N-acyl amides and analogs

Abstract

The present disclosure provides pharmaceutical compositions, dosage forms comprising the pharmaceutical composition, and methods of treating inflammation, decreasing inflammation, decreasing an inflammatory marker, treating inflammatory bowel disease, and treating colorectal cancer in a subject in need thereof, comprising administering the pharmaceutical compositions or dosage forms disclosed herein to a subject in need thereof.

Description

N-ACYL AMIDES AND ANALOGS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No.63 / 736,989, filed December 20, 2024 and U.S. Provisional Patent Application No.63 / 698,883, filed September 25, 2024, the disclosures of which are incorporated by reference herein. TECHNICAL FIELD

[0002] The present disclosure provides compounds, pharmaceutical compositions, dosage forms, and methods of treating inflammation, decreasing inflammation, decreasing inflammatory markers, treating inflammatory bowel disorder, or treating colorectal cancer. BACKGROUND

[0003] Many diseases are associated with the regulation of inflammatory processes. A huge part of the population is afflicted with or knows someone afflicted with a disease associated with the inflammatory process.

[0004] Such diseases include inflammatory conditions and cancer, among others. Inflammatory bowel disease (IBD) is one such inflammatory condition and typically refers to two conditions: Crohn’s disease and ulcerative colitis. Crohn’s disease is characterized by inflammation of the digestive tract lining and may often spread deep into affected tissues. Ulcerative colitis is a condition causing long-lasting inflammation and sores (ulcers) in the innermost lining of the large intestine (colon) and rectum. Typical symptoms of ulcerative colitis and Crohn’s disease include severe diarrhea, abdominal pain, fatigue, and weight loss. Without appropriate management, inflammatory bowel disease can progress and increase the subject’s risk of colon cancer, primary sclerosing cholangitis, and blood clots. Complications of Crohn’s disease include, e.g., bowel obstruction, malnutrition, ulcers, fistulas, and anal fissures. Complications of ulcerative colitis include, e.g., toxic megacolon, colon perforation, and severe dehydration. While various approaches for inflammatory bowel disease management have been developed, these approaches are typically systemic and rely on inflammation suppression rather than the treatment of the underlying condition.

[0005] Compounds that suppress inflammatory immune responses are needed. SUMMARY

[0006] In some aspects, the disclosure provides compounds of Formula I, or a pharmaceutically salt thereof, wherein A, R1-R7and R10-R14are defined herein 1 122091.000064\4909-9219-4150.2.

[0007] In further aspects, the disclosure provides compounds of Formula X, XX, or XXX, or pharmaceutically acceptable salts thereof, wherein m, n, A, R1-R7and R10-R22are defined herein

[0008] In other aspects, the disclosure provides a compound that is:acceptable salt thereof.

[0009] In further aspects, the disclosure provides pharmaceutical compositions comprising one or more compounds described herein.

[0010] In other aspects, the disclosure provides dosage forms comprising the compounds or pharmaceutical compositions described herein.

[0011] In other aspects, the disclosure provides methods of decreasing the level, expression, or activity of an inflammatory marker (e.g., in vitro, ex-vivo or in vivo in a subject), e.g., decreasing thelevel, expression, or activity of a marker selected from: (i) a cytokine, e.g., an interleukin (IL), e.g., IL-1 (including IL-1α and IL-1β), IL-4, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-17, IL-19, IL-23, IL- 35, and IL-36; (ii) tumor necrosis factor alpha (TNF-α); (iii) interferon gamma (IFNγ); (iv) granulocyte- macrophage colony stimulating factor (GM-CSF), (v) a prostaglandin such as prostaglandin E2 (PGE2); (vi) a chemokine such as GRO-α.

[0012] In further aspects, the disclosure provides methods of treating inflammation in a subject in need thereof, comprising administering the compounds, pharmaceutical compositions or dosage forms described herein to the subject in need thereof.

[0013] In yet other aspects, the disclosure provides methods of decreasing inflammation in a subject in need thereof, comprising administering the compounds, pharmaceutical compositions or dosage forms to the subject in need thereof.

[0014] In still further aspects, the disclosure provides methods of decreasing an inflammatory marker in a subject (e.g., a human) in need thereof, comprising administering the compounds, pharmaceutical compositions or dosage forms described herein to the subject in need thereof.

[0015] In other aspects, the disclosure provides methods of treating inflammatory bowel disease in a subject in need thereof, comprising administering the compounds, pharmaceutical compositions, or dosage forms described herein to the subject in need thereof.

[0016] In further aspects, the disclosure provides methods of treating colorectal cancer in a subject in need thereof, comprising administering the compounds, pharmaceutical compositions, or dosage forms described herein to the subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG.1 is a line graph showing the DAI score for compound I-2. In this figure, data represent mean ± SEM, n=8 per group. *p<0.05 **p<0.01 ***p<0.005 ****p<0.0001, versus Vehicle, ANOVA.

[0018] FIG.2 is a bar graph showing the cytokine score for compound I-2.

[0019] FIG.3 is a line graph showing the DAI score for compound I-166 for three PO QD dosages as compared to sham, vehicle, and 100 mg / kg QD mesalazine.

[0020] FIG.4 is a line graph showing % initial weight over a period of 6 days after administration of three PO QD dosages of compound I-166 as compared to sham, vehicle, and 100 mg / kg QD mesalazine.

[0021] FIG.5 is a bar graph of pro-inflammatory cytokine IP-10 present in the supernatant fraction.

[0022] FIG.6 is a line graph showing the DAI scores for compound 77.

[0023] FIG.7 is a bar graph showing the cytokine levels for compound 77.

