 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 13 is CON(R 7 )(R 8 In certain embodiments, R 13 is N(R 7 )(R 8 ) Specific embodiments So, R 13 is C1-C6 alkylN(R 7 )(R 8 )

[0390] In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0391] is.

[0392] In certain embodiments, R 13 is hydrogen or [ka]

[0393] is.

[0394] In certain embodiments, R 12 and R 13 are independently hydrogen and C1-C6 alkylO C1-C6 alkyl, C1-C6 alkyl.

[0395] In certain embodiments described herein, R 14 Each occurrence of is hydrogen, halogen , CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1 -C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, HaloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) independently selected from the group consisting of In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 Ha, Hello Suitable halogens include fluorine, chlorine, bromine or iodine. In an embodiment of the present invention, R 14 is CN. In certain embodiments, R 14 is OH.

[0396] In certain embodiments, R 14 is C1-C6 alkoxy. Suitable alkoxy groups include Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, In certain embodiments, R 14 is C1-C6 alkylO C1-C6 alkyl. In certain embodiments, R 14 is COOH. In the embodiment, R 14 is C1-C6 alkylCOOH. In certain embodiments, R 1 4 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. propyl, 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 In certain embodiments, examples include 1-ethyl-1-methylpropyl and 1-ethyl-1-methylpropyl. , R 14 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl Examples include fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In an embodiment of the present invention, R 14 is C1-C6 alkylOH. Examples of suitable alcohols are Examples include, but are not limited to, methanol, ethanol, propanol, butanol, and and isobutanol. In certain embodiments, R 14 is CON(R 7 )(R 8 In certain embodiments, R 14 is N(R 7 )(R 8 ) Specific embodiments So, R 14 is C1-C6 alkylN(R 7 )(R 8 )

[0397] In certain embodiments, X is C(R 14 )2, then R 14 is hydrogen, halogen, O H, C1-C6 alkyl OH, C1-C6 alkyl alkoxy, C1-C6 alkyl OC Independently selected from the group consisting of 1-C6 alkyl and C1-C6 alkyl.

[0398] In certain embodiments, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0399] is.

[0400] In the embodiments described herein, R 15 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 15 is hydrogen. In certain embodiments, R 15 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 15 is CN. In certain embodiments, R 15 is OH .

[0401] In certain embodiments, R 15 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 15 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 15 is COOH. In terms of form, R 15 is C1-C6 alkylCOOH. In certain embodiments, R 15 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15 is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 15 is ethyl.

[0402] In certain embodiments, R 15 is haloC1-C6 alkyl. Suitable haloalkyl groups are: Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl In certain embodiments, R 15 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propane, alcohol, butanol, and isobutanol. In certain embodiments, R 15 teeth, CON(R 7 )(R 8 In certain embodiments, R 15 is N(R 7 )(R 8 )in In certain embodiments, R 15 is C1-C6 alkylN(R 7 )(R 8 )

[0403] In certain embodiments, R 15 is methyl or ethyl.

[0404] In the embodiments described herein, R 16 are hydrogen, halogens, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 Alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 )in In certain embodiments, R 16 is hydrogen. In certain embodiments, R 16 Ha, ha Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R 16 is CN. In certain embodiments, R 16 is OH .

[0405] In certain embodiments, R 16 is C1-C6 alkoxy. Suitable alkoxy includes Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 16 is C1-C6 alkyl OC 1-C6 alkyl. In certain embodiments, R 16 is COOH. In terms of form, R 16 is C1-C6 alkylCOOH. In certain embodiments, R 16 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. There is.

[0406] In certain embodiments, R 16 is a C1-C6 alkyl group. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl butyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methyl Pentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylbutyl 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1 In certain embodiments, R 16 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl Fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In this state, R 16 is C1-C6 alkylOH. Examples of suitable alcohols include Examples include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 16 is CON(R 7 )(R 8 ) In certain embodiments, R 16 is N(R 7 )(R 8 In certain embodiments, R 16 is C1-C6 alkylN(R 7 )(R 8 )

[0407] In embodiments of the compounds described herein, 1 is 0 or 1. In embodiments, l is 0. In certain embodiments, l is 1.

[0408] In embodiments of the compounds described herein, m is 0 or 1. In embodiments, m is 0. In certain embodiments, m is 1.

[0409] In embodiments of the compounds described herein, p is 0 or 1. In embodiments, p is 0. In certain embodiments, p is 1.

[0410] In certain embodiments, m and p are 1 and X is O.

[0411] In certain embodiments, m and p are 1 and X is CH2.

[0412] In certain embodiments, m is 0, p is 1, and X is O.

[0413] In certain embodiments, m and p are 1 and X is SO2.

[0414] In certain embodiments, m is 0, p is 1, and X is C(R 14 )2 where R 14 Each occurrence of is hydrogen, halogen, OH, C1-C6 alkoxy, and Independently selected from the group consisting of C1-C6 alkyl.

[0415] In certain embodiments, m is 1 and X is C(R 14 )2, where: R 14 Each occurrence of is hydrogen, halogen, OH, C1-C6 alkoxy and C1-C6 alkyl are independently selected from the group consisting of:

[0416] For example, in certain embodiments of formula (I), as shown in formula (VII): l is 0; m is 1; p is 1; X is O; V, Y and Z are CH and Q is CH2. [ka]

[0417] For example, in certain embodiments of formula (I), as shown in formula (VIII): , l, m, and p are 1; X is O; V, Y, and Z are CH; and Q is O. be. [ka]

[0418] In the embodiments described herein, A contains at least one -CH2- group. Straight or branched chain saturated or unsaturated (C3-C 10 ) alkylene, phenyl (C3 -C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, where The one or more additional -CH2- groups in A are independently selected from O, S, NR, CONR, NRCO , SO2 and SO2NR. and wherein one or more of the hydrogens along A are selected from hydroxyl, halogen, and C 1- 3 haloalkyl. In this embodiment, A is a linear or branched, saturated or unsaturated (C3-C 10 ) alkylene or cyclo alkyl(C3-C 10 ) alkylene, where one or more -CH2- groups in A are , independently replaced by a moiety selected from the group consisting of O, S, and NH In certain embodiments, A always has at least one -CH2- group.

[0419] In certain embodiments, A is a straight chain (C3-C 10 ) alkylene. Straight chain (C3-C 10 ) Examples of alkylenes are: [ka]

[0420] etc.

[0421] In certain embodiments, A is a branched chain (C3-C 10 ) alkylene. Suitable branched chain (C3-C 10 ) Alkylene includes, but is not limited to, [ka]

[0422] etc.

[0423] In certain embodiments, A is saturated (C3-C 10 ) alkylene. Examples include , [ka]

[0424] etc.

[0425] In certain embodiments, A is an unsaturated (C3-C 10 ) alkylene. Suitable unsaturated (C3-C 10 ) alkylene, the saturated (C3-C 10 ) alkylene In which hydrogen has been removed and there are one or more double covalent bonds between adjacent carbon atoms or triple covalent bonds exist. 10 ) alkylene Examples include, but are not limited to: [ka]

[0426] etc.

[0427] In another embodiment, A is a straight chain cycloalkyl (C-C 10 ) alkylene. Suitable linear cycloalkyl (C3-C 10 ) alkylene, two carbons in the chain are (C 3-C 10 ) Cycloalkyl (C3-C 10 ) alkylene etc. Straight-chain cycloalkyl (C3-C 10 Examples of alkylene include, but are not limited to, Although, [ka]

[0428] etc.

[0429] In certain embodiments, A is a branched cycloalkyl (C-C 10 ) alkylene Suitable branched cycloalkyl (C3-C 10 ) For alkylene, two carbon atoms in the chain (C3-C 10 ) Cycloalkyl contains branched chain (C3-C 10 ) alkylene Cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to, However, [ka]

[0430] etc.

[0431] In certain embodiments, A is saturated cycloalkyl (C-C 10 ) alkylene. Saturated cycloalkyl (C3-C 10 Examples of alkylene include, but are not limited to: , [ka]

[0432] etc.

[0433] In certain embodiments, A is an unsaturated cycloalkyl (C-C 10 ) alkylene Unsaturated cyclo(C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0434] etc.

[0435] In certain embodiments, A is an unsaturated or saturated phenyl (C3-C 10 ) alkylene Unsaturated and saturated phenyl (C3-C 10 ) Examples of alkylene include, but are not limited to: There is no, [ka]

[0436] etc.

[0437] In another embodiment, one or more -CH2- groups in A are independently selected from O, S, NR, CON R, NRCO, SO2, and SO2NR. In another embodiment, one or more -CH2- groups in A are independently selected from O, S and and NH. In some embodiments, one or more -CH2- groups in A may be independently replaced by O. In embodiments, one or more -CH2- groups in A may be independently replaced with S. In another embodiment, one or more -CH2- groups in A are independently replaced with NR. In another embodiment, one or more -CH2- groups in A are independently CONR. In another embodiment, one or more -CH2- groups in A are independently In another embodiment, one or more -CH2 in A may be replaced by NRCO. In another embodiment, one or more of the - groups in A may be independently replaced by SO2. The -CH2- groups above may be independently replaced by SO2NR. , which are described in more detail below.

[0438] In the embodiments described herein, R is hydrogen, C1-C6 alkylCOOH , COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl , C1-C6 alkylOH, COC1-C6 alkyl or COOC1-C6 alkyl In certain embodiments, R is hydrogen, C1-C6 alkylCOOH, COOH, C3- C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 ar Kill OH.

[0439] In certain embodiments, R is hydrogen. In certain embodiments, R is C1-C6 alkyl. In certain embodiments, R is COOH. In certain embodiments, R is COOH. and R is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl In certain embodiments, R is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl Phenyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isobutyl sopentyl, 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-ethylbutyl Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: However, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxymethyl Examples include ethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In the form, R is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, Examples include methanol, ethanol, propanol, and butanol. and iso-butanol.

[0440] In certain embodiments, R is COC1-C6 alkyl. Suitable examples include those having the following limitations: In certain embodiments, R is COOC1- C alkyl. Suitable examples include, but are not limited to, COOCH3. be.

[0441] Examples of such embodiments include, but are not limited to: [ka]

[0442] etc.

[0443] In certain embodiments, A is [ka]

[0444] is.

[0445] In certain embodiments, one or more of the hydrogens along A can be selected from hydroxyl, halogen, and C 1-3 and haloalkyl. Examples of halogens include chlorine, bromine, fluorine, and iodine. ,A is, [ka]

[0446] is.

[0447] In each of the various embodiments of the present invention, the compounds used in the methods herein In each of the variables (each of formulas (I) to (VIII) and their various embodiments), It is understood that each moiety (including the elements of a group) is selected independently of the other moieties unless otherwise indicated. can be.

[0448] In each of the various embodiments of the present invention, each of Formulas (I) through (VIII) and their The compounds described herein, including those in various embodiments thereof, are The various forms of the compound, for example, any solvates, hydrates, stereoisomers and It may exist in the form of tautomers as well as any pharmaceutically acceptable salts thereof.

[0449] In certain embodiments, the compounds described herein include the following compounds: : [ka] TIFF2025183301000085.tif234135TIFF2025183301000086.tif235133TIFF2025183301000087.tif203135 TIFF2025183301000088.tif197133TIFF2025183301000089.tif190134TIFF2025183301000090.tif161134

[0450] In certain embodiments, the compounds described herein are the following compounds or their derivatives: and physiologically acceptable salts thereof: [ka] TIFF2025183301000092.tif236135TIFF2025183301000093.tif237134TIFF2025183301000094.tif234134 TIFF2025183301000095.tif214134TIFF2025183301000096.tif236134TIFF2025183301000097.tif208135

[0451] Definitions and Abbreviations: Terms used herein have their ordinary meanings and are intended to be illustrative, not restrictive. The meaning of a term is independent at each of its occurrences. Except where noted, the following definitions apply throughout the specification and claims: Chemical Name The common name and chemical structure may be used interchangeably to describe the same structure. These definitions apply whether the term is used by itself or in other contexts, unless otherwise indicated. Therefore, the definition of "alkyl" applies regardless of whether it is used in conjunction with any other term. "Alkyl", "hydroxyalkyl", "haloalkyl", arylalkyl It applies to the "alkyl" portion of alkyl, alkylaryl, "alkoxy," etc.

[0452] In various embodiments of the invention described herein, Any variable not expressly defined herein is as defined in formula (I). It should be understood that

[0453] In the various embodiments described herein, unless otherwise indicated, each possible The variable portions are selected independently of the remaining variable portions.

[0454] "Drug resistance" refers to the resistance of a strain of malaria parasite to at least one previously effective drug. No longer sensitive to at least one previously effective drug Plasmodium has developed the ability to withstand drug attacks. Drug-resistant strains can pass on their resistance to their offspring. Such resistance can occur in bacteria that have altered susceptibility to a single drug or to a variety of drugs. It can result from random genetic mutations in cells.

[0455] "Patient" includes both human and non-human animals. Non-human animals include mice, rats, and the like. Research animals and companion animals such as mice, primates, monkeys, chimpanzees, apes, dogs, and domestic cats Neon animals are included.

[0456] A "pharmaceutical composition" (or "pharmaceutically acceptable composition") is a composition suitable for administration to a patient. Such compositions may contain the neat compound(s) of the present invention or or mixtures thereof, or salts, solvates, prodrugs, isomers or tautomers thereof and one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutical composition" further refers to a pharmaceutical composition containing one or more (e.g., two) pharmaceutically active agents. an agent (e.g., a compound of the present invention and from the list of additional agents described herein) Bulk composition consisting of the drug (and any additional drugs of choice) and any pharmaceutically inactive excipients. The term "bulk composition" is intended to encompass both the bulk composition and the individual dosage units. Each dosage unit may contain a fixed amount of said "two or more pharmaceutically active agents." The bulk composition is material that has not yet been formed into individual dosage units. The dosage unit is an oral dosage unit such as a tablet, pill, etc. Similarly, the pharmaceutical composition of the present invention can be administered The methods described herein for treating a patient by administering the bulk composition and individual It is intended to encompass administering a dosage unit of

[0457] "Halogen" and "halo" mean fluorine, chlorine, bromine or iodine. are fluorine, chlorine and bromine.

[0458] "Alkylene," by itself or as part of another substituent, means an alkylene group having the specified number of carbon atoms. For example, -(C1-C5) alkylene is , for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2C H2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH2CH2CH2 Linear alkylene includes a divalent straight chain carbon atom having the specified number of carbon atoms. A branched alkylene radical has the specified number of carbon atoms. means a divalent branched hydrocarbon chain radical. Saturated alkylene has the stated number of carbon atoms. The term "unsaturated alkylene" refers to a divalent saturated hydrocarbon chain radical having a carbon atom. It has a number of carbon atoms specified above and has one or more double or triple covalent bonds in its chain. Cycloalkylene means a divalent hydrocarbon chain radical having the specified number of carbon atoms. means a divalent hydrocarbon chain radical having a carbon atom and a cycloalkyl moiety within the chain. Taste.

[0459] "Alkyl" means an alkyl group having about 1 to about 20 carbon atoms in the chain which may be straight or branched. The alkyl group preferably has about 1 to about 1 carbon atoms in the chain. More preferred alkyl groups have about 1 to about 6 carbon atoms in the chain. A branched chain is a linear alkyl chain containing one or more lower alkyl groups, such as "Lower alkyl" means that a radical (methyl, ethyl or propyl) is attached to the means a group having about 1 to about 6 carbon atoms in the chain which may be linear or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and the like. Examples include propyl and t-butyl.

[0460] "Haloalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a halo group as defined above. "Alkyl" means alkyl as defined above, wherein the alkyl group is substituted with aryl or aryl;

[0461] "Aryl" refers to an alkyl group having from about 6 to about 14 carbon atoms (preferably from about 6 to about 10 carbon atoms). The aryl groups are identical and may be any aromatic monocyclic or polycyclic ring system containing the aryl groups. one or more "ring system substituents" as defined herein, which may be the same or different; Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.