[0024] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0025] In the disclosure, the singular forms “a,” “an” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context indicates otherwise. For example, reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0026] When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0027] When a list is presented, unless stated otherwise, it is to be understood that each individual element and every combination is to be interpreted as separate embodiments. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0028] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

[0029] It is noted that the claims may be drafted to exclude an optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0030] The terms “subject” and “patient” are used interchangeably and include, without limitation, mammals. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or farm animal, a domestic animal or pet, or animal used for clinical research. In certain embodiments, the subject or patient is an adult, i.e., ≥ 18 years of age. In further embodiments, the subject or patient is a pediatric subject or patient, i.e., < 18 years of age.

[0031] The abbreviation “D,” as used herein, refers to a stable isotope of hydrogen that is deuterium (heavy hydrogen or2H). “D” include an amount of deuterium that is above the naturally occurring distribution of deuterium. In some embodiments, D has deuterium enrichment of no less than about 1%. In other embodiments, D has a deuterium enrichment of no less than about 5%. In further embodiments, D has a deuterium enrichment of no less than about 10%. In still other embodiments, D has a deuterium enrichment of no less than about 20%. In still other embodiments, D has a deuterium enrichment of no less than about 30%. In still other embodiments, D has a deuterium enrichment of no less than about 40%. In yet further embodiments, D has a deuterium enrichment of no less than about 50%. In still other embodiments, D has a deuterium enrichment of no less than about 60%. In other embodiments, D has a deuterium enrichment of no less than about 70%. In further embodiments, D has a deuterium enrichment of no less than about 80%. In yet other embodiments, D has a deuterium enrichment of no less than about 90%. In still further embodiments, D has a deuterium enrichment of no less than about 98% of deuterium. In still further embodiments, D has a deuterium enrichment of no less than about 99% of deuterium. In still further embodiments, D has a deuterium enrichment of at least 99% of deuterium.

[0032] The term “halo” represents chloro, fluoro, bromo, or iodo. In some embodiments, halo is chloro. In other embodiments, halo is fluoro. In further embodiments, halo is bromo. In yet other embodiments, halo is iodo.

[0033] The term “alkyl,” as used herein, refers to a straight- or branched-chain alkyl groups. In some embodiments, the alkyl has 1 to 24 carbons atoms, i.e., C1-24alkyl. In some embodiments, the alkyl has 1 to 20 carbon atoms, i.e., C1-20alkyl, 3 to 24 carbons atoms, i.e., C3-24alkyl, or 1 to 6 carbon atoms, i.e., C1-6alkyl. Examples of alkyls include methyl (C1alkyl) ethyl (C2alkyl), n-propyl (C3alkyl), isopropyl (C3alkyl). In some embodiments, the alkyl is methyl. In other embodiments, the alkyl is ethyl. In further embodiments, the alkyl is n-propyl or isopropyl. In still further embodiments, the alkyl is n-butyl, i-butyl, s-butyl, or t-butyl. In other embodiments, the alkyl is pentyl. In further embodiments, the alkyl is hexyl. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0034] The term “alkylphenyl,” as used herein, refers to an alkyl as described that is bound to a phenyl group. The alkyl and / or phenyl moiety is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0035] The term “alkylcycloalkyl,” as used herein, refers to an alkyl as described that is bound to a cycloalkyl group as described herein. The alkyl and / or cycloalkyl moiety is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0036] The term “-C(O)OC1-6alkyl,” as used herein refers to an ester or carboxy, wherein alkyl is described herein. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3- 8cycloalkyl, heterocyclyl, or aryl.

[0037] The term “-C(O)C1-6alkyl,” as used herein refers carbonyl group, wherein alkyl is described herein. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3- 8cycloalkyl, heterocyclyl, or aryl.

[0038] The term “-SO2NHC1-6alkyl,”refers to a sulfonamide, wherein alkyl is described herein. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0039] The term -SO2N(C1-6alkyl)2,” also refers to a sulfonamide, wherein the alkyls are described herein. In some embodiments, the alkyl groups are the same. In other embodiments, the alkyl groups differ. Each alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0040] The term “-SO2C1-6alkyl,” refers to a sulfone, wherein alkyl is described herein. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0041] The term “NH(C1-6alkyl),” refers to a substituted amine, wherein alkyl is described herein. The alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0042] The term “NH(C1-6alkyl)2,” also refers to a substituted amine, wherein alkyl is described herein. In some embodiments, the alkyl groups are the same. In other embodiments, the alkyl groups differ. Each alkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C2-6alkynyl, C1-6alkoxy, C(O)OC1-6alkyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0043] As used herein, “alkenyl” refers to a straight or branched chain hydrocarbon radical having 2 to 24 carbon atoms that has at least one double bond. In some embodiments, the number of carbon atoms is designated (i.e., C2-24). In other embodiments, the alkenyl has 2 to 20 carbon atoms, i.e., C2-20alkenyl. In further embodiments, the alkenyl is a straight chain hydrocarbon. In other embodiments, the alkenyl is a branched chain hydrocarbon. The alkenyl has at least one carbon-carbon double bond. In some embodiments, the alkenyl has one double bond. In other embodiments, the alkenyl has two or moredouble bonds. In further embodiments, the alkenyl has three or more double bonds. The alkenyl group may exist as the cis isomer or trans isomer. The alkenyl may be substituted with one or more group as described herein. An alkenyl is optionally substituted with one, two, or three substituents selected from halo, OH, C1-6alkyl, C2-6alkynyl, C1-6alkoxy, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0044] As used herein, “alkynyl” refers to a straight or branched chain hydrocarbon radical having 2 to 24 carbon atoms that has at least one triple bond. In some embodiments, the number of carbon atoms is designated (i.e., C2-24). In other embodiments, the alkynyl has 2 to 20, i.e., C2-24alkynyl, or 2 to 6 carbon atoms, i.e., C2-6alkynyl. In further embodiments, the alkynyl is a straight chain hydrocarbon. In other embodiments, the alkynyl is a branched chain hydrocarbon. The alkynyl has at least one carbon-carbon triple bond. In some embodiments, the alkynyl has one triple bond. In other embodiments, the alkynyl has two or more triple bonds. The alkynyl may be substituted with one or more group as described herein. An alkynyl is optionally substituted with one, two, or three substituents selected from halo, OH, C1-6alkyl, C1-6alkoxy, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0045] The term “alkoxy” (alone or part of a group) as used herein refers to a straight- or branched-chain alkoxy groups. In some embodiments, the alkoxy has from 1 to 20 carbons atoms, i.e., C1-20alkyl. In other embodiments, the alkoxy has 1 to 6 carbon atoms, i.e., C1-6alkoxy or OC1-6alkyl,. Examples of alkoxys include methoxy (C1alkoxy) ethoxy (C2alkoxy), n-propoxy (C3alkoxy), isopropoxy (C3alkoxy). In some embodiments, the alkoxy is methoxy. In other embodiments, the alkoxy is ethoxy. In further embodiments, the alkoxy is n-propoxy or isopropoxy. In still further embodiments, the alkoxy is n-butoxy, i-butoxy, s-butoxy, or t-butoxy. In other embodiments, the alkoxy is pentoxy. In further embodiments, the alkoxy is hexoxy. The alkoxy is optionally substituted with one, two, or three substituents selected from halo, OH, C1-6alkyl, C2-6alkynyl, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0046] “Cycloalkyl” as used herein refers to a monocyclic, non-aromatic hydrocarbon group. In some embodiments, the cycloalkyl has from 3 to 8 carbon atoms (“C3-8”). In some embodiments, the cycloalkyl has from 3 to 6 carbon atoms. Examples of cycloalkyls include, e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), 1-methylcyclopropyl (C4), or 2-methylcyclopentyl (C4), among others. A cycloalkyl is optionally substituted with one, two, or three substituents selected from halo, OH, C1-6alkyl, C2-6alkynyl, C1-6alkoxy, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0047] The term “heterocyclyl” refers to a stable 3- to 14-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl contains 3 ring atoms, 4 ring atoms, etc., up to and including 14 ring atoms. The heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is unsaturated, partially saturated, or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). “Heterocyclyl” also includes bicyclic ring systems wherein one non-aromatic ring contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic. In some embodiments, the heterocyclyl is indolyl. Examples of heterocyclyl include, but are not limited to, azepanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2- d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6- dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H- cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2- d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). A heterocyclyl is optionally substituted with one, two, three, or four substituents selected from halo, OH, -C(O)OH, C1-6alkyl, C2- 6alkynyl, C1-6alkoxy, CN, NH2, NH(C1-6alkyl), NH(C1-6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl.

[0048] The term “aryl” refers to carbocyclic aromatic groups having from 6 to 10 carbon atoms (“C6-10”) such as phenyl, naphthyl, and the like. An aryl is optionally substituted with one, two, or three substituents selected from halo, OH, C1-6alkyl, C2-6alkynyl, C1-6alkoxy, CN, NH2, NH(C1-6alkyl), NH(C1- 6alkyl)2, C3-8cycloalkyl, heterocyclyl, or aryl. In some aspects, the aryl (e.g., phenyl) is substituted at the ortho position. In other aspects, the aryl (e.g., phenyl) is substituted at the meta position. In further aspects, the aryl (e.g., phenyl) is substituted at the para position. In yet other aspects, the aryl (e.g., phenyl) is monosubstituted. In still further aspects, the aryl (e.g., phenyl) is disubstituted.

[0049] The term “oxo” as used herein refers to (=O). An oxo may be formed with two H- atoms bound to an atom combine to form an =O. In some embodiments, the oxo is bound to a carbon atom. Compounds I

[0050] The disclosure provides compounds of Formula I, or a pharmaceutically acceptable salt thereof:.

[0051] According to the disclosure, each A is, independently, C or N, provided that no more than three A moieties are simultaneously N. In some embodiments, each A is C. In other embodiments, one A is N. In further embodiments, two A are N. In yet other embodiments, three A are N.

[0052] According to the disclosure, R1is C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1- 20alkylphenyl, C1-20alkylcycloalkyl, or C2-20alkynyldiazirinyl. In some embodiments, R1is C1-20alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, C6alkyl, C7alkyl, C8alkyl, C9alkyl, C10alkyl, C11alkyl, C12alkyl, C13alkyl, C14alkyl, C15alkyl, C16alkyl, C17alkyl, C18alkyl, C19alkyl, or C20alkyl. In other embodiments, R1is C2-20alkenyl such as C2alkenyl, C3alkenyl, C4alkenyl, C5alkenyl, C6alkenyl, C7alkenyl, C8alkenyl, C9alkenyl, C10alkenyl, C11alkenyl, C12alkenyl, C13alkenyl, C14alkenyl, C15alkenyl, C16alkenyl, C17alkenyl, C18alkenyl, C19alkenyl, or C20alkenyl. In further embodiments, R1is C2-20alkynyl such as C2alkynyl, C3alkynyl, C4alkynyl, C5alkynyl, C6alkynyl, C7alkynyl, C8alkynyl, C9alkynyl, C10alkynyl, C11alkynyl, C12alkynyl, C13alkynyl, C14alkynyl, C15alkynyl, C16alkynyl, C17alkynyl, C18alkynyl, C19alkynyl, or C20alkynyl. In yet other embodiments, R1is C1-20alkylphenyl such as C1alkylphenyl, C2alkylphenyl, C3alkylphenyl, C4alkylphenyl, C5alkylphenyl, C6alkylphenyl, C7alkyphenyll, C8alkylphenyl, C9alkylphenyl, C10alkylphenyl, C11alkylphenyl, C12alkylphenyl, C13alkylphenyl, C14alkylphenyl, C15alkylphenyl, C16alkylphenyl, C17alkylphenyl, C18alkylphenyl, C19alkylphenyl, or C20alkylphenyl. In still further embodiments, R1is C1-20alkylcycloalkyl such asC1alkylcycloalkyl, C2alkylcycloalkyl, C3alkylcycloalkyl, C4alkylcycloalkyl, C5alkylcycloalkyl, C6alkylcycloalkyl, C7alkylcycloalkyl, C8alkylcycloalkyl, C9alkylcycloalkyl, C10alkylcycloalkyl, C11alkyl, C12alkylcycloalkyl, C13alkylcycloalkyl, C14alkylcycloalkyl, C15alkylcycloalkyl, C16alkylcycloalkyl, C17alkylcycloalkyl, C18alkylcycloalkyl, C19alkylcycloalkyl, or C20alkylcycloalkyl. In other embodiments, R1is hexadec-9-enyl.