[0462] "Cycloalkyl" refers to a group having from about 3 to about 12 carbon atoms (preferably from about 3 to about 10 carbon atoms). A non-aromatic monocyclic or polycyclic ring system containing a ring atom is also referred to as a cycloaromatic ring system. The cycloalkyl ring contains from about 5 to about 10 ring atoms. may be substituted with one or more of the substituents described, which may be the same or different. Monocyclic cycloalkyl can be any cycloalkyl moiety described herein. Non-limiting examples of suitable monocyclic cycloalkyls include: , cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cyclic cycloalkyl refers to polycyclic rings (which includes bicyclic rings) containing a non-aromatic ring. ) Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl In certain embodiments, the non-aromatic ring is an aromatic ring, such as norbornyl, norbornyl, and adamantyl. fused to an aromatic ring.

[0463] A "heterocycloalkyl" (or "heterocyclyl") is a heterocyclic alkyl group having from about 3 to about 10 ring atoms. (preferably about 5 to about 10 ring atoms) In a monocyclic or polycyclic ring system, one or more atoms in the ring system may be an element other than carbon, e.g. , nitrogen, oxygen or sulfur), alone or in combination. and there are no adjacent oxygen and / or sulfur atoms. Preferred heterocyclyls are those having about 5 Contains up to about 6 ring atoms. The prefix aza, oxa, or Thia has at least one nitrogen atom, oxygen atom or sulfur atom as a ring atom. Any -NH in a heterocyclyl ring can be, for example, an -N(Boc) group, It can exist in a protected state as an -N(CBz) group, an -N(Tos) group, etc. such protections are also considered part of the present invention. may be substituted with one or more of the substituents described, which may be the same or different. The nitrogen or sulfur atom of the heterocyclyl can be oxidized to the corresponding N-nitrogen. It can be an oxide, an S-oxide or an S,S-dioxide. Hence the term "oxide". "Sid" refers to the group of groups that appear in the definitions of variables in the general structures described herein. When the term "N-oxide", "S-oxide" or "S,S-dioxide" is used, it means the corresponding N-oxide, S-oxide or S,S-dioxide. "Terocyclyl" furthermore means that =O replaces two available hydrogens on the same carbon atom. (i.e., heterocyclyls contain a carbonyl group in the ring) Such =0 groups may be referred to herein as "oxo." An example of such a moiety is pyrrolidinone (or pyrrolidone): [ka]

[0464] As used herein, the term "monocyclic heterocycloalkyl" refers to a represents a monocyclic version of the heterocycloalkyl moieties described herein; and 1 to 4 ring heteroatoms (wherein the ring heteroatoms are N, N-oxide, O, S, S-oxide, S(O) and S(O)2) The point of attachment to the parent moiety is Any available ring carbon or ring heteroatom. Typical examples include piperidyl, oxetanyl, pyrrolyl, piperazinyl, and morpholinyl. , thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, Tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactam These include monocyclic heterocyclic rings, δ-lactones, pyrrolidinones, and their oxides. Non-limiting examples of cycloalkyl groups include the substructure: [ka]

[0465] Non-limiting examples of polycyclic heterocycloalkyl groups include bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to, [ka]

[0466] etc.

[0467] "Alkoxy" refers to an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propyl, The bond to the parent moiety is an ether. via oxygen.

[0468] The term "substituted" means that one or more hydrogens on a designated atom have been replaced with a group selected from the indicated group. This means that the existing situation has been replaced by the one selected, but The normal valence of the atom is not exceeded and the substitution does not result in a stable compound. Combinations of substituents and / or variables are not construed as limiting the scope of such combinations. The term "stable compound" or "stable structure" is acceptable only if the resulting compound is stable. " is intended for isolation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent. "Compounds having sufficient strength to withstand the effects of

[0469] The term "optionally substituted" refers to any selection by the specified group, radical or moiety. means substitution of alternatives.

[0470] When a variable moiety occurs more than once within a group (e.g., -N(R 8 )2 in R 8 ),also When a variable appears more than once in the structures described herein, that variable is The moieties can be the same or different.

[0471] A solid line, as a bond, generally represents a mixture of possible isomers (e.g., (R)-stereochemistry). and mixtures containing (S)-stereochemistry), or any of its possible isomers. For example, [ka]

[0472] teeth, [ka]

[0473] means that it contains either one or both of the following:

[0474] As used herein, a wavy line 〜〜 shown crossing a line representing a chemical bond indicates that Indicates the point of attachment to the rest of the compound. Lines drawn in ring systems, e.g. [ka]

[0475] indicates that the indicated line (bond) may be attached to any of the substitutable ring atoms. do.

[0476] "Oxo" refers to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkyl, an oxygen double-bonded to a ring carbon of a chloroalkenyl or another ring described herein; Atoms are defined as atoms, e.g. [ka]

[0477] is.

[0478] As used herein, when multiple oxygen and / or sulfur atoms are present in a ring system, There cannot be adjacent oxygen and / or sulfur atoms in the ring system.

[0479] As is well known in the art, the moieties at the ends of the bonds are not depicted. A bond drawn from a particular atom represents the number of atoms connected to that atom through that bond, unless otherwise indicated. It shows the methyl group attached to the molecule. For example, [ka]

[0480] teeth, [ka]

[0481] Represents.

[0482] In another embodiment, compounds useful in the methods of the invention and / or compounds useful in the methods The compositions containing them are useful in isolated and / or purified form. The terms "purified," "in purified form," or "isolated and purified" in reference to a compound "In a derived form" means that the compound is derived from a synthetic process (e.g., from a reaction mixture) or from a natural source or It represents the physical state of the compound after it has been isolated from its combination. The terms "purified," "in purified form," or "isolated and purified" in reference to a compound "In purified form" refers to one or more of the purification processes described herein or the corresponding One or more purification processes (e.g., chromatography) well known to those skilled in the art After being obtained from the solubility test (e.g., recrystallization), sufficient quality to be suitable for in vivo or pharmaceutical use. purity and / or by standard analytical techniques described herein or by methods known to those skilled in the art. The compound (or its tautomers) can be characterized by known analytical techniques. Isomers or stereoisomers, or pharmaceutical preparations of said compounds, said stereoisomers or said tautomers The physical state of the compound (compounds or solvates thereof) is shown.

[0483] Unsatisfied carbons and and heteroatoms are assumed to have sufficient hydrogen atoms to satisfy their valence. It should be understood that:

[0484] When a functional group in a compound is said to be "protected," this means that the compound is In order to prevent undesired side reactions at the protected site when the compound is subjected to a reaction, the group Suitable protecting groups are, for example, "TW Gre ene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York, etc. Those skilled in the art will recognize this by reference to standard textbooks.

[0485] Another embodiment provides prodrugs and / or solvates of the compounds of the invention. For a discussion of drugs, see T. Higuchi and V. Stella, P Ro-drugs as Novel Delivery Systems (1987 ) 14 of the ACS Symposium Series” and “B ioreversible Carriers in Drug Design, (1 987) Edward B. Roche, ed., American Phar Maceutical Association and Pergamon Pres The term "prodrug" refers to a compound that is converted in vivo to produce a compound of the present invention. or a compound which produces a pharmaceutically acceptable salt, hydrate or solvate of said compound. Such conversion can occur by a variety of mechanisms (e.g., drug precursors). by metabolic or chemical processes), e.g., by hydrolysis in the blood , possible. A discussion of the use of prodrugs is given in T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium m Series" and "Bioreversible Carriers in Dr ug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0486] For example, a compound useful in the methods of the present invention, or a pharmaceutically acceptable salt thereof, may be carbohydrate. If the prodrug contains an acid functional group, the prodrug may be a prodrug in which a hydrogen atom of the acid group is substituted, e.g., (C1-C 8) Alkyl, (C2-C 12 ) Alkanoyloxymethyl, having 4 to 9 carbon atoms 1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, 1-methyl-1- (Alkanoyloxy)-ethyl, alkoxycarbonyloxy having 3 to 6 carbon atoms 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms; 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 4 to 10 carbon atoms 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl having carbon atoms , 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C1-C2 ) alkylamino(C2-C3) alkyl (e.g., β-dimethylaminoethyl), carbazole Bamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl- (C1-C2) alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3) It can include esters formed by substituting groups such as alkyl. .

[0487] Similarly, when the compound used in the method of the present invention contains an alcohol functional group, The prodrug may be prepared by replacing the hydrogen atom of the alcohol group with, for example, (C1-C6)alkanoyl Oxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-( (C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxy dimethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C 1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α -aminoacyl or α-aminoacyl-α-aminoacyl (wherein each α-aminoacyl The group is a natural L-amino acid, P(O)(OH), -P(O)(O(C1-C6) alkyl )2 or glycosyl (by removing the hydroxyl group of the hemiacetal form of carbohydrate The resulting radicals are independently selected from the group consisting of aryl, ... It can be achieved.

[0488] When the compound used in the method of the present invention contains an amine functionality, a prodrug The amine group may be substituted with a hydrogen atom, for example, R-carbonyl, RO-carbonyl, NRR-carbonyl, or the like. '-carbonyl (wherein R and R' are each independently (C-C 10 ) alkyl , (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a naturally occurring α -aminoacyl or naturally occurring -aminoacyl], -C(OH)C(O)OY 1 〔child So, Y 1 is H, (C1-C6) alkyl or benzyl], -C(OY 2 )Y 3 [where Y 2 is (C1-C4) alkyl, and Y 3 is (C1-C6) Al alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N - or di-N,N-(C1-C6) alkylaminoalkyl], -C(Y 4 ) Y 5 [where Y 4 is H or methyl, and Y 5 is mono-N- or di-N , N-(C1-C6) alkylamino, morpholino, piperidin-1-yl or pyrrolidine The aryl group can be formed by replacing the aryl group with a group such as phenyl-1-yl.

[0489] One or more of the compounds used in the methods of the present invention may be present in unsolvated form and in aqueous, ethanolic, or ethanolic solutions. It may exist in a solvated form with a pharmaceutically acceptable solvent such as alcohol, and The present invention is intended to encompass both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. The cases involve varying degrees of ionic and covalent bonding (which includes hydrogen bonding). In certain instances, for example, one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. When present, the solvate can be isolated. "Solvates" include solution-phase and Non-limiting examples of suitable solvates include ethanol, ethanol-isolated ... "Hydrate" is a solvate in which the solvent molecule is H2O. It is a thing.

[0490] One or more of the compounds used in the methods of the present invention may be converted to a solvate. The preparation of solvates is generally known. t al, J. Pharmaceutical Sci., 1993, 3, 6 "01-611" contains the antifungal fluconazole in ethyl acetate and from water. The preparation of solvates is described. Similar preparations of solvates, hemisolvates, hydrates, etc. are also described. “EC van Tonder et al, AAPS PharmSciTe ch., 5(1), article 12 (2004)" and "AL Bi ngham et al, Chem. Commun., 603-604 (200 1) A typical, non-limiting process is to The compound of the present invention is dissolved in a desired amount of a desired solvent (organic or aqueous or a mixture thereof) at 20°C. and cooling the solution at a rate sufficient to cause crystals to form, The crystals are then isolated by standard methods. The presence of solvent (or water) in the crystals as solvates (or hydrates) is shown.

[0491] An "effective amount" or "therapeutically effective amount" is an amount effective to inhibit the above-described diseases or enzyme activity. effective, and therefore effective in producing the desired therapeutic, ameliorative, suppressive or preventative effect is intended to represent the amount of a compound or composition used in the methods of the invention.

[0492] In another embodiment, a pharmaceutically acceptable salt of a compound used in the method of the present invention is Thus, references herein to compounds used in the methods of the present invention include References to salts thereof are understood to include references to salts thereof unless otherwise indicated. "(a) number or numbers" as used herein refers to the use of inorganic and / or organic acids. The acid salts formed and the basic salts formed with inorganic and / or organic bases are Furthermore, the compounds of the present invention may contain a basic moiety (such as, but not limited to, pyrimidine). an alkyl group consisting of an alkyl group (e.g., an alkyl amine or an imidazole) and an acidic moiety (e.g., but not limited to, a carboxylic acid) If both are present, zwitterions ("inner salts") may form, and This is encompassed by the term "salt(s)" as used herein. Acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. The salts of the compounds used in the methods of the present invention are, for example, salts of the compounds of the present invention in a medium (e.g., a specific amount (e.g., equivalent amount) of the salt in an aqueous medium (e.g., the medium in which the salt precipitates) It can be formed by reaction with an acid or base followed by freeze-drying.

[0493] Representative acid addition salts include acetate, ascorbate, benzoate, and benzenesulfonate. Phosphate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfate Phosphate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, Methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propyl Salicylate, succinate, sulfate, tartrate, thiocyanate, toluene sulfonates (also known as tosylates).

[0494] Additionally, it is generally known to be suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds. Possible acids are, for example, those described in "P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts . Properties, Selection and Use. (2002) Zurich: Wiley-VCH”, “S. Berge et al, Jour nal of Pharmaceutical Sciences (1977) 66 (1) 1-19”, “P. Gould, International J. of Pharmaceutics (1986) 33 201-217," "Ander son et al, The Practice of Medicinal Che Mistry (1996), Academic Press, New York” and "The Orange Book (Food & Drug Administration ration, Washington, DC on their website e),” the disclosures of which are incorporated herein by reference.

[0495] Representative basic salts include ammonium salts, alkali metal salts, e.g., sodium salts. , lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts salts with organic bases (e.g., organic amines), e.g., with dicyclohexylamine; salts with t-butylamine, as well as salts with amino acids, for example, salts with arginine, The basic nitrogen-containing group may be a lower alkyl halide (e.g., methyl butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., sulfur dimethyl sulfate, diethyl sulfate and dibutyl sulfate), long chain halides (e.g., decyl, uryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. , benzyl bromide and phenethyl bromide).

[0496] All such acid and base salts are considered pharmaceutically acceptable salts within the scope of the present invention. and all acid and base salts are intended to be of relevance for the purposes of this invention. and are considered equivalent to the free forms of the corresponding compounds.

[0497] Another embodiment is a pharmaceutically acceptable ester of the compound used in the method of the present invention. Such esters include the following groups: (1) hydroxy groups Carboxylic acid esters obtained by esterification (wherein the carboxylic acid moiety of the ester group The non-carbonyl portion of butyl, t-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), Aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl) ), aryl (e.g., halogen, C 1-4 Alkyl or C 1-4 Alkoxy or (2) sulfo phosphate esters, such as alkylsulfonyl or aralkylsulfonyl (e.g., methane sulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucine); (4) phosphate esters, and (5) mono-, di-, or triphosphate esters. Stell, for example, C 1-20 by alcohol or its reactive derivatives, or ,3-Di(C 6-24 ) may be further esterified by acylglycerols.

[0498] As described herein, in another embodiment, the method The tautomers of the compounds of the present invention, as well as salts, solvates, esters and derivatives thereof, are also known. All tautomeric forms of such compounds are contemplated by the methods of the present invention. It should be understood that the compounds used in All keto-enol and imine-enamine forms of the compounds, when present, are included in the present invention. can be.

[0499] The compounds used in the methods of the present invention may contain asymmetric or chiral centers. and therefore can exist in various stereoisomeric forms. All stereoisomeric forms of the compounds and mixtures thereof (this includes racemic mixtures) ) are intended to form part of the present invention. For example, the compounds used in the methods of the present invention include the use of isomers and positional isomers. If the compound contains a double bond or a fused ring, it may be present in cis and trans, (E) and Both the (Z) and (Z) forms as well as mixtures are encompassed within the scope of the present invention.

[0500] In another embodiment, a diastereomeric mixture of the compounds used in the methods of the present invention and the individual enantiomers. Diastereomeric mixtures are well known to those skilled in the art. They can be isolated by methods known in the art, for example, by chromatography and / or fractional crystallization. can be separated into their individual diastereomers based on their physical and chemical differences Enantiomers can be synthesized by the addition of suitable optically active compounds (e.g., chiral auxiliaries, e.g., chiral auxiliaries). The enantiomeric mixture is then reacted with dichloromethane (e.g., methylpropional alcohol or Mosher's acid chloride) to form a dichloromethane mixture. Converting to an asterisk mixture, separating the diastereomers, and then isolating the individual diastereomers. Conversion (e.g., hydrolysis) of stereomers to the corresponding pure enantiomers Furthermore, the chemicals used in the method of the present invention can be separated by Some of the compounds may be atropisomers (e.g., substituted biaryls). and are considered part of the present invention. Enantiomers may also be expressed as chiral HP Separation can also be performed using an LC column.

[0501] The compounds used in the methods of the present invention (including salts, solvates, esters, etc. of the compounds) and prodrugs, as well as salts, solvates and esters of said prodrugs) All stereoisomers (e.g., geometric isomers, optical isomers, etc.), e.g., on the various substituents Isomers that may exist due to asymmetric carbons, such as enantiomeric forms (which are (which may exist even in the absence of isomers, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl), are within the scope of the present invention. (For example, compounds of the invention that have double bonds or fused rings are also contemplated as embodiments.) When present, both the cis and trans forms and mixtures thereof are included within the scope of the present invention. Furthermore, for example, all keto-enol and imine-enamine forms of the compound types are encompassed by the methods of the present invention).

[0502] Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers. It is possible or, for example, to mix as a racemate or all other The chiral centers of the present invention may be mixed with the stereoisomer of 1 or other selected stereoisomers. , as defined by the "IUPAC 1974 Recommendations" They may have the S or R configuration. "Salts," "solvates," "esters" The use of terms such as "prodrug" and "prodrug" does not include the use of enantiomers, stereoisomers, Rotamers, tautomers, positional isomers, racemic compounds or prodrug salts, solvates, It is intended to apply equally to esters and prodrugs.

[0503] In another embodiment, there is provided an isotopically labeled compound for use in the methods of the present invention. Compounds such as except for the fact that it has been replaced by an atom with a different atomic mass or mass number. are the same as those described herein. Examples of isotopes that may be present include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g. Ba, respectively, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P , 35 S, 18 F and 36 Examples include Cl.

[0504] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) is a compound labeled Useful in compound and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e., 14 C) Isotopes are characterized by their ease of preparation and detectability. In addition, deuterium (i.e., 2 by heavier isotopes such as H The substitution may result in greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). ) may provide certain therapeutic benefits and may therefore be preferred in some circumstances. The isotopically labeled compounds of the present invention may generally be those shown in the following schemes and / or examples. Following methods similar to those disclosed, non-isotopically labeled reagents can be converted to suitable isotopically labeled reagents. It can be prepared by substituting the reagents.

[0505] In the compounds used in the methods of the present invention, the atoms are It can show abundance or the number of atoms with the same atomic number in more than one type of atom. However, the atomic mass or mass number is different from the atomic mass or mass number mainly found in nature. The present invention relates to the compound of the present invention. All appropriate isotopic variations are intended to be encompassed. For example, different isotopic variations of hydrogen (H) are The isotopic form is protium ( 1 H) and deuterium ( 2 H) and the like. The presence of deuterium in a substance is indicated by a "D." Protium is the predominant element found in nature. Deuterium enrichment has certain therapeutic advantages (e.g., in or by treating a biological sample with a compound that is a soluble form of the compound, resulting in increased half-life in vivo or reduced dosage requirements. The isotopes of the present invention can provide compounds useful as standards for characterization. The enriched compounds may be isolated by conventional techniques well known to those skilled in the art or by suitable methods. The schemes and methods described herein may be carried out using appropriate isotopically enriched reagents and / or intermediates. and processes similar to those described in the Examples, without undue experimentation. It can be prepared without

[0506] Polymorphic forms of compounds used in the methods of the invention, as well as salts, solvates of compounds of the invention Polymorphic forms of the compounds, esters and prodrugs are intended to be included in the present invention. .

[0507] Treatment method The present invention is directed to a method of treating a malaria parasite infection, wherein the method comprises: administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need of such treatment; More specifically, the method of the present invention comprises administering a salt of a compound represented by formula (I): In certain embodiments, the method includes administering a compound or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a pharmaceutically acceptable carrier. Alternatively, it may be administered in the form of a pharmaceutical composition further comprising an excipient.

[0508] The present invention relates to a method for treating a malaria parasite infection or a method for treating malaria or a method for treating malaria. A method of inhibiting mepsin X is provided, wherein the method is for treating a subject in need of such treatment. The method comprises administering to a subject a therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof. wherein the compound has structural formula (I) as set forth in the Summary of the Invention. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is The compound is administered as a pharmaceutical composition together with a commercially acceptable carrier. Various embodiments of these methods are also provided herein.

[0509] The present invention further relates to a method for treating malaria parasite infections, for inhibiting plasmepsin X activity. or for treating malaria. The present invention also relates to the use of the compound or a pharmaceutically acceptable salt thereof. In the manufacture of a medicament for inhibiting IL-1 activity, In the manufacture of a medicine or in the manufacture of a medicament for treating malaria, VIII) or a pharmaceutically acceptable salt thereof. The compounds of formula (I)-(VIII) described in any of the embodiments of the present invention are The compound or a pharmaceutically acceptable salt thereof is useful for any of the above uses.

[0510] The present invention relates to a method for treating a malaria parasite infection or a method for treating malaria or a method for treating malaria. A method of inhibiting mepsin IX is provided, wherein the method is for treating a subject in need of such treatment. The method comprises administering to a subject a therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof. wherein the compound has structural formula (I) as described in the Summary of the Invention. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is The compound is administered as a pharmaceutical composition together with a commercially acceptable carrier. Various embodiments of these methods are also provided herein.

[0511] The present invention further provides a method for treating malaria parasite infections, for inhibiting plasmepsin IX activity. or for treating malaria, The present invention also relates to the use of the compound or a pharmaceutically acceptable salt thereof. In the manufacture of a medicament for inhibiting synthase IX activity, for treating malaria parasite infections or in the manufacture of a medicament for treating malaria, The present invention also relates to the use of a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof. The compounds of formula (I)-(VIII) described in any of the embodiments of the present invention in the specification The compound or a pharmaceutically acceptable salt thereof is useful for any of the above uses.

[0512] The present invention relates to a method for treating a malaria parasite infection or a method for treating malaria or a method for treating malaria. A method for inhibiting mepsin X and plasmepsin IX is provided, wherein the method comprises: A therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof is administered to a subject in need of such treatment. wherein the compound has the structure described in the Summary of the Invention. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts is Acceptable salts are administered as pharmaceutical compositions together with a pharmaceutically acceptable carrier. Various embodiments of these methods, as described below, are also incorporated herein by reference. Provided.

[0513] The present invention further provides a method for inhibiting the activity of plasmepsin X and plasmepsin IX. , a compound of formula (I)- for treating a malaria parasite infection or for treating malaria The present invention also relates to the use of a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof. The present invention further provides a method for the preparation of a pharmaceutical for inhibiting the activity of plasmepsin X and plasmepsin IX. in the manufacture of a medicament for treating a malaria parasite infection or in the manufacture of a medicament for treating a malaria parasite infection a compound of Formula (I)-(VIII) or a compound thereof in the manufacture of a medicament for treating The present invention also relates to the use of pharmaceutically acceptable salts of any of the embodiments of the invention herein. A compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof is useful for any of the above uses.

[0514] The methods of the present invention are advantageous in that they inhibit the onset, development or progression of the condition. Treating the condition in terms of ameliorating the symptoms of the condition, causing regression of the condition, in the treatment of, or otherwise at risk of suffering from, the condition It is useful in treating malaria in improving the general health of a subject. Therefore, in accordance with the presently disclosed subject matter, the terms "treat," "cure," and "treatment" are used interchangeably. "treating" and their grammatical variations, as well as the phrase "method of treating" " refers to any desired therapeutic intervention, including but not limited to, in subjects with infectious diseases. for example, in subjects exposed to the parasites disclosed herein. The present invention is intended to encompass methods for treating infectious diseases.

[0515] Embodiments of the present invention further include (i) for use in: or (iii) for use as a medicament or composition for: A compound of formula (I)-(VIII) for use in the preparation of a medicament against (a) therapeutic (e.g., therapeutically effective for treating a human (b) medical treatment; (c) inhibition of parasite / malaria parasite growth; (d) plus Treatment or prevention of infections caused by Plasmodium species; (e) reducing the progression, onset, or severity of pathological symptoms associated with malaria parasite infection; and and / or reducing the likelihood of severe Plasmodium infection; or (f) Plasmodium-associated The treatment, prevention, or amelioration of diseases, including but not limited to malaria, Delaying the onset, severity, or progression of the disease.

[0516] Thus, in another embodiment, a method for treating malaria or a method for treating a malaria parasite infection is provided. wherein the method comprises administering a specific amount of at least one compound represented by formula (I)-(VIII). Any one of the compounds or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof and an effective amount of one or more additional agents listed below. In certain embodiments, the methods described herein include administering a method for treating a malarial parasite infection, wherein the method comprises, a fixed amount of at least one compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof a salt, solvate, ester, or prodrug thereof and an effective amount of one or more additional anti-inflammatory drugs. In certain embodiments, the method of the present invention includes administering a combination comprising a malaria drug. The document describes that it inhibits plasmepsin X and plasmepsin IX and A method of treating malaria by at least one alternative mechanism, wherein the method comprises: a specific amount of at least one compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof an acceptable salt, solvate, ester, or prodrug thereof and an effective amount of one or more additional and administering a combination containing an additional antimalarial agent, wherein the additional antimalarial agent Antimicrobials act through mechanisms distinct from inhibition of plasmepsin IX or plasmepsin X. Pharmacological properties of the compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof The biological properties can be confirmed by several pharmacological assays. The above is exemplified in this specification.

[0517] Dosage and Administration In another embodiment, suitable dosages and administration forms of the compounds used in the methods of the present invention Suitable methods for administering the compounds used in the methods of the present invention to patients are provided. The dosage can be readily determined by one of ordinary skill in the art, for example, an attending physician, pharmacist, or other skilled person. and the patient's health, age, weight, frequency of administration, use with other active ingredients and / or may vary depending on the indication for which the compound is administered. In one embodiment, the dosage ranges from 100 mg / kg body weight to 500 mg / kg body weight / day of a compound of the present invention. The dosage is about 0.01 to about 25 mg / kg body weight / day of the compound of the present invention or a pharmaceutical formulation of said compound. In another embodiment, the unit dose of the formulation is The amount of active compound may range from about 1 mg to about 100 mg, depending on the particular application, and in certain embodiments, , about 1 mg to about 50 mg, and in certain embodiments, about 1 mg to about 25 mg. In another embodiment, the typical recommended dosage for oral administration can be adjusted. The daily dosage regimen is approximately 1 mg / day to approximately 500 mg / day in 2 to 4 divided doses. In an embodiment, the range may be from 1 mg / day to 200 mg / day.

[0518] As discussed above, the dosage and administration of the compounds of the present invention and / or pharmaceutically acceptable salts thereof The frequency and duration of treatment should take into account factors such as the age, condition, and size of the patient and the severity of the condition being treated. and adjusted according to the judgment of the attending clinician.

[0519] Liquid formulations include solutions, suspensions, and emulsions. , aqueous solution or water-propylene glycol solution for parenteral injection, or oral solution, oral suspension For suspensions and oral emulsions, sweeteners and opacifiers may be added. Liquid form preparations may also include solutions for intranasal administration.

[0520] Aerosol formulations suitable for inhalation include solutions and solids in powder form, which , may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas (e.g., nitrogen). can.

[0521] Furthermore, immediately prior to use, the preparation may be in liquid form for either oral or parenteral administration. Also included are solid form preparations that are intended to be converted into liquid forms. Examples include solutions, suspensions and emulsions.

[0522] In another embodiment, a compound of Formulas (I)-(VIII) formulated for transdermal delivery or a pharmaceutically acceptable salt thereof. , creams, lotions, aerosols and / or emulsions, and transdermal delivery systems of the matrix or reservoir type conventional in the art for this purpose. It can be included in the patch.

[0523] In another embodiment, a compound of Formulas (I)-(VIII) formulated for subcutaneous delivery or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a composition suitable for oral delivery, comprising a compound of Formula (I)-(VII) Pharmaceutical formulations containing one or more compounds of formula I) or pharmaceutically acceptable salts thereof include It may be advantageous to prepare the preparation in unit dosage form. In such form, the preparation may be administered in a suitable a suitable size containing an amount of active ingredient (e.g., an effective amount to achieve a desired purpose); Each of the foregoing alternatives may be used in various embodiments of the present invention. It is considered to be included.

[0524] When used in combination with one or more additional therapeutic agents ("combination therapy"), the present invention The compounds used in the method, i.e., the compounds represented by formulas (I)-(VIII), are When administered sequentially, the compounds of the present invention may be administered in a manner known to those skilled in the art or may be administered before or after the one or more additional therapeutic agents, as determined by patient preference. It can be given.

[0525] When formulated as a fixed dose, such combination products may be administered in the manner described herein. The compounds of formula (I)-(VIII) or pharmaceutically acceptable salts thereof are within the dosage ranges set forth in the present specification. The salts and other pharmaceutically active agents or treatments within the dosage ranges are used. do.

[0526] Combination therapy In another embodiment, the compounds of the present invention can be administered as neat chemicals or optionally with additional components. The present invention also provides methods of treatment using pharmaceutically acceptable compositions further comprising a component. Such compositions are contemplated for preparation and use in monotherapy or in combination therapy. For preparing pharmaceutical compositions from the compounds, inert, pharmaceutically acceptable carriers can be solid or The solid form of the preparation may be a powder, a tablet, a dispersible granule, or a liquid. Available in capsules, cachets, and suppositories. Powders and tablets contain about 5 to 95% of the active ingredient. Suitable solid carriers are known in the art and may be composed of, for example, magnesium carbonate. The ingredients are cereals containing cereals containing glutathione, ... Pills and capsules can be used as solid dosage forms suitable for oral administration. Examples of biologically acceptable carriers and methods for preparing various compositions are described in "A. Gennaro (ed.), Remington's Pharmaceutical Science ces, 18th Edition, (1990), Mack Publishing ng Co., Easton, Pennsylvania. Cut.

[0527] Non-limiting examples of additional drugs and active agents useful in combination therapy for treating malaria include: Notable examples include: Coartem® (Novartis International AG, Basel, Switzerland; Temeter + lumefantrine), Eurartesim® (Sigma-Aldrich) u Pharmaceuticals, Inc., Rome, Italy; dihydro Artemisinin-piperaquine), Pyramax® (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronaridine-artesunate), ASAQ Winthrop® (Sano fi SA(Gentilly, France) / DNDi(Geneva, Swi tzerland); artesunate + amodiaquine), ASMQ (Cipla Li mited(Mumbai, India) / DNDi; artesunate + mefloquine) , SPAQ-CO TM (Guilin Pharmaceutical Co., Lt. d. (Shanghai); amodiaquine + sulfadoxine, pyrimethamine), Ar tesun® (Guilin Pharmaceutical; Artesun) artemether, artesunate, dihydroartemisinin, lumefantrine, Modiaquine, mefloquine, piperaquine, quinine, chloroquine, atovaquone, and proguam nitril and sulfadoxine-pyrimethamine, tafenoquine (Glaxosmithkli ne), OZ439 / PQP(Sanofi), OZ439 / FQ(Sanofi), K AE609 (Novartis), KAF156 (Novartis), DSM265 ( NIH / Takeda), and MK-4815 (Merck & Co., Inc. , Powles et al., Antimicrobial Agents an d Chemotherapy 56(5): 2414-2419(2012)). The choice of such additional active ingredients depends on the existing disease or disorder for which treatment is desired, This will be determined by your doctor or other healthcare provider.