[0053] According to the disclosure, R1is optionally substituted by one or more OH, -C(O)OC1- 6alkyl, -C(O)OH, C1-6alkyl, C1-6alkoxy, -C(O)H, C(O), cycloalkyl, CN, or halo. In some embodiments, R1is substituted by one or more OH. In other embodiments, R1is substituted by one or more -C(O)OC1- 6alkyl such as -C(O)OC1alkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)OC4alkyl, -C(O)OC5alkyl, or - C(O)OC6alkyl. In further embodiments, R1is substituted by one or more -C(O)OH. In yet other embodiments, R1is substituted by one or more C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R1is substituted by one or more C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In other embodiments, R1is substituted by one or more -C(O)H. In still other embodiments, R1is substituted by one or more cycloalkyl such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In yet further embodiments, R1is substituted by one or more CN. In other embodiments, R1is substituted by one or more halo such as chloro, bromo, fluoro, or iodo.

[0054] According to the disclosure, R2is, , , ,. , . In other embodiments, R2is. In further embodiments, R2is. In yet other embodiments, R2is . In still further embodiments, R2is, wherein each Z is, independently, C or N, provided that only one Z moiety is N and each E is, independently, CH, N, O, or S. In some embodiments, each Z is C. In other embodiments, one Z is N. In further embodiments, at least one E is CH. In yet other embodiments, at least one E is N. In still further embodiments, at least one E is O. In other embodiments, at least one E is S. In certain embodiments, R2isindependently, CH or N, provided that no more than three G moieties are simultaneously N. In someembodiments, at least one G is CH. In other embodiments, one G is N. In further embodiments, two G are N. In yet other embodiments, three are N.

[0055] According to the disclosure, R3is CH2, NH, N(C1-6alkyl), N(C3-6cycloalkyl), or NCF3. In some embodiments, R3is CH2. In other embodiments, R3is NH. In further embodiments, R3is N(C1- 6alkyl) such as N(C1alkyl), N(C2alkyl), N(C3alkyl), N(C4alkyl), N(C5alkyl), or N(C6alkyl). In still other embodiments, R3is N(C3-6cycloalkyl) such as N(cyclobutyl), N(cyclopentyl), N(cyclohexyl), N(cycloheptyl), or N(cyclooctyl). In yet further embodiments, R3is NCF3.

[0056] According to the disclosure, R4and R5are, independently, H, D, -C(O)OH, -C(O)OC1- 6alkyl, C1-6alkyl, or combine to form a cycloalkyl. In some embodiments, R4is H. In other embodiments, R4is D. In further embodiments, R4is -C(O)OH. In yet other embodiments, R4is - C(O)OC1-6alkyl such as -C(O)OC1alkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)OC4alkyl, - C(O)OC5alkyl, or -C(O)OC6alkyl. In still further embodiments, R4is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In other embodiments, R5is H. In further embodiments, R5is D. In yet other embodiments, R5is -C(O)OH. In still further embodiments, R5is -C(O)OC1-6alkyl such as - C(O)OC1alkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)OC4alkyl, -C(O)OC5alkyl, or -C(O)OC6alkyl. In other embodiments, R5is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In further embodiments, R4and R5combine to form a cycloalkyl such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0057] According to the disclosure, R6and R7are, independently, H, OH, D, C1-6alkyl, halo, or combine to form a cycloalkyl. In some embodiments, R6is H. In other embodiments, R6is OH. In further embodiments, R6is D. In still other embodiments, R6is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In yet further embodiments, R6is halo such as chloro, bromo, fluoro, or iodo. In other embodiments, R7is H. In further embodiments, R7is OH. In yet other embodiments, R7is D. In still further embodiments, R7is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In other embodiments, R7is halo such as chloro, bromo, fluoro, or iodo. In further embodiments, R6and R7combine to form a cycloalkyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0058] According to the disclosure, R10, R11, R12, R13, and R14are, independently, H, OH, N3,, C1-6alkoxy, C1-6alkyl, CN, -C(O)H, -C(O)C1-6alkyl, halo, -SO2NH2, -SO2NHC1-6alkyl, - SO2N(C1-6alkyl)2, -SO2C1-6alkyl, -CF3, -CHF2, or -SF5, provided that if A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent. In certain embodiments, when A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent, provided at least one A is N-oxo.