[0528] Therefore, the present invention further provides a method for the preparation of plasmepsin X, plasmepsin IX or plasmepsin for inhibiting plasmepsin X and plasmepsin IX, and for treating malaria parasite infections or a compound of formula (I)-(VIII) or its derivatives for treating malaria. and methods of using pharmaceutically acceptable salts thereof, wherein the methods include inhibiting or Further encouragement of subjects in need of treatment to receive one or more additional antimalarial drugs. In some embodiments, the one or more additional antimalarial drugs include: Selected from the group consisting of: artemether, lumefantrine, dihydroartemisin piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfa Doxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone and propranolol Loganil. [Example]

[0529] Example The meanings of the abbreviations used in the examples are as follows: [Table 1] TIFF2025183301000108.tif248170TIFF2025183301000109.tif193160

[0530] The meanings of the abbreviations in the nuclear magnetic resonance spectrum are as follows: s = singlet, d = doublet, d d = double line of double, dt = triple line of double, ddd = double line of double, Sept = seven lines line, t = triplet, m = multiplet, br = broad line, brs = broad singlet, q = quartet, J = knot Combined constant and Hz = Hertz.

[0531] Several methods for preparing the compounds of the present disclosure are described in the following schemes and examples. Starting materials and intermediates were either purchased commercially from standard catalog sources or or prepared using known methods or as otherwise exemplified. Some commonly applied routes to compounds of formula I) are listed below: In some cases, the order of carrying out the reaction steps in the schemes is It may be varied to facilitate the reaction or to avoid undesired reaction products. can.

[0532] Scheme 1 [ka]

[0533] The compound represented by formula S-2 can be prepared by macrolactamization using an amide coupling reagent. Then, prepare from S-1.

[0534] Scheme 2 [ka]

[0535] The intermediate compound represented by formula S-4 is a second generation Grubbs catalyst, a Zhan catalyst, and After ring-closing metathesis (RCM) reactions using catalysts such as the Hoveyda / Grubbs catalyst The double bond in S-4 can be reduced, for example, under hydrogenation conditions, to give a compound of formula A product designated S-5 can be produced.

[0536] Scheme 3 [ka]

[0537] The intermediate compound represented by formula S-7 is a transition metal-catalyzed intramolecular cross-coupling reaction. After the reaction (e.g., Heck reaction), S The resulting double bond in S-7 can be reduced, for example, under hydrogenation conditions, to give The product of formula S-8 can be obtained.

[0538] Scheme 4 [ka]

[0539] The product represented by formula S-10 can be obtained by a transition metal-catalyzed intramolecular cross-coupling reaction ( For example, after a palladium-catalyzed CO coupling reaction), X may be a halogen (e.g., It is prepared from S-9, which is a tetrahydrofuran derivative (Cl, Br, and I).

[0540] Scheme 5 [ka]

[0541] The product represented by formula S-12 can be obtained from S-11 by the reaction of an alcohol and X (where X is Cl). , Br, I, OMs, OTs, or OTf) N After 2 reactions The product of formula S-12 can be further prepared from the S-11 diol by the reaction of an acid or can also be prepared after dehydration conditions using other dehydration reagents.

[0542] Scheme 6 [ka]

[0543] The product of formula S-12 can be prepared from intermediates S-13 or S-14 by the reaction of TMSOTf and It is prepared after intramolecular reductive etherification using conditions such as Et3SiH.

[0544] Moisture- or air-sensitive reactions should be performed in a glove box or under nitrogen or The reaction was carried out under argon and using anhydrous solvents and reagents. ck pre-coated TLC plate (silica gel 60F-254, layer thickness 0.25 mm) or by analytical thin layer chromatography (TLC), which is typically performed using liquid Confirmation was achieved by chromatography-mass spectrometry (LC / MS).

[0545] Typically, the analytical LC-MS system used was an Agi equipped with an autosampler. Electrospray in positive ion detection mode using a Lent 1100 series HPLC Waters ZQ with Ray ionization TM It consisted of a platform. The ram is generally "Waters Xterra MS C18, 3.0 x 50 mm, 5 μm" or "Waters Acquity UPLC® BEH C The diameter was 1.0 × 50 mm, 1.7 μm. The flow rate was 1 mL / min, and the injection volume was The volume was 10 μL. UV detection was in the range of 210-400 nm. The mobile phase was It consists of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA). The gradient was as follows: 100% solvent A for 0.7 min, 100% over 3.75 min % solvent B, held for 1.1 minutes, then returned to 100% solvent A over 0.2 minutes.

[0546] Preparative HPLC purification is typically performed using a mass spectrometry-oriented system (mass spectromet). ry directed system or non-mass directed system These were usually performed using either the LC-M S System (which consists of: Waters ZQ TM s single quad MS system (electrospray ionization), Water rs 2525 Gradient Pump, Waters 2767 Inject o / Collector, Waters 996 PDA Detector;MS Article The conditions are as follows: 150-750amu, Positive Electrospray ray, Collection Triggered by MS, and Waters SUNFIRE® C-18 5 micron, 30 mm (id) x 100 mm Waters Chromatography Work The mobile phase was acetone in water containing 0.1% TFA. The flow rate was maintained at 50 mL / min. The injection volume was 1800 μL and the UV detection range was 210-400 nm. An alternative preparative HPLC system used was the Gilson Workstation (which , consisting of: Gilson GX-281 Injector / Co llector, Gilson UV / VIS-155 Detector, Gilso n 333 and 334 Pumps and Phenomenex Gemini -NX C-18 5 micron, 50 mm (id) x 250 mm column or Wat ers XBridge TM C-18 5 micron OBD TM , 30mm(id)× The mobile phase contained 5 mmol (NH4)HCO3. It consisted of a mixture of acetonitrile in water (0-75%). s Xbridge TM For the column, the flow rate was maintained at 50 mL / min, and the Pheno For the Menex Gemini column, the injection volume was maintained at 90 mL / min. The volume ranged from 1000-8000 μL, and the UV detection range was 210-400 nm. The mobile phase gradient was optimized for each compound. Reactions are typically run using Emrys Optimizer (Personal Chemistry). The solution was concentrated using a chromatograph (manufactured by Biotage) or Initiator (manufactured by Biotage). Flash chromatography was typically performed on a rotary evaporator under reduced pressure. , silica gel (32-63 μM, 6 0 Å pore size) using either: Biotage Trademark) Flash Chromatography apparatus(Dyax Corp.), ISCO CombiFlash® RF equipment s, or ISCO CombiFlash® Companion XL. 1 H NMR spectra were obtained in CDCl3 solution at 500 MΩ unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Trimethylsilane (TMS) was used as an internal standard in CDCl3 solution, and residual CH The 3OH peak or TMS was used as an internal standard in the CD3OD solution. J) is reported in Hertz (Hz). Chiral analytical chromatography is the most Generally, CHIRALPAK® AS column (250 × 4.6 mm), CHI RALPAK (registered trademark) AD column (250 x 4.6 mm), CHIRALCEL (registered trademark) OD column (250 x 4.6 mm), CHIRALCEL IA column column (250 x 4.6 mm) or CHIRALCEL® OJ column (250 x 4 .6mm) (Daicel Chemical Industries, Ltd.) One of them is ethanol in hexane (%Et / Hex) in the percentage indicated. or isopropanol in heptane (% IPA / Hep) as an isocratic solvent system. Chiral preparative chromatography was carried out using a CHIRALPAK AS column. column (20 x 250 mm), CHIRALPAK AD column (20 x 250 mm), CH IRALCEL® OD column (20 x 250 mm), CHIRALCEL® IA column (20 x 250 mm), CHIRALCEL OJ column (20×250mm)(Daicel Chemical Industries, L td.) and is certified for chiral analytical chromatography. The reaction was carried out in an isocratic solvent system or under supercritical fluid (SFC) conditions.

[0547] Chiral centers in the compounds may exist in the "S" or "R" configuration, or It is understood that mixtures of both can exist. Each bond drawn as a straight line encompasses both the (R) and (S) stereoisomers. , as well as mixtures thereof.

[0548] Intermediate 1 Preparation of Intermediate 1-2 [ka]

[0549] DBU (21.72 mL, 144 mmol) and diphenylphosphinyl were dissolved in THF ( Methyl (S)-4-hydroxychroman-6-carboxylate (IN 80 mL) T1-1) (10 g, 48.0 mmol). Then, azide (35. 0 g, 144 mmol) was added under N. The mixture was stirred at 50 °C for 12 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®). 330 g SepaFlash® Silica Flash Color mn, eluent 15% EtOAc / petroleum ether gradient @ 50 mL / min) Methyl (R)-4-azidochroman-6-carboxylate (INT1-2) was obtained. Ta.

[0550] MS (ESI) m / z 234.0(M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0551] Pd-C (2.510 g, 4.72 mmol) was added to methyl (R)-4 -Azidochroman-6-carboxylate (INT1-2) (11 g, 47.2 mmol) ) in THF (200 mL). The mixture was degassed and washed with H2. The resulting mixture was stirred at 25°C for 12 hours under H2 (15 psi) atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give methyl (R)-4-amino Chroman-6-carboxylate (INT1-3) was obtained.

[0552] MS (ESI) m / z: 191.1 (M-17+H + ) Preparation of Intermediate 1 [ka]

[0553] Sodium hydride (3.77 g, 94 mmol) was added to N,N-bisBoc-thio A solution of urea (16.94 g, 61.3 mmol) in THF (250 mL) was It was added in small portions at 0° C. After 1 hour at this temperature, 2,2,2-trifluoroacetic acid Anhydride (8.82 mL, 61.3 mmol) was added dropwise, and the mixture was stirred at 0° C. for 1 hour. The mixture was stirred for 1 hour. Methyl (R)-4-aminochroman-6-carboxylate (INT1- 3) (9.77 g, 47.1 mmol) in THF (50 mL) was heated at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was diluted with water (80 mL). It was quenched and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (40 mL ), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (ISCO®); 220 g SepaFla sh® Silica Flash Column, eluent 20% EtOAc / petroleum ether gradient @ 50 mL / min) to give methyl (R)-4-(3-( tert-Butoxycarbonyl)thioureido)chroman-6-carboxylate(IN T-1) was obtained.

[0554] MS (ESI) m / z 367.1 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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) Intermediate 2 Preparation of Intermediate 2-2 [ka]

[0555] Pent-4-enoic acid (INT2-1) (40 g, 400 mmol) and EDCI (92 g , 479 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (6 4.8 g, 479 mmol) and N-ethyl-N-isopropylpropan-2-amine (2 79 mL, 1598 mmol) in DCM (400 mL) Methylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added to the reaction. The mixture was stirred at 25°C under N2 atmosphere for 12 hours. LCMS showed the desired mass. The mixture was quenched with water (300 mL) and extracted with DCM (3 x 100 mL). The layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 22 0g Agela Silica Flash Column, eluent 8% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give N-methoxy-N-methylpentene. Ter-4-enamide (INT2-2) was obtained.

[0556] MS (ESI) m / z 144.1 (M+H) + 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0557] N-Methoxy-N-methylpent-4-enamide (INT2-2) (20g, 140 A solution of 100 mmol) in THF (200 mL) was added to ethylmagnesium chloride under a N2 atmosphere. Diazolidinium bromide (69.8 mL, 210 mmol) was added dropwise at 0° C. The reaction The mixture was stirred at 25°C under N2 atmosphere for 1 hour. TLC showed a new spot. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and water (100 mL) and diluted with EtOAc. (3×100 mL). The organic layer was washed with brine (50 mL) and The crude product was dried over O4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography. Raffy (ISCO®); 120g Agela Silica Flash Column, eluent 5% ethyl acetate / petroleum ether gradient @ 40 mL / min) Purification gave hept-6-en-3-one (INT2-3).

[0558] 1 H NMR (500 MHz, chloroform-d) δ 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, 3 H) Preparation of Intermediate 2-4 [ka]

[0559] Hept-6-en-3-one (INT2-3) (10 g, 89 mmol) was dissolved in THF ( 00 mL), (R)-2-methylpropane-2-sulfinamide ( 12.97 g, 107 mmol) was added, followed by Ti(EtO)4 (37.5 mL, 178 mmol) was added and the reaction was then stirred at 75°C under N2 atmosphere for 12 hours. TLC showed a new spot. The final mixture was cooled to room temperature and then Dilute with DCM (200 mL), stir for 15 min, then add ice-cold saturated aqueous sodium bicarbonate The solution (50 mL) and Na2SO4 was then filtered and concentrated under reduced pressure. Flash silica gel chromatography (ISCO®; 120 g Agel a Silica Flash Column, eluent 8% ethyl acetate / petroleum ether The (R,E)-N-(hept-6-en-3-yl) lysine-2-methylpropane-2-sulfinamide (INT2-4) was obtained.

[0560] MS (ESI) m / z 216.2 (M+H) + 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0561] Diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) The solution was treated with butyllithium (55.7 mL, 13 9 mmol) was added dropwise. The reaction was stirred at 0° C. for 30 min to give LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) was added to anhydrous THF (90 mL). The mixture was then heated to -78°C. Then, LDA (76 mL, 93 mmol) was added dropwise. After 1 hour, (R,E )-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinyl The amide (INT2-4) (10 g, 46.4 mmol) was dissolved in anhydrous THF (20 mL). The solution was added dropwise and the mixture was stirred at -78°C for 3 hours. The color was 0.05g. LCMS showed a predominant DP mass. The mixture was diluted with ice-cold half-saturated ammonium chloride The mixture was quenched with aqueous ammonium hydroxide (60 mL). The slurry was diluted with EtOAc (200 mL). The organic layer was diluted with brine (50 mL), then filtered and rinsed with EtOAc and water. ), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (ISCO®; 120 g Agela Sil ica Flash Column, eluent: 25% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give methyl 3-(((R)-tert-butylsulfinyl) (I)amino)-3-ethylhept-6-enoate (INT2-5) was obtained.

[0562] MS (ESI) m / z 290.1 ​​(M+H) + 1 H NMR (500 MHz, chloroform-d) δ 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), 1.76-1.81 (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 [ka]

[0563] Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylheptan Ter-6-enoate (INT2-5) (12 g, 41.5 mmol) was loaded onto SFC column DA ICEL CHIRALPAK AD(250mm×50mm, 10um) Conditions 0. 1%NH3H2O ​​IPA Start B 15 End B 15 Gradient Time (min) 10 0%B Retention time (min) Flow rate (mL / min) 200 Injection 200) and column DICE L CHIRALPAK AD (250mm×50mm, 10um) Conditions 0.1%N H3H2O ​​IPA Start B 12 End B 12 Gradient Time (min) 100%B Retention time (min) Flow rate (mL / min) 200 Injection 240 )-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6 -enoate (INT2-6_P1, desired) (tR = 1.978 min, UV = 220 nm) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3- Ethyl hept-6-enoate (INT2-6_P2) (tR = 2.132 min, UV = 2 20 nm) was obtained.

[0564] MS (ESI) m / z 290.1 ​​(M+H) + INT2-6_P1 : 1 H NMR (500 MHz, chloroform-d) δ 5.79 (tdd, J = 6.56, 1 0.32, 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) δ 5.71-5.87 (m, 1H), 4.9 4-5.07 (m, 2H), 3.65-3.73 (m, 3H), 2.72 (d, J = 16.02 Hz, 1H), 2.52 (d, J = 16.0 2 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 [ka]

[0565] Methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ene Tyrhept-6-enoate (INT2-6_P1) (20 g, 69.1 mmol) was dissolved in H A solution of Cl-dioxane (4N) (100 mL) and MeOH (200 mL) The mixture was stirred at 25° C. for 2 hours. LCMS showed that the reaction was complete. The solvent was removed under reduced pressure. Evaporation at 400°C afforded the product methyl (R)-3-amino-3-ethylhept-6-enoate. The hydrochloride salt (INT2-7) was obtained.

[0566] MS (ESI) m / z 186.3 (M+H) + 1 H NMR (500 MHz, methanol-d4) δ 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, J = 7.6 Hz, 3H) Preparation of Intermediate 2-8 [ka]

[0567] DMB-BOC-thiourea (5 g, 15.32 mmol) and methyl (R)-3-amino 3-ethylhept-6-enoate hydrochloride (INT2-7) (3.74 g, 16.8 Dissolve EDC (7.34 g, 38.3 mmol) in acetonitrile (100 mL DIEA (12.04 mL, 68.9 mmol) was added to the solution. The reaction was stirred under N2 at 15°C for 12 hours. LCMS showed the desired mass and The mixture was then heated to 50°C and stirred at 50°C for 2 hours. LCMS showed only the mass of the desired product and the mixture was concentrated under reduced pressure. The crude material was dissolved in EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash column (ISCO®; 80 g Agela Silica Fla sh Column, eluent 15% ethyl acetate / petroleum ether gradient @ 30mL / (R,E)-(4-(but-3-en-1-yl) -1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidin The 2(1H)-ylidene carbamate (INT2-8) was obtained.

[0568] MS (ESI) m / z 390.1 (M+H-56) + 1 H NMR (400 MHz, chloroform-d) δ 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 (d d, J = 1.6, 4.4 Hz, 6H), 2.61 (s, 2H), 1.98-2.12 (m, 2H), 1.59-1.70 (m, 4H), 1.4 9 (s, 9H), 0.92 (t, J = 7.6 Hz, 3H) Preparation of Intermediate 2-9 [ka]

[0569] tert-Butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4 -dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H) -ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) was dissolved in TFA (10 mL) was stirred at 60° C. for 16 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was diluted with petroleum ether / EtOAc (v / v The mixture was partitioned between ethanol (4:1, 10 mL) and water (10 mL). LCMS showed that the product The product was present only in the aqueous phase, indicating that it was fairly pure. -6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidine The -4(1H)-one (INT2-9) was used directly in the next step.

[0570] MS (ESI) m / z 196.0 (M+H) + Preparation of intermediate 2 [ka]

[0571] (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropi Rimidin-4(1H)-one (INT2-9) (438 mg, 2.243 mmol) was dissolved in water. (10 mL) and THF (3 mL) were dissolved in NaHCO3 (942 mg, 11 (0.22 mmol) and (BOC)2O (1.042 mL, 4.49 mmol) were added at 0°C. The reaction was stirred at 25° C. for 16 hours. LCMS showed the desired mass. The mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. 12 g Agela Silica Flask (ISCO®); h Column, eluent 20% EE (EtOAC / EtOH=3:1) / petroleum ether Purification with a cyclohexane gradient @ 30 mL / min gave tert-butyl (R,E)-(4-(butyl)-2-propanol). 1H-tert-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H )-ylidene)carbamate (Intermediate 2) was obtained.

[0572] MS (ESI) m / z 296.2 (M+H) + 1H NMR (400 MHz, chloroform-d) δ 9.37 (br s, 1H), 5.74-5.81 (m, 1H), 4.90-5.1 7 (m, 2H), 2.59 (s, 2H), 2.07-2.10 (m, 2H), 1.62-1.78 (m, 4H), 1.51 (s, 9H), 0.9 7 (t, J = 7.2 Hz, 3H) Example 1 [ka]

[0573] (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-9- Methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5 .210,13.012,16.022,26]Hentriakonta-10,12,19, 21,26,28-Hexaene-18,31-dione Preparation of Compound 1-2 [ka]

[0574] Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosulfonic acid Cinimide (596 mg, 3.35 mmol) was added to (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 heated under N2 atmosphere The mixture was stirred at 18° C. for 1 hour. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) at 0° C. Quench and extract with DCM (1 x 10 mL) and then with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, and filtered. The crude product was purified by flash silica gel chromatography (ISCO ( Registered trademark); 12 g SepaFlash® Silica Flash Column, eluent: 10% MeOH / DCM (1% ammonium hydroxide added) gradient @ 50 mL / min) to obtain (1R,2R)-1-amino-6-bromo-2,3- Dihydro-1H-inden-2-ol (1-2) was obtained.

[0575] MS (ESI) m / z: 228.1, 230.1(M+H + ) 1 H NMR (400 MHz, methanol-d4) δ 7.50 (s, 1H), 7.33 (dd, J=1.6, 8.0 Hz, 1H), 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 Compounds 1-3 [ka]

[0576] (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4- Ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidine-1 (2H)-yl)chroman-6-carboxylic acid (1-2) (96 mg, 0.198 mmol ) and EDC (189 mg, 0.989 mmol) and 1H-benzo[d][1,2,3]trimethylsilyl Triazol-1-ol (134 mg, 0.989 mmol) and (1R,2R)-1-azoline Imino-6-bromo-2,3-dihydro-1H-inden-2-ol (45.1 mg, 0 0.198 mmol) in THF (5 mL) and DIEA (0.276 mL) , 1.582 mmol) was added. The reaction was stirred at 18° C. for 2 hours. The mixture The mixture was quenched with water (5 mL) and extracted with EtOAc (3×5 mL). Wash with ethanol (5 mL), dry over Na2SO4, filter, and concentrate under reduced pressure to give the crude product. was purified by prep-TLC (petroleum ether / EtOAc=1:1) to give tert-butyl (R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxybenzoyl) 2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman-4-yl )-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin The di-2(1H)-ylidene carbamate (1-3) was obtained.

[0577] MS (ESI) m / z: 695.1, 697.1 (M+H + ) Preparation of Compounds 1-4A, 1-4B, and 1-4C [ka]

[0578] tert-Butyl ((R,E)-1-((R)-6-((1R,2R)-6-bromo -2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chloro Man-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tet Hydropyrimidin-2(1H)-ylidene)carbamate (1-3) (100mg, 0 A solution of 0.144 mmol) in dioxane (1.5 mL) was placed in a glove box. In a solution of chloro[tri(o-tolyl)phosphine][2-(2'-amino-1, 1'-biphenyl)]palladium(II) (8.83 mg, 0.014 mmol) and N ,N-Dicyclohexylmethylamine (140 mg, 0.719 mmol) was added. The reaction was stirred at 70° C. for 16 h. The mixture was quenched with water (3 mL) and The organic layer was washed with brine (5 mL) and diluted with Na2SO4. The crude was dried over O4, filtered, concentrated under reduced pressure, and purified by reverse preparative HPLC (instrument ED; Method Column Boston Prime C18 150×30mm, 5um; Conditions Water (0.04%NH3H2O+10mM NH4HCO3)-ACN Start B 65; End B 95 Gradient time (min) 10; 100% B Hold time ( Purification at 25 mL / min; injection 5 gave the following: t-Butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-1 8-Hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18 ,18a,19,20-Dodecahydro-3H,6H-1,21-(epietane[1,2] Diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pi Lano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4A); tert-butyl ((4aR,8R,12Z,18R,18aR,28 E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,1 0,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-( Epietan[1,2]diylidene)-8,5-(epiminomethano)-14,16-etheno Cyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-y butyl ((4aR,8R,17 R,17aR,E)-8-Ethyl-17-hydroxy-12-methylene-6,19-dioxide Xo-4, 4a, 6, 7, 8, 9, 10, 11, 12, 16, 17, 17a, 18, 19 -Tetradecahydro-3H-1,20-(epietane[1,2]diylidene)-8,5- (Epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1 ,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C).

[0579] MS (ESI) m / z: 486.2 (M+H + ) 1-4A: 1 H NMR (500 MHz, chloroform-d) δ 10.09 (s, 1H), 7.93 (dd, J=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, 1H), 4.40-4.5 0 (m, 2H), 4.25-4.35 (m, 1H), 3.34 (dd, J=8.0, 15.5 Hz, 1H), 2.99-3.05 (m, 1H), 2.67-2.86 (m, 2H), 2.57 (d, J=13.5 Hz, 1H), 2.40 (d, J=15.5 Hz, 1H), 2.07 (s, 2H ), 1.82 (d, J=11.0 Hz, 2H), 1.62-1.67 (m, 4H), 1.49 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 1-4B:1 H NMR (500 MHz, クロロホルム-d) δ 10.13 (s, 1H), 7.90 (dd, J=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, J=8.50 Hz, 1H), 6.41-6.48 (m, 2H), 6.26 (dd, J=7. 0, 9.0 Hz, 1H), 5.60-5.70 (m, 1H), 5.34 (t, J=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, J=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: 1 H NMR (500 MHz, クロロホルム-d) δ 10.04 (s, 1H), 7.81 (dd, J=2.0, 8.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.99-7.16 (m, 2H), 6.91 (d, J=8.50 Hz, 1H), 6.38-6.50 (m, 2H), 5.44 (s, 1H), 5.31 (t, J=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, J=8.0, 16.0 Hz, 1H), 2.98 (dd, J=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, J=12.0 Hz, 2 H), 1.53-1.65 (m, 4H), 1.45 (s, 9H), 0.98 (t, J=7.5 Hz, 3H) Preparation of Compounds 1-5 [ka]

[0580] 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-( Epietan[1,2]diylidene)-8,5-(epiminomethano)-13,15-etheno Cyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine-27- Iylidene carbamate (1-4C) (10 mg, 0.016 mmol) was dissolved in MeOH (2 A solution of Pd-C (1.731 mg, 3.25 μmol mL) was added under a N2 atmosphere. l) was added. The mixture was degassed and backfilled with H2 (3 times). The resulting mixture The mixture was stirred under H2 (15 psi) at 25°C for 12 hours. The catalyst was removed by filtration, and the filtrate was Concentrate under reduced pressure to give tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl 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-(epietane[1,2]diylidene)-8,5-(epiminomethano)-13,15 -Ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine The resulting 2-(27-ylidene)carbamate (1-5) was obtained.

[0581] MS (ESI) m / z: 617.3 (M+H + ) Preparation of Example 1 [ka]

[0582] tert-Butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxybenzoate 12-hydroxy-6,19-dioxo-4,4a,6,7,8,9,10,11 ,12,16,17,17a,18,19-Tetradecahydro-3H-1,20-(epi Ethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenosyl Ropenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-yl Dissolve the benzophenone carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 mL). The dissolved solution was added with zinc bromide (II) (29.2 mg, 0.130 mmol) under N2 atmosphere. ) was added at 22° C. The mixture was stirred at 22° C. for 16 hours. The mixture was cooled and 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 150×30 mm, 5 um condition, water (TFA)-ACN start B 22 end B 52 gradient Time (min) 10, 100% B hold time (min) 2, flow rate (mL / min) 25, purified by injection 1) Thus, Example 1 was obtained.

[0583] MS (ESI) m / z: 517.2 (M+H + ) 1 1H NMR (500 MHz, methanol-d4) δ 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) Example 2

Chemical formula

[0584] (1R,5R,16R,17R)-5-ethyl-16-hydroxy-3-imino-24 -Oxa-2,4,18-triazahexacyclo[18.6.2.22,5.211,1 4.013,17.023,27] Dotriaconta-11,13,20,22,27,2 9-Hexaene-19,32-dione Preparation of Compound 2-1

Chemical formula

[0585] tert-Butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethoxy 18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,1 7,18,18a,19,20-dodecahydro-3H,6H-1,21-(epietane[ 1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta [h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)cal Bamate (2-1) (13 mg, 0.021 mmol) was dissolved in MeOH (4 mL). To the resulting solution was added Pd—C (2.250 mg, 4.23 μmol) under a N 2 atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was then cooled to 100°C and cooled to 150°C. The mixture was stirred at 20° C. for 2 hours under si). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give te rt-Butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydro Oxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,1 8,18a,19,20-Tetradecahydro-3H,6H-1,21-(epietane[1 ,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[ h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carba Mate (2-1) was obtained.

[0586] MS (ESI) m / z: 617.2 (M+H + ) Preparation of Example 2 [ka]

[0587] tert-Butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18- Hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,1 7,18,18a,19,20-Tetradecahydro-3H,6H-1,21-(epieta Benzene[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopentadiene pentane[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene Carbamate (2-1) (13 mg, 0.021 mmol) was dissolved in DCM (3 mL). To the resulting solution, zinc bromide (II) (47.5 mg, 0.211 mmol) was added under a N2 atmosphere. The mixture was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure to give a crude The residue was purified by reverse preparative HPLC (instrument EJ; method Col umn Boston Green ODS 150×30mm, 5um, Condition Water (T FA)-ACN Start B 22; End B 52 Gradient Time (min) 10; 100 %B Retention time (min) 2 Flow rate (mL / min) 25; Injection 1) R,18R,18aR)-8-Ethyl-18-hydroxy-28-imino-4,4a,8 ,9,10,11,12,13,17,18,18a,19-dodecahydro-3H,6H -1,21-(epietane[1,2]diylidene)-8,5-(epiminomethano)-14 ,16-Ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononade Syn-6,20(7H)-dione (Example 2) was obtained.

[0588] MS (ESI) m / z: 517.2 (M+H + ) 1 H NMR (500 MHz, メタノール-d4) δ 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, 1H), 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) Example 3A

change

[0589] (1R,5R,17S)-5-Ethyl-3-imino-15,15-dimethyl-14,2 4-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

change

[0590] Tono-4-ethanoic acid (40g, 400mmol) and EDC (92g, 479mmol) and 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 To a solution of N,O-dimethylhydroxybenzoate (1598 mmol) in DCM (400 mL) was added Hydroxylamine hydrochloride (54.6 g, 559 mmol) was added. The reaction was heated under N The mixture was stirred under atmospheric pressure at 25° C. for 12 hours. The mixture was quenched with water (300 mL) and The organic layer was washed with brine (100 mL) and Drying over Na2SO4, filtering, concentrating under reduced pressure, and the crude product was purified by flash silica gel chromatography. Matography (ISCO®); 220g Agela Silica Fla sh Column, eluent 8% ethyl acetate / petroleum ether gradient @ 50mL / min ) to give N-methoxy-N-methylpent-4-enamide (3-2). .

[0591] MS (ESI) m / z 144.1 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0592] N-Methoxy-N-methylpent-4-enamide (3-2) (20 g, 140 mmol) l) in THF (200 mL) was added to a solution of ethylmagnesium bromide under a N2 atmosphere. Iodide (69.8 mL, 210 mmol) was added dropwise at 0° C. The reaction was heated under N The mixture was stirred under atmospheric pressure at 25°C for 1 hour. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 5% ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give hept-6-en-3-one (3 -3) was obtained.

[0593] 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0594] Hept-6-en-3-one (3-3) (10 g, 89 mmol) was dissolved in THF (100 ml) L), and (R)-2-methylpropane-2-sulfinamide (12. 97 g, 107 mmol) was added to Ti(EtO)4 (37.5 mL, 178 mmol) ) was also added and the reaction was stirred at 75° C. under N atmosphere for 12 hours. The mixture was then heated at room temperature The mixture was cooled to rt, diluted with DCM (200 mL) and stirred for 15 min. Aqueous sodium hydroxide (50 mL) and Na2SO4 were added, and the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®); 20g Agela Silica Flash Column, eluent 8% ethyl acetate Purification with ethanol / petroleum ether gradient @ 40 mL / min gave (R,E)-N-(hepta- 6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) was obtained. was made.

[0595] MS (ESI) m / z 216.2(M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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 Compounds 3-5 [ka]

[0596] Diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) The solution was treated with butyllithium (55.7 mL, 13 9 mmol) was added dropwise. The reaction was stirred at 0 °C for 30 min to form LDA. The obtained LDA (76 mL, 93 mmol) was dissolved in acetic acid in anhydrous THF (90 mL). Ethyl (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 After 1 hour, (R,E)-N-(heptane)-2-hydroxybenzoates were added dropwise to a mixture of (R,E)-N-(heptane)-2-hydroxybenzoates (2-hydroxybenzoates) at -78°C. (6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was added dropwise. The mixture was stirred at -78°C for 3 hours. The mixture was added ice-cold half-saturated ammonium chloride solution. The slurry was quenched with 60 mL of aqueous ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), filtered, and rinsed with EtOAc and water. The residue was evaporated, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (ISCO®); 120g Agela Silica F Flash Column, eluent 25% ethyl acetate / petroleum ether gradient @ 40mL / min) to give methyl 3-(((R)-tert-butylsulfinyl)amino) 3-Ethylhept-6-enoate (3-5) was obtained.

[0597] MS (ESI) m / z 290.1 ​​(M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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), 1.76-1.81 (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 Compounds 3-6 [ka]

[0598] Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylheptan The 6-enoate (3-5) (9 g, 31.1 mmol) was dissolved in 4N HCl-dioxane (20 mL) and MeOH (20.00 mL) were dissolved in 200 mL of ethanol under N2 atmosphere at 25°C. The mixture was stirred at rt for 1 h. The solvent was evaporated under reduced pressure to give the crude product methyl 3-amino-3-enol The resulting ethylhept-6-enoate hydrochloride (3-6) was used crude for the next step. was used directly.