[0059] In some embodiments, R10is H. In other embodiments, R10is OH. In further embodiments, R10is C1-6alkoxy. In yet other embodiments, R10is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R10is CN. In other embodiments, R10is -C(O)H. In further embodiments, R10is -C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, - C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In still other embodiments, R10is halo such as chloro, bromo, fluoro, or iodo. In yet further embodiments, R10is -SO2NH2. In other embodiments, R10is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, - SO2NHC5alkyl, or -SO2NHC6alkyl. In further embodiments, R10is -SO2N(C1-6alkyl)2such as - SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In yet other embodiments, R10is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In still further embodiments, R10is CF3. In other embodiments, R10is CHF2. In further embodiments, R10is SF5. In yet other embodiments, R10is oxo. In still further embodiments, R10is absent.

[0060] In some embodiments, R11is H. In other embodiments, R11is OH. In further embodiments, R11is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In yet other embodiments, R11is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R11is CN. In other embodiments, R11is -C(O)H. In further embodiments, R11is -C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In still other embodiments, R11is halo such as chloro, bromo, fluoro, or iodo. In yet further embodiments, R11is -SO2NH2. In other embodiments, R11is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In further embodiments, R11is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, - SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In yet other embodiments, R11 is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or - SO2C6alkyl. In still further embodiments, R11is CF3. In other embodiments, R11is CHF2. In further embodiments, R11is SF5. In yet other embodiments, R11is oxo. In still further embodiments, R11is absent.

[0061] In some embodiments, R12is H. In other embodiments, R12is OH. In further embodiments, R12is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In yet other embodiments, R12is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R12is CN. In other embodiments, R12is -C(O)H. In further embodiments, R12is -C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In still other embodiments, R12is halo such as chloro, bromo, fluoro, or iodo. In yet further embodiments, R12is -SO2NH2. In other embodiments, R12is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In further embodiments, R12is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In yet other embodiments, R12 is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or - SO2C6alkyl. In still further embodiments, R12is CF3. In other embodiments, R12is CHF2. In further embodiments, R12is SF5. In yet other embodiments, R12is oxo. In still further embodiments, R12is absent.

[0062] In some embodiments, R13is H. In other embodiments, R13is OH. In further embodiments, R13is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In yet other embodiments, R13is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R13is CN. In other embodiments, R13is -C(O)H. In further embodiments, R13is -C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In still other embodiments, R13is halo such as chloro, bromo, fluoro, or iodo. In yet further embodiments, R13is -SO2NH2. In other embodiments, R13is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In further embodiments, R13is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, - SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In yet other embodiments, R13 is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or - SO2C6alkyl. In still further embodiments, R13is CF3. In other embodiments, R13is CHF2. In further embodiments, R13is SF5. In yet other embodiments, R13is oxo. In still further embodiments, R13is absent.

[0063] In some embodiments, R14is H. In other embodiments, R14is OH. In further embodiments, R14is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In yet other embodiments, R14is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In still further embodiments, R14is CN. In other embodiments, R14is -C(O)H. In further embodiments, R14is -C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In still other embodiments, R14is halo such as chloro, bromo, fluoro, or iodo. In yet further embodiments, R14is -SO2NH2. In other embodiments, R14is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In further embodiments, R14is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, - SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In yet other embodiments, R14 is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or - SO2C6alkyl. In still further embodiments, R14is CF3. In other embodiments, R14is CHF2. In further embodiments, R14is SF5. In yet other embodiments, R14is oxo. In still further embodiments, R14is absent.

[0064] In certain embodiments, the compound is of formula I-A:.

[0065] In certain embodiments, the compound is of formula I-B:.

[0066] In certain embodiments, the compound is of formula I-C:.

[0067] In certain embodiments, the compound is of formula I-D:.

[0068] In certain embodiments, the compound is of formula I-E:.

[0069] In certain embodiments, the compound is of formula I-F:. In certain embodiments, the compound is of formula I-G:.

[0070] In certain embodiments, the compound is of formula II-A, wherein R is R10-R14:.

[0071] In certain embodiments, the compound is of formula III-A, wherein R is R10-R14:

[0072] In certain embodiments, the compound is of formula IV-A, wherein R is R10-R14:.

[0073] In certain embodiments, the compound is of formula IV-B, wherein R is R10-R14:.

[0074] In certain embodiments, the compound is of formula V-A, wherein R is R10-R14:.

[0075] In yet other aspects, the pharmaceutical compositions contain compounds of formula IMID-II or a pharmaceutically acceptable salt thereof:In this structure, R5is C6-19alkyl, such as C6alkyl, C7alkyl, C8alkyl, C9alkyl, C10alkyl, C11alkyl, C12alkyl, C13alkyl, C14alkyl, C15alkyl, C16alkyl, C17alkyl, C18alkyl, or C19alkyl. In some embodiments, R5is substituted by C2-6alkynyl, such as C2alkynyl, C3alkynyl, C4alkynyl, C5alkynyl, or C6alkynyl. In further embodiments, two H-atoms of R5are joined to form diazirinyl.

[0076] In further aspects, the pharmaceutical compositions contain compounds of formula PROP-IG, or a pharmaceutically acceptable salt thereof, wherein R5is defined herein:In this structure, the COOH is in the ortho, meta, or para position of the phenyl ring. In some embodiments, the COOH is in the ortho position of the phenyl ring. In other embodiments, the COOH is in the meta of the phenyl ring. In further embodiments, the COOH is in the para position of the phenyl ring.