[0599] MS (ESI) m / z 186.2 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 5.75-5.80 (m, 1H), 5.08 (dd, J=1.0, 18.0 Hz, 1H), 4.98 (d, J=10.22 Hz, 1H), 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 compounds 3-7 [ka]

[0600] EDC (9.08 g, 47.4 mmol) and methyl 3-amino-3-ethylhepta- 6-enoate hydrochloride (3-6) (3.5 g, 15.79 mmol) and methyl (R)- 4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxy Dissolve the ester (INT-1) (5.78 g, 15.79 mmol) in ACN (30 mL). To the resulting solution, N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol) was added, and the reaction was stirred at 25° C. under N atmosphere for 12 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Condensed, methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3 -(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino) Chroman-6-carboxylate (3-7) was obtained, which was carried on crude to the next step. Used directly.

[0601] MS (ESI) m / z 518.2 (M+H + ) Preparation of Compounds 3-8 [ka]

[0602] Methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3 -ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chroma Benzene-6-carboxylate (3-7) (8.17 g, 15.78 mmol) was dissolved in THF ( To a solution of 100mg of HCl in 1000mg of HCl (11.90mL, 79mmol) was added DBU (11.90mL, 79mmol). The mixture was stirred at 50 °C under N2 atmosphere for 16 h. The mixture was diluted with water (50 mL). It was quenched and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (30 mL ), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (ISCO®); 120 g Agela Silica Lica Flash Column, eluent: 25% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain methyl (4R)-4-((E)-4-(buta-3- En-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6 -oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (3-8) was obtained.

[0603] MS (ESI) m / z 486.2(M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 7.77 (td, J=2.0, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (dd, J=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 and 3-9B [ka]

[0604] Methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((te rt-Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine -1(2H)-yl)chroman-6-carboxylate (3-8) (4 g, 8.24 mm ol) to SFC(Column Boston Green ODS 150×30mm , 5um Conditions Water (TFA)-ACN Start B 48 End B 78 Gradient Time (min) 10 100% B retention time (min) 2 Flow rate (mL / min) 25 Injection 1) (P1) Methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2 -((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydro Pyrimidine-1(2H)-yl)chroman-6-carboxylate (3-9A)(t R = 2.105 min, UV=220 nm) and (P2) methyl (4R)-4-((E)-4- (But-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4 -ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-chlor carboxylate (3-9B)(t R = 2.251 min, UV = 220 nm).

[0605] MS (ESI) m / z 486.2 (M+H + ) 3-9A: 1 H NMR (500 MHz, chloroform-d) δ 7.77 (dd, J=1.5, 8.5 Hz, 1H), 7. 62 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.37 (br dd, J=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: 1 H NMR (500 MHz, chloroform-d) δ 7.77 (br d, J=8.70 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.39 (br 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, 3H), 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 Compounds 3-10 [ka]

[0606] Methyl (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((t (ert-Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin 1-(2H)-yl)chroman-6-carboxylate (3-9A) (550 mg, 1 A solution of 133 mmol of methylsilanol in 5 mL of THF was added to the solution. Sodium (872 mg, 6.80 mmol) was added and the reaction was stirred at 25° C. for 0.5 h. (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((te rt-Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine The solution of 3-10-1(2H)-yl)chroman-6-carboxylic acid was further It was used directly in the next step without any manipulation or purification.

[0607] MS (ESI) m / z 472.2 (M+H + ). Preparation of Compounds 3-11 [ka]

[0608] (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert- Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1( 2H)-Il)chroman-6-carboxylic acid (3-10) (534 mg, 1.132 mmol) l) and EDC (1085 mg, 5.66 mmol) and 1H-benzo[d][1,2,3] Triazol-1-ol (765 mg, 5.66 mmol) and (S)-2,2-dimethyl Dissolve 1,2-dichloro-6-vinylchroman-4-amine (253 mg, 1.246 mmol) in THF (5 DIEA (1.582 mL, 9.06 mmol) was added to the solution. The reaction was stirred at 25°C for 12 hours. The mixture was quenched with water (20 mL). The organic layer was washed with brine (15 mL) and extracted with EtOAc (3×20 mL). , dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by prep-TLC ( Purification with ether / EtOAc (2:1) gave tert-butyl ((R,E)-4- (But-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6 -vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6- Oxotetrahydropyrimidine-2(1H)-ylidene carbamate (3-11) was obtained. was made.

[0609] MS (ESI) m / z 657.3 (M+H + ) Preparation of Compounds 3-12 [ka]

[0610] tert-Butyl ((R,E)-4-(but-3-en-1-yl)-1-((R) -6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl) Chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)- Iylidene carbamate (3-11) (500 mg, 0.761 mmol) was added to DCE (5 00mL) and add (1,3-bis-(2,4,6-trimethylphenyl) -2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium Ammonia (95 mg, 0.152 mmol) was added. The reaction was stirred for 50 minutes under a N2 atmosphere. The mixture was stirred at 5°C for 5 hours. The mixture was concentrated under reduced pressure, and the crude was purified by flash column ( Purification with oil ether / EtOAc / EtOH=8:3:1 gave tert-butyl (( 4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6, 20-Dioxo-4,4a,7,8,9,10,18,18a,19,20-Decahydro -3H,6H,17H-8,5-(epimethylamino)-1,21:13,15-dietheno Dipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-28- Ylidene carbamate (3-12) was obtained.

[0611] MS (ESI) m / z 629.3 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 7.67 (dd, J=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), 2.35-2.4 1 (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 Compounds 3-13 [ka]

[0612] tert-Butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-1 7,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a ,19,20-Decahydro-3H,6H,17H-8,5-(epiminomethano)-1,2 1:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazashi Chlooctadecin-28-ylidene)carbamate (3-12) (300 mg, 0.47 7 mmol) in MeOH (10 mL), and 0.8 mg, 0.048 mmol) was added. The mixture was degassed and backfilled with H2. The resulting mixture was stirred under H2 (15 psi) at 25 °C for 0.5 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,18 aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7, 8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,1 7H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3 -b: 4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carba The mate (3-13) was obtained, which was used directly in the next step.

[0613] MS (ESI) m / z 631.3(M+H + ) Preparation of Example 3A [ka]

[0614] tert-Butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-di Methyl-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]diaza Cyclooctadecin-28-ylidene)carbamate (3-13) (280 mg, 0.4 A solution of 44 mmol) in HCl-dioxane (4N) (30 mL) was heated at 25°C. The mixture was stirred at rt for 16 h. The solvent was evaporated under reduced pressure to give the crude product. Preparative HPLC (Column Boston Green ODS 150×30mm, 5um Conditions Water (HCl)-ACN Start B 30 End B 50 Gradient Time ( Purify with 6) 100% B retention time (min) 2 flow rate (mL / min) 25 injection (4aR,8R,18aS)-8-ethyl-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-dietenodipira No[4,3-b:4',3'-h][1,7]diazacyclooctadecine-6,20-di On (Example 3A) was obtained.

[0615] MS (ESI) m / z 531.2 (M+H + ) 1 H NMR (500 MHz, methanol-d4) δ 7.73 (dd, J=2.0, 8.5 Hz, 1H), 7.45 (s, 1H), 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), 2.2 3-2.31 (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) Example 4 [ka]

[0616] (1R,5R,18S)-5-ethyl-3-imino-16,16-dimethyl-10,1 5,25-trioxa-2,4,19-triazahexacyclo[19.6.2.22,5 .211,14.013,18.024,28] Tritriakonta-11,13,21, 23,28,30-Hexaene-20,33-dione Preparation of Compound 4-2 [ka]

[0617] Hexa-5-enoic acid (4-1) (8 g, 70.1 mmol) and EDC (20.15 g, 105 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (14 0.21g, 105mmol) and N,O-dimethylhydroxylamine hydrochloride (7.52g , 77 mmol) in THF (100 mL) was added to a solution of DIEA (36.7 mL , 210 mmol) was added. The reaction was stirred at 25° C. for 5 hours. The mixture was diluted with water ( The mixture was quenched with 150 mL of ethyl acetate and extracted with 3 x 50 mL of EtOAc. The crude product was washed with ethanol (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, elution Purification with 5% EtOAc / petroleum ether gradient @ 80 mL / min gave N-methoxy. C1-N-methylhex-5-enamide (4-2) was obtained.

[0618] MS (ESI) m / z 157.7 (M+H + ) Preparation of compound 4-3 [ka]

[0619] N-Methoxy-N-methylhex-5-enamide (4-2) (9 g, 57.2 mmol) l) in THF (120 mL) was added to a solution of ethylmagnesium bromide under a N2 atmosphere. C. Then, bromine (38.2 mL, 114 mmol) was added dropwise at 0.degree. C. The mixture was then The mixture was stirred at 20°C for 2 hours. The mixture was quenched with saturated aqueous NH4Cl (25 mL). The mixture was quenched with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, and filtered. The solvent was evaporated under reduced pressure to give a crude product, which was purified by column chromatography. (SiO2, petroleum ether: EtOAc = 100:1 to 10:1) and 4-7-en-3-one (4-3) was obtained.

[0620] 1H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0621] Oct-7-en-3-one (4-3) (5.5 g, 43.6 mmol) was dissolved in THF (8 2-methylpropane-2-sulfinamide (6.34 g) , 52.3 mmol) was added, followed by Ti(EtO)4 (18.31 mL, 87 mm ol) was added. The reaction was stirred at 75°C under N2 atmosphere for 16 hours. The mixture was cooled to 0° C., diluted with DCM (100 mL) and stirred for 15 min. Aqueous sodium carbonate (15 mL) was added and the solution was filtered and concentrated under reduced pressure. The crude product was purified by flash column (SiO, petroleum ether / EtOAc = 100:1 → 5:1 ) and purified with (E)-2-methyl-N-(oct-7-en-3-ylidene)propane The 2-sulfinamide (4-4) was obtained.

[0622] MS (ESI) m / z 230.2 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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, 9 H), 1.06-1.21 (m, 3H) Preparation of Compounds 4-5 [ka]

[0623] LiHMDS (22.67 mL, 22.67 mmol) was dissolved in anhydrous THF (35 mL). The dissolved solution was added with methyl acetate (1.545 mL, 19.18 mL) at −78°C under a N2 atmosphere. The reaction was stirred at -78°C for 15 minutes. Then THF (15 mL) in (E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2 Sulfinamide (4-4) (4 g, 17.44 mmol) was added dropwise and the mixture was stirred. The mixture was stirred at -78°C for 3 hours. The mixture was added to an ice-cold half-saturated aqueous ammonium chloride solution (30 The slurry was diluted with EtOAc (50 mL), filtered, and The organic layer was washed with brine (50 mL) and Na2SO4 The residue was dried over 1000 kJ / h, filtered, and concentrated under reduced pressure. The resulting mixture was purified with 100:0 → 10:1 ethanol / Et0Ac to give methyl 3-((tert- (butylsulfinyl)amino)-3-ethyl oct-7-enoate (4-5) was obtained. Ta.

[0624] MS (ESI) m / z 304.3 (M+H + ). 1 H NMR (500 MHz, chloroform-d) δ 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 Compounds 4-6 [ka]

[0625] Methyl 3-((tert-butylsulfinyl)amino)-3-ethylocta-7- The enoate (4-5) (2 g, 6.59 mmol) was dissolved in HCl-dioxane (4N A solution of 5 mL of HCl in MeOH (5 mL) was heated at 15°C for 1 hour under N2 atmosphere. The solution was concentrated under reduced pressure to give the crude product methyl 3-amino-3-ethylamino Cuta-7-enoate hydrochloride (4-6) was obtained, which was then purified without further purification. Used.

[0626] 1 H NMR (500 MHz, chloroform-d) δ 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 Compounds 4-7 [ka]

[0627] Methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman methyl 3-carboxylate (INT-1) (1.5 g, 4.09 mmol) -amino-3-ethyl oct-7-enoate hydrochloride (4-6) (1.448 g, 6.1 4mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride The salt (2.354 g, 12.28 mmol) was dissolved in acetonitrile (30 mL). The solution was treated with N-ethyl-N-isopropylpropan-2-amine (4.37 mL, 24.56 The mixture was stirred at 15° C. for 10 hours. The mixture was then cooled to 10° C. with water (50 mmol). The mixture was quenched with 1 mL of ethyl acetate and extracted with EtOAc (3×40 mL). The organic layer was washed with brine ( 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl (4 R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1- Methoxy-1-oxooct-7-en-3-yl)guanidino)chroman-6-carbo The xylate (4-7) was obtained, which was used directly crude in the next step.

[0628] MS (ESI) m / z 532.3 (M+H+). Preparation of Compounds 4-8 [ka]

[0629] Methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl))-3-( 3-Ethyl-1-methoxy-1-oxooct-7-en-3-yl)guanidino)chloro Man-6-carboxylate (4-7) (2.0 g, 3.76 mmol) was dissolved in THF (20 To a solution of 1000mg DBU (2.84 mL, 18.81 mmol) was added DBU (2.84 mL, 18.81 mmol). The mixture was stirred at 50° C. for 10 h. The mixture was quenched with water (40 mL) and E The organic layer was washed with brine (20 mL) and The crude was dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (ISCO®); 20 g Agela Silica Fl Ash Column, eluent 15% ethyl acetate / petroleum ether gradient @ 60mL ) and purified with methyl (4R)-4-((E)-2-((tert-butoxycarbonyl) (I)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydrofuran (2H)-Dropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-8) was obtained. It was.

[0630] MS (ESI) m / z: 500.6 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ 10.10 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.6 1 (s, 1H), 6.83 (dd, J = 0.8, 8.8 Hz, 1H), 6.31-6.46 (m, 1H), 5.77 (m, 1H), 4.97 -5.10 (m, 2H), 4.43 (d, J = 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 and 4-9B [ka]

[0631] Methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl 6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidine-1(2 H)-yl)chroman-6-carboxylate (4-8) (1.8 g, 3.60 mmol ) to SFC (equipment SFC-22 Method Column DAICEL CHI RALPAK AD (250mm×30mm, 10um) Conditions 0.1%NH3H2O IPA Start B 10% End B 10% Gradient Time (min) 100% B hold The product (methyl (R)- 4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6 -Oxo-4-(pent-4-en-1-yl)tetrahydropyrimidine-1(2H)- yl)chroman-6-carboxylate (4-9A) (peak 1, R t =0.816) and (methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-enyl) thyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidine-1( 2H)-yl)chroman-6-carboxylate (4-9B) (peak 2, R t =0.8 79) was obtained.

[0632] MS (ESI) m / z: 500.2 (M+H + ) Preparation of Compounds 4-10 [ka]

[0633] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino )-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin Diazin-1(2H)-yl)chroman-6-carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL) 2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium oxide The resulting solution was heated at 25°C. The mixture was stirred at RT for 0.2 hours. Sodium periodate (171 mg, 0.801 mmol) was added. The resulting solution was stirred at 25 °C for 2 h. The mixture was diluted with saturated NaSO (10 mL ) and water (5 mL) and extracted with EtOAc (3 x 10 mL). The extract was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)- 4-Ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1(2H )-yl)chroman-6-carboxylate (4-10), which was obtained crude. It was used directly in the next step.

[0634] MS (ESI) m / z: 502.3 (M+H + ) Preparation of Compounds 4-11 [ka]

[0635] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino )-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1( 2H)-Il)chroman-6-carboxylate (4-10) (95 mg, 0.189 m mol) in MeOH (2 mL) at 0 °C. g, 0.284 mmol) was added portionwise. The mixture was stirred at 0°C for 1 hour. LC MS showed a major mass of the desired product. The mixture was quenched with water (5 mL) and Extract with EtOAc (4 x 5 mL). The combined organic layers were washed with brine (5 mL). The crude product was purified by prep-TLC ( Petroleum ether / Et0Ac (3:1) to give methyl (R)-4-((R,E)- 2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxy (butyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-chlor The carboxylates (4-11) were obtained.

[0636] MS (ESI) m / z: 504.4 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ 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, 9 H), 1.43-1.49 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of Compounds 4-12 [ka]

[0637] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino )-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine- 1(2H)-yl)chroman-6-carboxylate (4-11) (53 mg, 0.10 5 mmol) in THF (1 mL) and potassium trimethylsilanolate (81 mg, 0.631 mmol) was added. The reaction was stirred at 25° C. for 0.5 h. LCMS showed the mass of the major desired product. (R)-4-((R,E)-2-( (tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl )-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid The solution of (4-12) was used in the next step without further manipulation or purification. .

[0638] MS (ESI) m / z: 490.2 (M+H + ) Preparation of Compounds 4-13 [ka]

[0639] (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4- Ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H )-yl)chroman-6-carboxylic acid (4-12) (50 mg, 0.102 mmol) EDC (98 mg, 0.511 mmol) and 1H-benzo[d][1,2,3]triazo (S)-6-bromo-2,2-diol (69.0 mg, 0.511 mmol) -Dimethylchroman-4-amine (28.8 mg, 0.112 mmol) was dissolved in THF (5 m To the solution dissolved in 1 L of DIEA (0.143 mL, 0.817 mmol) was added The reaction was stirred at 25° C. for 3 h. The mixture was quenched with water (5 mL) and The organic layer was washed with brine (5 mL) and diluted with Na2SO4. The crude was dried over O4, filtered, and concentrated under reduced pressure. Purification with ethanol / EtOAc (3:1) yielded tert-butyl ((R,E)-1-((R -6-((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chlor (4-hydroxybutyl)-6-oxotetrahydrofuran-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydrofuran Dropyrimidine-2(1H)-ylidene)carbamate (4-13) was obtained.

[0640] MS (ESI) m / z: 727.2, 729.2 (M+H + ) Preparation of Compounds 4-14 [ka]

[0641] In a glovebox, tert-butyl ((R,E) -1-((R)-6-(((S)-6-bromo-2,2-dimethylchroman-4-yl) Carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6 -oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13) ( 70 mg, 0.096 mmol) of [(2-di-tert-butylphosphino -2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino -1,1'-biphenyl)]palladium(II) methanesulfonate (7.64 mg, 9 CsCO3 (37.1 mg, 0.192 mmol) and CsCO3 (37.1 mg, 0.192 mmol) were added. The mixture was stirred at 70° C. for 3 h. The mixture was diluted with water (10 mL) and (3×10 mL). The organic layer was washed with brine (5 mL) and The crude product was purified by prep-TLC (petroleum ether / EtOAc = 2:1) to give tert-butyl ((4aR,5R,8R,19a S,E)-8-Ethyl-18,18-dimethyl-6,21-dioxo-4,4a,7,8 ,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18 H-1,22-(epietane[1,2]diylidene)-8,5-(epiminomethano)-1 4,16-Ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]di Azacyclononadecin-29-ylidene)carbamate (4-14) was obtained.

[0642] MS (ESI) m / z: 647.3 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0643] tert-Butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,1 8-dimethyl-6,21-dioxo-4,4a,7,8,9,10,11,12,19, 19a,20,21-dodecahydro-3H,6H,18H-1,22-(epietane[1 ,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3, 4-d: A solution of [3',4'-j] [1] was added with DCM (3 mL) at 25 °C under a N2 atmosphere. Zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diaza Cyclononadecin-29-ylidene)carbamate (4-14) (30 mg, 0.046 The mixture was stirred at 25° C. for 16 hours. The solvent was evaporated under reduced pressure. The residue was purified by reverse preparative HPLC (instrument, e.g., Method Column Welch Xtimate C18 150×25mm, 5um; Water (TFA)-ACN Start B 25; End B 55 Gradient Time (min) 11 100% B retention time (min) 2 flow rate (mL / min) 25; injection 1) and purified (4 aR,5R,8R,19aS)-8-Ethyl-29-imino-18,18-dimethyl-4 ,4a,7,8,9,10,11,12,18,19,19a,20-dodecahydro-3 H,6H,21H-1,22-(epietane[1,2]diylidene)-8,5-(epime Nomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa [6,12]Diazacyclononadecyne-6,21-dione (Example 4) was obtained.

[0644] MS (ESI) m / z: 547.2 (M+H + ) 1H NMR (500 MHz, methanol-d4) δ 8.55 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 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) Example 5 [ka]

[0645] (11R,14R,14aR,21aS)-11-ethyl-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)-4,6:1 7,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diaza ... Kutadecin-13,20(14aH)-dione Preparation of Compound 5-2 [ka]

[0646] 5-Bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol) ) and ethane-1,2-dithiol (5-1) (26.6 mL, 317 mmol) and 4-methyl- Diethylbenzenesulfonic acid (8.16 g, 47.4 mmol) in toluene (500 mL) The resulting solution was heated to 130° C. using a Dean-Stark apparatus for 16 hours. TLC showed the reaction was complete. The cooled solution was diluted with 10% NaOH (600 The aqueous layer was washed with DCM (3 x 600 mL) and the combined organic layers were extracted with DCM (3 x 600 mL). Wash with brine (300 mL), dry over Na2SO4, filter, and evaporate the solvent under reduced pressure. The crude product was purified by flash silica gel chromatography. ISCO® 330 g SepaFlash® Silica ca Flash Column, eluent 10% EtOAc / petroleum ether gradient @ 60 mL / min) to obtain 5-bromo-2,3-dihydrospiro[indene-1,2 '-[1,3]dithiolane] (5-2) was obtained.

[0647] MS (ESI) m / z 286.9, 288.9 (M+H) + 1 H NMR (500 MHz, chloroform-d) δ 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, 2 H) Preparation of compound 5-3 [ka]

[0648] 1,3-Dibromo-5,5-dimethylhydantoin (194 g, 679 mmol) A solution of the solution dissolved in water (700 mL) and CH2Cl2 was added in a dry ice-acetone bath. The mixture was cooled to -70°C. Pyridine hydrofluoride (57) was added under N2 at a temperature below -65°C. 0.4 mL, 226 mmol) was added dropwise and the mixture was stirred at -70°C for 30 min. 5-Bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane] A solution of (5-2) (65 g, 226 mmol) in CHCl (200 mL) was added dropwise and the mixture was stirred at -70°C for 4 hours and then at 25°C overnight. TLC showed the reaction was complete. The mixture was diluted with 39% NaHSO3 (600 The aqueous layer was poured into a solution of NaOH (2M, 300 mL) containing CH Extract with Cl2 (2 x 600 mL) and wash the combined organic layers with brine (300 mL). The mixture was 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®); 220 g SepaFlash® Silica Flash Column n, eluent 100% petroleum ether gradient @ 60 mL / min) to give 2,5- Dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3) was obtained. Ta.

[0649] No LCMS signal.

[0650] 1 H NMR (500 MHz, chloroform-d) δ 7.52-7.58 (m, 1H), 7.47 (d, J = 6.5 Hz, 2H), 4.57 (tt, J = 7.0, 10.5 Hz, 1H), 3.57 (ddd, J = 2.0, 7.5, 16.5 Hz, 1H), 3.27 (d d, J = 7.0, 16.5 Hz, 1H) Preparation of compound 5-4 [ka]

[0651] 2,5-Dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3 ) (60 g, 192 mmol) in DCM (600 mL) was added with DBU (4 3.5 mL, 289 mmol) was added, and the mixture was stirred at 25° C. for 16 hours. MS showed the mass of the desired product. Water (600 mL) was added and the mixture was diluted with concentrated HCl The mixture was acidified to pH = 7 with 100 mL of 100 mL of 100% HCl. The mixture was filtered through diatomaceous earth and the aqueous layer was (2 x 600 mL), and the combined organic layers were washed with brine (300 mL) and N Drying over a2SO4, filtration and evaporation of the solvent under reduced pressure gave the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Purification with 100% petroleum ether (gradient @ 50 mL / min) gave 5-bromo-1, 1-Difluoro-1H-indene (5-4) was obtained.

[0652] No LCMS signal.

[0653] 1 H NMR (500 MHz, chloroform-d) δ 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 [ka]

[0654] 5-Bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mm ol) in iPrOH (250 mL) that had been aerated with O2 for 1 hour. Lusilane (14.05 g, 130 mmol) and Mn(TMHD)3 (3.93 g, 6. The mixture was stirred at 0°C for 2 hours under O2 (15 psi). The reaction was shown to be complete. The mixture was quenched with water (300 mL) and The organic layer was washed with brine (300 mL) and Drying over O4, filtration and evaporation of the solvent under reduced pressure gave the crude product. The product was purified by flash silica gel chromatography (ISCO®; 40 g Se paFlash® Silica Flash Column, Eluent 17 % EtOAc / petroleum ether gradient @ 50 mL / min) to give 6-bromo-3, 3-Difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo Mo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (5-5a) A mixture of the following was obtained (5-5:5-5a=7:2).

[0655] 1 H NMR (500 MHz, chloroform-d) δ 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 Compounds 5-6 [ka]

[0656] 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and Mixture of 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol The compound (11.56g, 47.3mmol) (5-5:5-5a=7:2) was dissolved in MeOH (1 A solution of [1,1'-biphenyl]-2,2'-dichloro-1,2'-diisopropyl ... [(diphenylphospino)ferrocene]dichloropalladium(II) (2.64 g, 3. 61 mmol) and triethylamine (15.67 mL, 108 mmol) were added at 20°C. The mixture was then stirred under a CO atmosphere (3.5 mbar) at 80°C for 48 hours. C indicated that the reaction was complete. After cooling, the mixture was filtered through diatomaceous earth and the mixture was The mixture was diluted with HO (200 mL), extracted with EtOAc (3 x 200 mL), and Drying over O4, filtration and evaporation of the solvent under reduced pressure gave the crude product. The product was purified by flash silica gel chromatography (ISCO®; 120 g S epaFlash® Silica Flash Column, Eluent 1 7% EtOAc / petroleum ether gradient @ 80 mL / min) to give methyl 1,1 -Difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate ester (5-6) and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1 Mixture of H-indene-5-carboxylate (5-6a) (5-6:5-6a = 3:1 ) was obtained.

[0657] 1 H NMR (500 MHz, chloroform-d) δ 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, 1 H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) Preparation of compound 5-7_P1 [ka]

[0658] Methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene 5-Carboxylate and methyl 1,1-difluoro-2-hydroxy-2,3-dihydroxide Mixture of 1H-indene-5-carboxylates (8.3 g, 36.36 mmol) The mixture (5-6:27-6a = 3:1) was subjected to SFC (column: Chiralpak AD-3 1 50×4.6mm ID, 3um, Mobile phase: A: CO2 B: Isopropanol ( 0.05% DEA), gradient: 5% → 40% B in 5 minutes, 40% → 5% B in 0.5 minutes, After that, the column was separated at 5% B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 35°C. The product methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro -1H-indene-5-carboxylate (5-7_P1, desired) (peak 1, R t =2 .577), methyl (R)-1,1-difluoro-3-hydroxy-2,3-dihydro -1H-indene-5-carboxylate (5-7_P2) (peak 2, R t =2.94 A mixture of 4) and (5-7_P2 and 5-6a) (2 g, 8.77 mmol) was obtained. The mixture of (5-7_P2 and 5-6a) was subjected to SFC (column: Cellulose 2 15 0×4.6mm ID, 5um, Mobile phase: A:CO2B:MeOH(0.05%D EA) Gradient: 5% B → 40% B in 5 minutes, 40% B → 5% B in 0.5 minutes, then 5% B The column was separated at 35°C for 1.5 minutes and held at 35°C for 1.5 minutes. Methyl 2,3-dihydro-1H-indene-5-carboxylate (5-6a) was obtained. It was.

[0659] (5-7_P1): 1 H NMR (500 MHz, chloroform-d) δ 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): 1 H NMR (500 MHz, chloroform-d) δ 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): 1 H NMR (500 MHz, chloroform-d) δ 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 Compounds 5-8 [ka]

[0660] Methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-isopropyl ndene-5-carboxylate (5-7_P1) (585 mg, 2.56 mmol) and t ert-butyl (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6- Oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT-2) ( 757 mg, 2.56 mmol) and Ph3P (1009 mg, 3.85 mmol) A solution of 10 mL of F dissolved in 0.997 mL of DIAD was added to the solution at 0°C under a N2 atmosphere. , 5.13 mmol) was added dropwise and then the mixture was stirred at 18° C. for 2 hours. TLC showed no SM. The mixture was concentrated under reduced pressure and the residue was purified by flash scrubbing. Silica gel chromatography (ISCO®); 20 g SepaFlash® Registered trademark) Silica Flash Column, eluent 20% EtOAc / silica Purification with oil ether gradient @ 60 mL / min gave the crude product. The product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent Purify again with DCM gradient @ 60 mL / min to give the product methyl (R)-3-((R ,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl) Imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1, 1-Difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8) was obtained.

[0661] MS (ESI) m / z 506.2 (M+H) + 1 H NMR (400 MHz, chloroform-d) δ 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 H z, 3H) Preparation of Compounds 5-9 [ka]

[0662] Methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((t (ert-Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin Indene-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5 -carboxylate (5-8) (900 mg, 1.780 mmol) in THF (9 mL) To the solution of potassium trimethylsilanolate (1370 mg, 10.68 mm ol) was added. The reaction was stirred at 18° C. for 0.5 h. LCMS showed the desired mass H3PO4 (0.1 g / mL in H2O) was added to adjust the pH to approximately 6-7, and the The mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((t (ert-Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin Indene-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5 -carboxylic acid (5-9) was obtained.

[0663] MS (ESI) m / z 492.1 (M+H) + 1 H NMR (400 MHz, chloroform-d) δ 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 Compounds 5-10 [ka]

[0664] (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert- Butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1( 2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carbo Phosphonic acid (5-9) (0.87 g, 1.770 mmol) and EDC (1.697 g, 8.85 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.718 mmol) g, 5.31 mmol) in THF (15 mL) was added to a solution of DIEA (2.47 3mL, 14.16mmol) and (S)-2,2-dimethyl-6-vinylchroman-4 -amine (0.396 g, 1.947 mmol) was added and the reaction was stirred at 18° C. for 12 hours. The mixture was stirred for 1 hour. LCMS showed the desired mass. The mixture was quenched with water (15 mL). The mixture was extracted with EtOAc (3×15 mL). The organic layer was washed with brine (10 mL). The crude material was purified by evaporation to dryness using Na2SO4, filtered, and concentrated under reduced pressure. Gel chromatography (ISCO®); 12 g SepaFlash® Silica Flash Column, eluent 17% EtOAc / petroleum ether Purification with ether gradient @ 60 mL / min gave the product tert-butyl ((R,E) -4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl (6-vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-difluoro Hydro-1H-inden-1-yl)-4-ethyl-6-oxotetrahydropyrimidine -2(1H)-ylidene)carbamate (5-10) was obtained.

[0665] MS (ESI) m / z 677.4 (M+H) + 1 H NMR (400 MHz, chloroform-d) δ 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 Compounds 5-11 [ka]

[0666] tert-Butyl ((R,E)-4-(but-3-en-1-yl)-1-((R) -6-((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)- 3,3-Difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6 -oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10) ( 1 g, 1.478 mmol) in DCE (500 mL) ,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropylphenyl) propoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol ) was added. The reaction was stirred under N2 at 50 °C for 4 h. LCMS showed the desired mass The mixture was concentrated under reduced pressure and the crude product was purified by flash silica gel chromatography. Raffi (ISCO®); 12 g SepaFlash® Sil ica Flash Column, eluent 15% EtOAc / petroleum ether gradient @ 60 mL / min to give tert-butyl ((7Z,11R,14R,14a R,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl- 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]diazacycloocta Decyn-24-ylidene)carbamate (5-11a, cis olefin; minor product ) and tert-butyl ((7E,11R,14R,14aR,21aS,24E)- 11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1 ,2,10,11,12,13,14a,15,16,20,21,21a-Dodecahydride rho-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta ta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene The carbamate (5-11, trans olefin; major product) was obtained.