[0077] In certain embodiments, the compound is:

[0078] The compounds herein also include pharmaceutically acceptable salts thereof. The term “pharmaceutically acceptable salt,” as used herein, includes salts that are suitable for administration to a subject as defined herein. Pharmaceutically acceptable salts are well known in the art. See, e.g., Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0079] The compounds described herein may be synthetically prepared whether or not found in nature. When found in nature, such compounds may also be isolated. Compounds II

[0080] According to the disclosure, compounds of Formula X, XX, or XXX, or pharmaceutically acceptable salts thereof, are provided.:In some embodiments, the compound is of Formula X. In some embodiments, the compound is of Formula XX. In some embodiments, the compound is of Formula XXX.

[0081] According to the disclosure, - - - is a single or double bond. In some embodiments, - - is a single bond. In some embodiments, - - is a double bond.

[0082] According to the disclosure, each A is, independently, C or N, provided that no more than three A moieties are simultaneously N. In some embodiments, each A is, independently, C. In some embodiments, each A is, independently, N. In some embodiments, each A is C. In other embodiments, one A is N. In further embodiments, two A are N. In yet other embodiments, three A are N.

[0083] According to the disclosure, R1is C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1- 20alkylphenyl, or C1-20alkylcycloalkyl, wherein R1is optionally substituted by one or more D, OH, NH2, - C(O)OC1-6alkyl, -C(O)OH, C1-6alkyl, C1-6alkoxy, -C(O)H, C(O), cycloalkyl, CN, or halo. In someembodiments, R1is C1-20alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, C6alkyl, C7alkyl, C8alkyl, C9alkyl, C10alkyl, C11alkyl, C12alkyl, C13alkyl, C14alkyl, C15alkyl, C16alkyl, C17alkyl, C18alkyl, C19alkyl, or C20alkyl. In some embodiments, R1is C2-20alkenyl such as such as C2alkenyl, C3alkenyl, C4alkenyl, C5alkenyl, C6alkenyl, C7alkenyl, C8alkenyl, C9alkenyl, C10alkenyl, C11alkenyl, C12alkenyl, C13alkenyl, C14alkenyl, C15alkenyl, C16alkenyl, C17alkenyl, C18alkenyl, C19alkenyl, or C20alkenyl. In some embodiments, R1is C2-20alkynyl such as such as C2alkynyl, C3alkynyl, C4alkynyl, C5alkynyl, C6alkynyl, C7alkynyl, C8alkynyl, C9alkynyl, C10alkynyl, C11alkynyl, C12alkynyl, C13alkynyl, C14alkynyl, C15alkynyl, C16alkynyl, C17alkynyl, C18alkynyl, C19alkynyl, or C20alkynyl. In some embodiments, R1is C1- 20alkylphenyl such as C1alkylphenyl, C2alkylphenyl, C3alkylphenyl, C4alkylphenyl, C5alkylphenyl, C6alkylphenyl, C7alkyphenyll, C8alkylphenyl, C9alkylphenyl, C10alkylphenyl, C11alkylphenyl, C12alkylphenyl, C13alkylphenyl, C14alkylphenyl, C15alkylphenyl, C16alkylphenyl, C17alkylphenyl, C18alkylphenyl, C19alkylphenyl, or C20alkylphenyl. In some embodiments, R1is C1-20alkylcycloalkyl such as C1alkylcycloalkyl, C2alkylcycloalkyl, C3alkylcycloalkyl, C4alkylcycloalkyl, C5alkylcycloalkyl, C6alkylcycloalkyl, C7alkylcycloalkyl, C8alkylcycloalkyl, C9alkylcycloalkyl, C10alkylcycloalkyl, C11alkyl, C12alkylcycloalkyl, C13alkylcycloalkyl, C14alkylcycloalkyl, C15alkylcycloalkyl, C16alkylcycloalkyl, C17alkylcycloalkyl, C18alkylcycloalkyl, C19alkylcycloalkyl, or C20alkylcycloalkyl. In other embodiments, R1is hexadec-9-enyl.. so e e o e s, s . In some embodiments, R2is. In some embodiments, R2is. In this structure, each E is, independently, CH, N, O, or S. In some embodiments, each E is, independently, CH. In some embodiments, each E is, independently, N. In some embodiments, each E, independently, is S. In this structure, each Z is, independently, C or N, provided that only one Z moiety is N. In some embodiments, each Z is, independently, C. In some embodiments, each Z is C. In other embodiments, one Z is N. In further embodiments, at least one E is CH. In yet other embodiments, at least one E is N. In still further embodiments, at least one E is O. In other embodiments, at least one E is S. In some embodiments, each Z is, independently, N. In someembodiments, R2is. In this structure, each G is, independently, CH or N, provided that no more than three G moieties are simultaneously N;. In some embodiments, each G is, independently, CH. In some embodiments, each G is, independently, N. In some embodiments, at least one G is CH. In other embodiments, one G is N. In further embodiments, two G are N. In yet other embodiments, three are N.

[0085] According to the disclosure R3is CH2, NH, N(C1-6alkyl), N(C3-6cycloalkyl), or NCF3. In some embodiments, R3is CH2. In some embodiments, R3is NH. R3is N(C1-6alkyl) such as N(C1alkyl), N(C2alkyl), N(C3alkyl), N(C4alkyl), N(C5alkyl), or N(C6alkyl). In some embodiments, R3is N(C3-6cycloalkyl) such as N(cyclobutyl), N(cyclopentyl), N(cyclohexyl), N(cycloheptyl), or N(cyclooctyl). In some embodiments, R3is NCF3.

[0086] According to the disclosure, R4and R5are, independently, H, D, CH2OH, -C(O)OH, - C(O)OC1-6alkyl, C1-6alkyl, or combine to form a cycloalkyl or oxo. In some embodiments, R4is H. In some embodiments, R4is D. In some embodiments, R4is -C(O)OH. In some embodiments, R4is - C(O)OC1-6alkyl such as -C(O)OC1alkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)OC4alkyl, - C(O)OC5alkyl, or -C(O)OC6alkyl. In some embodiments, R4is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R5is H. In some embodiments, R5is D. In some embodiments, R5is -C(O)OH. In some embodiments, R5is -C(O)OC1-6alkyl such as - C(O)OC1alkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)OC4alkyl, -C(O)OC5alkyl, or -C(O)OC6alkyl. In some embodiments, R5is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R4and R5combine to form a cycloalkyl or oxo, such as cycloalkyl (e.g., such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), or such as oxo.

[0087] According to the disclosure R6and R7are, independently, H, OH, D, C1-6alkyl, halo, or combine to form a cycloalkyl or oxo; or R4and R6are joined, together with the atoms to which they are attached to form cyclopropyl. In some embodiments, R6is H. In some embodiments, R6is OH. In some embodiments, R6is D. In some embodiments, R6is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R6is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R7is H. In some embodiments, R7is OH. In some embodiments, R7is D. In some embodiments, R7is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R7is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R6and R7combine to form a cycloalkyl or oxo, such as cycloalkyl (e.g., such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), or such as oxo. In some embodiments, R4and R6are joined, together with the atoms to which they are attached to form cyclopropyl.

[0088] According to the disclosure R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are, independently, H, C(O)OH, OH, O-(optionally substituted tetrahydropyranyl), C1-6alkoxy, C1-6alkyl, CN, -C(O)H, -C(O)C1-6alkyl, halo, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -SO2C1-6alkyl, -CF3, -CHF2, or -SF5, provided that if A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent; or R10and R11, or R11and R12, or R12and R13, or R13and R14, or R15and R16, or R16and R17, or R17and R18, or R19and R20, or R21and R22are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