[0667] (5-11a, cis olefin): MS (ESI) m / z 649.3 (M+H) + 1H NMR (400 MHz, クロロホルム-d) δ 10.12 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.7 3 (d, J = 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), 5.5 8-5.61 (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), 1.5 1 (s, 9H), 1.46 (s, 3H), 1.39 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H) (5-11, trans olefin): MS (ESI) m / z 649.3 (M+H) + 1 H NMR (400 MHz, クロロホルム-d) δ 10.15 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.7 0 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H ), 6.73 (d, J = 8.4 Hz, 1H), 6.61-6.70 (m, 1H), 6.39 (d, J = 15.6 Hz, 1H), 6.06 (d, J = 9.2 Hz, 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, J = 7.6 Hz, 3H) Preparation of Compounds 5-12 [ka]

[0668] tert-Butyl ((7E,11R,14R,14aR,21aS,24E)-11 -ethyl-16,16-difluoro-2,2-dimethyl-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)cal Bamate (5-11) (780 mg, 1.202 mmol) was dissolved in MeOH (10 mL). The dissolved solution was added with 10% Pd-C (128 mg, 0.120 mmol) under N2 atmosphere. The mixture was degassed and back-filled with H2 (3 times). The mixture was stirred under 15 psi at 18° C. for 10 minutes. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl ((1 1R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2 ,2-dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,1 4a,15,16,20,21,21a-tetradecahydro-7H-11,14-(epi (aminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h] [1,7]diazacyclooctadecin-24-ylidene)carbamate (5-12) was obtained. This was used directly in the next step.

[0669] MS (ESI) m / z 651.4 (M+H) + Preparation of Example 5 [ka]

[0670] tert-Butyl ((11R,14R,14aR,21aS,E)-11-ethyl- 16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,8,9, 10,11,12,13,14a,15,16,20,21,21a-Tetradecahydro -7H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta [b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)ca Dissolve 5-12 (700 mg, 1.076 mmol) in HCl-dioxane (4 N) (10 mL) was stirred at 18° C. for 12 h. LCMS showed that the reaction The reaction was shown to be complete. The solvent was evaporated under reduced pressure to give the crude product. Preparative HPLC (Instrument 3-101(EK) Method Phase separate ion Column Boston Uni C18 150×40mm, 5um strip Water (0.04% HCl)-ACN Start B 33 End B 63 Gradient Time ( Purify with 100% B retention time 2 flow rate (mL / min) 60 injection 2) and (1 1R,14R,14aR,21aS)-11-ethyl-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)-4,6:17,1 9-Diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctade Syn-13,20(14aH)-dione (Example 5) was obtained.

[0671] MS (ESI) m / z 551.3 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ 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 (br 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), 1.5 5-1.72 (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 by methods similar to those described for Example 1 and / or Example 5. The isomers were separated by preparative HPLC and / or preparative chiral SFC.

[0672] An asterisk (*) may be used in chemical structure diagrams to indicate the location of a chiral center. [Table 2] TIFF2025183301000180.tif191166TIFF2025183301000181.tif210166TIFF2025183301000182.tif197166TIFF2025183301000183.tif210166TIFF2025183301000184.tif204166TIFF2025183301000185.tif198167TIFF2025183301000186.tif197166TIFF2025183301000187.tif216167TIFF2025183301000188.tif198169TIFF2025183301000189.tif248168TIFF2025183301000190.tif248169TIFF2025183301000191.tif191170TIFF2025183301000192.tif191168TIFF2025183301000193.tif199168TIFF2025183301000194.tif198168TIFF2025183301000195.tif246169TIFF2025183301000196.tif247169TIFF2025183301000197.tif190169TIFF2025183301000198.tif191168TIFF2025183301000199.tif192168TIFF2025183301000200.tif186168TIFF2025183301000201.tif198169TIFF2025183301000202.tif198168TIFF2025183301000203.tif210169TIFF2025183301000204.tif203170TIFF2025183301000205.tif211169TIFF2025183301000206.tif204169TIFF2025183301000207.tif204169TIFF2025183301000208.tif185170TIFF2025183301000209.tif211169TIFF2025183301000210.tif217168TIFF2025183301000211.tif210169TIFF2025183301000212.tif209169TIFF2025183301000213.tif210170TIFF2025183301000214.tif190168TIFF2025183301000215.tif191169TIFF2025183301000216.tif198168TIFF2025183301000217.tif190168TIFF2025183301000218.tif197169TIFF2025183301000219.tif197168TIFF2025183301000220.tif210168TIFF2025183301000221.tif204168TIFF2025183301000222.tif210168TIFF2025183301000223.tif211168TIFF2025183301000224.tif198169TIFF2025183301000225.tif199168TIFF2025183301000226.tif209169TIFF2025183301000227.tif217169TIFF2025183301000228.tif210168TIFF2025183301000229.tif217168TIFF2025183301000230.tif211169TIFF2025183301000231.tif211169TIFF2025183301000232.tif209167TIFF2025183301000233.tif193168TIFF2025183301000234.tif198169TIFF2025183301000235.tif203168TIFF2025183301000236.tif197168TIFF2025183301000237.tif210168TIFF2025183301000238.tif199168TIFF2025183301000239.tif211169TIFF2025183301000240.tif209168TIFF2025183301000241.tif210169TIFF2025183301000242.tif210168TIFF2025183301000243.tif210168TIFF2025183301000244.tif217168TIFF2025183301000245.tif237168TIFF2025183301000246.tif222170TIFF2025183301000247.tif223169TIFF2025183301000248.tif20916 8TIFF2025183301000249.tif211168TIFF2025183301000250.tif217168TIFF2025183301000251.tif210170TIFF2025 183301000252.tif197169TIFF2025183301000253.tif223169TIFF2025183301000254.tif198169TIFF202518330100 0255.tif229168TIFF2025183301000256.tif210169TIFF2025183301000257.tif223168TIFF2025183301000258.tif2 22169TIFF2025183301000259.tif235169TIFF2025183301000260.tif216169TIFF2025183301000261.tif209169TIF F2025183301000262.tif211168TIFF2025183301000263.tif230169TIFF2025183301000264.tif223169TIFF20251833 01000265.tif224169TIFF2025183301000266.tif223169TIFF2025183301000267.tif224170TIFF2025183301000268. tif216169TIFF2025183301000269.tif224168TIFF2025183301000270.tif223169TIFF2025183301000271.tif79168.

[0673] Evaluation of antiparasitic efficacy in the parasite LDH proliferation assay (parasite assay) Parasite stocks are prepared in RPMI-Hepes medium (which is buffered with sodium bicarbonate). and supplemented with 5% heat-inactivated human serum and 0.5% albumax The hematocrit was maintained at 4% in the blood.

[0674] Approximately 42 hours before setting up the potency assay, parasites were synchronized with 5% sorbitol. On the day of assay setup, blood smears of parasite cultures were taken and ring stage parasites were selected. The tissue was stained with Giemsa and counted. The parasitemia was adjusted to 0.7% rings. The RT values ​​were measured in RPMI-Hepes medium (which is buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumin) 30 μL of diluted parasites were then added to a pre-prepared Greiner Add 10uL of medium + compound to the TC assay plate. The cells were placed in a single layer in a gas-filled, humidified box and incubated at 37°C for 72 hours. After 72 hours of growth, the assay plates were sealed with parafilm and stored at -80°C. Freeze flat in single file overnight. The next day, thaw the assay plates at room temperature for 4 hours. , and an LDH assay is performed to measure parasite growth.

[0675] Assay EC 50 The results are shown in Table 2. [Table 3] TIFF2025183301000273.tif248133TIFF2025183301000274.tif249134TIFF2025183301000275.tif248133TIFF2025183301 000276.tif249134TIFF2025183301000277.tif248132TIFF2025183301000278.tif248132TIFF2025183301000279.tif99131

Claims

1. Structural formula (I): 【Chemistry 1】 [During the ceremony, A is at least one —CH ２ - containing linear or branched saturated or unsaturated ( C ３ -C １０ ) alkylene, phenyl (C ３ -C １０ ) alkylene or cycloalkyl ( C ３ -C １０ ) alkylene, wherein one or more additional —CH ２ -The base is independent Standing, O, S, NR, CONR, NRCO, SO ２ and SO ２ Selected from the group consisting of NR and wherein one of the hydrogens along A is The above are hydroxyl, halogen and C １－３ haloalkyl Can be replaced; X is a bond, C(R １４ ) ２ ,O,S,SO,SO ２ or NH; Y is CR ９ or N, where when Y is N, Z is CR １１ and V is CR １０ and V is CR １０ or N, where when V is N, Z is CR １１ and , Y is CR ９ and Z is CR １１ or N, where when Z is N, V ​​is CR １０ and , Y is CR ９ and R is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ａ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O C １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ cycloalkyl , C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, —C １ -C ６ a LuKilOHaroC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ alkylOH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) ( R ８ ) or R ｂ When combined with C ３ -C ６ Cycloalkyl or heterocyclic and forming a cycloalkyl, wherein the C ３ -C ６ Cycloalkyl or heterocyclo Alkyl may be unsubstituted or substituted with halogen, CN, OH, C １ -C ６ Alkoxy , C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, Oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ a Rukill, -C １ -C ６ Alkyl O halo C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ a Rukill N (R ７ ) (R ８ and substituted with one or two substituents selected from the group consisting of Ori; R ｂ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O C １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ cycloalkyl , C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, —C １ -C ６ a LuKilOHaroC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ alkylOH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) ( R ８ ) or R ａ When combined with C ３ -C ６ Cycloalkyl or heterocyclic and forming a cycloalkyl, wherein the C ３ -C ６ Cycloalkyl or heterocyclo Alkyl may be unsubstituted or substituted with halogen, CN, OH, C １ -C ６ Alkoxy , C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, Oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ a Rukill, -C １ -C ６ Alkyl O halo C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ a Rukill N (R ７ ) (R ８ substituted with 1 to 3 substituents selected from the group consisting of: R ３ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O C １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkane Lu, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON( R ７ ) (R ８ ), N(R ７ ) (R ８ ), C １ -C ６ AlkylN(R ７ ) (R ８ ), C １ - C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) (R ８ ) or C １ -C ６ Alkyl Oha ROC １ -C ６ alkyl or R ４ When combined with C ３ -C ６ Cycloalkane Ru or C ３ -C ６ forming a heterocycloalkyl; R ４ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O C １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkane Lu, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON( R ７ ) (R ８ ), N(R ７ ) (R ８ ), C １ -C ６ AlkylN(R ７ ) (R ８ ), C １ - C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) (R ８ ) or C １ -C ６ Alkyl Oha ROC １ -C ６ alkyl or R ３ When combined with C ３ -C ６ Cycloalkane Ru or C ３ -C ６ forming a heterocycloalkyl; R ７ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ８ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ９ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O C １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkane Lu, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON( R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and ； R １０ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloal Kill, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) the law of nature; R １１ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloal Kill, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) the law of nature; R １２ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloal Kill, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) the law of nature; R １３ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloal Kill, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) the law of nature; R １４ Each occurrence of is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ S Chloroalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH , CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) independently selected from the group consisting of: R １５ are hydrogen, halogens, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloal Kill, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, CON (R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) the law of nature; R １６ Each occurrence of is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ S Chloroalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH , CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) independently selected from the group consisting of: m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein m is 1, p is 1, and X is O. Pharmaceutically acceptable salts.

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

4. R ａ is R ｂ and together form a heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

5. R ａ is R ｂ together with Lukil said, 【Chemistry 2】 and wherein the heterocycloalkyl is a heterocyclic group having two C １ -C ６ Alkyl-substituted 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. R ａ is R ｂ Together with C ３ -C ６ The compound according to claim 1 which forms a cycloalkyl. or a pharmaceutically acceptable salt thereof.

7. R ａ is R ｂ Together with C ３ -C ６ cycloalkyl, wherein the heterocyclo Roalkyl, 【Transformation 3】 and where C ３ -C ６ Cycloalkyl is unsubstituted or substituted with OH.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

8. R ３ But hydrogen, C １ -C ６ Alkyl OC １ -C ６ Alkyl or C １ -C ６ Alkyl or R ４ When combined with C ３ -C ６ forming a heterocycloalkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. R ３ is hydrogen or C １ -C ６ alkyl or R ４ When combined with C ３ -C ６ The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound forms a heterocycloalkyl. Acceptable salt.

10. R ３ and R ４ and R are both halogens, or a pharmaceutically acceptable salt thereof Acceptable salts.

11. R １５ is hydrogen or C １ -C ６ The compound of claim 1 or a pharmaceutical composition thereof, A commercially acceptable salt.

12. R ３ and R ４ But hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ Archi Rualkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ - C ６ Alkyl O halo C １ -C ６ Alkyl, CON(C １ -C ６ alkyl) ２ , C １ -C ６ AlkylN(R ７ ) (R ８ ) and C １ -C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) ( R ８ ) independently selected from the group consisting of: R ７ But hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ８ But hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; and n is 3; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. R １２ and R １３ But hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ a alkylalkoxy and C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl or 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: salt.

14. X is C(R １４ ) ２ and R １４ But hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ Alkylalkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl and C １ -C ６ 10. The compound of claim 1 or its derivatives, wherein the compound is independently selected from the group consisting of alkyl, Pharmaceutically acceptable salts.

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

16. 15. The compound of claim 1, wherein Z is CH, or a pharmaceutically acceptable salt thereof.

17. 15. The compound of claim 1, wherein V is CH, or a pharmaceutically acceptable salt thereof.

18. A is a linear saturated or unsaturated (C ３ -C １０ ) alkylene The compound or a pharmaceutically acceptable salt thereof.

19. A is a branched, saturated or unsaturated (C ３ -C １０ ) alkylene, claims 1-14 or a pharmaceutically acceptable salt thereof.

20. A is, 【Chemistry 4】 15. The compound of claim 1, wherein:

21. below 【Transformation 5】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharmaceutically acceptable salt thereof.

22. formula 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

23. formula 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

24. formula 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

25. A method for treating a malaria parasite infection or a method for treating malaria, comprising administering to said patient a therapeutically effective amount of a medicament for treating said malaria parasite infection. A therapeutically effective amount of a compound or compound according to any one of claims 1 to 24 is administered to a subject in need of treatment. comprising administering a pharmaceutically acceptable salt thereof.

26. A method for inhibiting plasmepsin X, comprising administering the treatment to a subject in need of such treatment. An effective amount of the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof The method comprising administering.

27. A method of inhibiting plasmepsin IX, comprising administering the therapeutic agent to a subject in need of such treatment. A therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof. The method comprises administering

28. A method for dually inhibiting plasmepsin X and plasmepsin X, comprising: A therapeutically effective amount of a compound according to any one of claims 1 to 24 or administering a pharmaceutically acceptable salt thereof.

29. Plasmodium infection in patients who need to be treated for malaria or malaria A compound according to any one of claims 1 to 24 for treating infectious diseases or malaria Use of a pharmaceutically acceptable salt thereof.

30. To inhibit plasmepsin X in patients in need of plasmepsin X inhibition. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof for the treatment of For.

31. Inhibition of plasmepsin IX in patients in need of such inhibition A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof for use in a method for treating a rheumatoid arthritis. Use of.

32. In patients who need to inhibit plasmepsin IX and plasmepsin X, A compound according to claim 1 or its derivatives for inhibiting mepsin IX and plasmepsin X. Use of a pharmaceutically acceptable salt.

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

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

35. A method for treating a malaria parasite infection or a method for treating malaria, comprising the steps of claim 1 The compound or a pharmaceutically acceptable salt thereof and an effective amount of one or more additional antimalarials. The method further comprises administering a drug.

36. Inhibiting plasmepsin X, plasmepsin IX, and at least one other function 10. A method for treating malaria by administering to a subject a compound of claim 1 or a pharmaceutically acceptable salt thereof. and administering an acceptable salt thereof and an effective amount of one additional antimalarial drug, wherein The additional antimalarial drug may have a function other than inhibition of plasmepsin IX or plasmepsin X. The method operates by a mechanism.

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