[0089] According to the disclosure, m and n are, independently, 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0090] In some embodiments, R10is H. In some embodiments, R10is C(O)OH. In some embodiments, R10is OH. In some embodiments, R10is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R10is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R10is CN. In some embodiments, R10is -C(O)H. In some embodiments, R10is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R10is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R10is -SO2NH2. In some embodiments, R10is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, - SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R10is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In some embodiments, R10is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R10is -CF3. In some embodiments, R10is -CHF2. In some embodiments, R10is -SF5. In some embodiments, R10is oxo. In some embodiments, In some embodiments, R10is absent. In some embodiments, R11is H. In some embodiments, R11is C(O)OH. In some embodiments, R11is OH. In some embodiments, R11is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R11is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R11is CN. In some embodiments, R11is -C(O)H. In some embodiments, R11is - C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or - C(O)C6alkyl. In some embodiments, R11is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R11is -SO2NH2. In some embodiments, R11is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or - SO2NHC6alkyl. In some embodiments, R11is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, - SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R11is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, - SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R11is -CF3. In some embodiments, R11is - CHF2. In some embodiments, R11is -SF5. In some embodiments, R11is oxo. In some embodiments, R11is absent. In some embodiments, R12is H. In some embodiments, R12is C(O)OH. In some embodiments, R12is OH. In some embodiments, R12is C1-6alkoxy such as C1alkoxy, C2alkoxy,C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R12isC1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R12is CN. In some embodiments, R12is -C(O)H. In some embodiments, R12is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O) C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R12is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R12is -SO2NH2. In some embodiments, R12is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, - SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R12is -SO2N(C1-6alkyl)2such as - SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In some embodiments, R12is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R12is -CF3. In some embodiments, R12is -CHF2. In some embodiments, R12is -SF5. In some embodiments, R12is oxo. In some embodiments, R12is absent. In some embodiments, R13is H. In some embodiments, R13is C(O)OH. In some embodiments, R13is OH. In some embodiments, R13is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R13is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R13is CN. In some embodiments, R13is -C(O)H. In some embodiments, R13is -C(O)C1-6alkyl such as - C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R13is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R13is - SO2NH2. In some embodiments, R13is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, - SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R13is - SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, - SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R13is -SO2C1-6alkyl such as - SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R13is -CF3. In some embodiments, R13is -CHF2. In some embodiments, R13is -SF5. In some embodiments, R13is oxo. In some embodiments, R13is absent. In some embodiments, R14is H. In some embodiments, R14is C(O)OH. In some embodiments, R14is OH. In some embodiments, R14is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R14is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R14is CN. In some embodiments, R14is -C(O)H. In some embodiments, R14is - C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or - C(O)C6alkyl. In some embodiments, R14is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R14is -SO2NH2. In some embodiments, R14is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or - SO2NHC6alkyl. In some embodiments, R14is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, - SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R14is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R14is -CF3. In some embodiments, R14is -CHF2. In some embodiments, R14is -SF5. In some embodiments, R14is oxo. In some embodiments, R14is absent. In some embodiments, R15is H. In some embodiments, R15is C(O)OH. In some embodiments, R15is OH. In some embodiments, R15is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R15is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R15is CN. In some embodiments, R15is -C(O)H. In some embodiments, R15is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R15is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R15is -SO2NH2. In some embodiments, R15is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, - SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R15is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In some embodiments, R15is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R15is -CF3. In some embodiments, R15is -CHF2. In some embodiments, R15is -SF5. In some embodiments, R15is oxo. In some embodiments, R15is absent. In some embodiments, R16is H. In some embodiments, R16is C(O)OH. In some embodiments, R16is OH. In some embodiments, R16is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R16is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R16is CN. In some embodiments, R16is -C(O)H. In some embodiments, R16is -C(O)C1-6alkyl such as - C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R16is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R16is - SO2NH2. In some embodiments, R16is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, - SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R16is - SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, - SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R16is -SO2C1-6alkyl such as - SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R16is -CF3. In some embodiments, R16is -CHF2. In some embodiments, R16is -SF5. In some embodiments, R16is oxo. In some embodiments, R16is absent. In some embodiments, R17is H. In some embodiments, R17is C(O)OH. In some embodiments, R17is OH. In some embodiments, R17is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R17is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R17is CN. In some embodiments, R17is -C(O)H. In some embodiments, R17is - C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or - C(O)C6alkyl. In some embodiments, R17is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R17is -SO2NH2. In some embodiments, R17is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or - SO2NHC6alkyl. In some embodiments, R17is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, - SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R17is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, - SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R17is -CF3. In some embodiments, R17is -CHF2. In some embodiments, R17is -SF5. In some embodiments, R17is oxo. In some embodiments, R17is absent. In some embodiments, R18is H. In some embodiments, R18is C(O)OH. In some embodiments, R18is OH. In some embodiments, R18is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R18is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R18is CN. In some embodiments, R18is -C(O)H. In some embodiments, R18is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R18is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R18is -SO2NH2. In some embodiments, R18is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, - SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R18is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In some embodiments, R18is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R18is -CF3. In some embodiments, R18is -CHF2. In some embodiments, R18is -SF5. In some embodiments, R18is oxo. In some embodiments, R18is absent. In some embodiments, R19is H. In some embodiments, R19is C(O)OH. In some embodiments, R19is OH. In some embodiments, R19is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R19is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R19is CN. In some embodiments, R19is -C(O)H. In some embodiments, R19is -C(O)C1-6alkyl such as - C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R19is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R19is - SO2NH2. In some embodiments, R19is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, - SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R19is - SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, - SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R19is -SO2C1-6alkyl such as - SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R19is -CF3. In some embodiments, R19is -CHF2. In some embodiments, R19is -SF5. In some embodiments, R19is oxo. In some embodiments, R19is absent. In some embodiments, R20is H. In some embodiments, R20is C(O)OH. In some embodiments, R20is OH. In some embodiments, R20is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R20is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In someembodiments, R20is CN. In some embodiments, R20is -C(O)H. In some embodiments, R20is - C(O)C1-6alkyl such as -C(O)C1alkyl, -C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or - C(O)C6alkyl. In some embodiments, R20is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R20is -SO2NH2. In some embodiments, R20is -SO2NHC1-6alkyl such as - SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, -SO2NHC5alkyl, or - SO2NHC6alkyl. In some embodiments, R20is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, - SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R20is H, -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, - SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R20is -CF3. In some embodiments, R20is -CHF2. In some embodiments, R20is -SF5. In some embodiments, R20is oxo. In some embodiments, R20is absent. In some embodiments, R21is H. In some embodiments, R21is C(O)OH. In some embodiments, R21is OH. In some embodiments, R21is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R21is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R21is CN. In some embodiments, R21is -C(O)H. In some embodiments, R21is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R21is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R21is -SO2NH2. R21is - SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, -SO2NHC4alkyl, - SO2NHC5alkyl, or -SO2NHC6alkyl. R21is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, - SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or -SO2N(C6alkyl)2. In some embodiments, R21is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, -SO2C3alkyl, -SO2C4alkyl, - SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R21is -CF3. In some embodiments, R21is -CHF2. In some embodiments, R21is -SF5. In some embodiments, R21is oxo. In some embodiments, R21is absent. In some embodiments, R22is H. In some embodiments, R22is C(O)OH. In some embodiments, R22is OH. In some embodiments, R22is C1-6alkoxy such as C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, or C6alkoxy. In some embodiments, R22is C1-6alkyl such as C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. In some embodiments, R22is CN. In some embodiments, R22is -C(O)H. In some embodiments, R22is -C(O)C1-6alkyl such as -C(O)C1alkyl, - C(O)C2alkyl, -C(O)C3alkyl, -C(O)C4alkyl, -C(O)C5alkyl, or -C(O)C6alkyl. In some embodiments, R22is halo such as chloro, bromo, fluoro, or iodo. In some embodiments, R22is -SO2NH2. In some embodiments, R22is -SO2NHC1-6alkyl such as -SO2NHC1alkyl, -SO2NHC2alkyl, -SO2NHC3alkyl, - SO2NHC4alkyl, -SO2NHC5alkyl, or -SO2NHC6alkyl. In some embodiments, R22is -SO2N(C1-6alkyl)2such as -SO2N(C1alkyl)2, -SO2N(C2alkyl)2, -SO2N(C3alkyl)2, -SO2N(C4alkyl)2, -SO2N(C5alkyl)2, or - SO2N(C6alkyl)2. In some embodiments, R22is -SO2C1-6alkyl such as -SO2C1alkyl, -SO2C2alkyl, - SO2C3alkyl, -SO2C4alkyl, -SO2C5alkyl, or -SO2C6alkyl. In some embodiments, R22is -CF3. In some embodiments, R22is -CHF2. In some embodiments, R22is -SF5. In some embodiments, R22is oxo. Insome embodiments, R22is absent. In some embodiments, R10and R11are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R11and R12are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R12and R13are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R13and R14are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R15and R16are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R16and R17are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R17and R18are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R19and R20are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. In some embodiments, R21and R22are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl. According to the disclosure, the compound is of Formula X-1 to X-6, XX-1 to XX-4, XXX-1 to XXX-3, I-A, I-B, I-C, I-D, I-E, I-F, I-G, II-A, III-A, IV-A, IV-B, or V-A:. Pharmaceutical Compositions

[0091] The disclosure provides pharmaceutical compositions containing one or more of the compounds described herein, such as the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, II-A, III-A, IV-A, IV-B, V-A, X, XX, XXX, X-1 to X-6, XX-1 to XX-4, XXX-1 to XXX-3, or a pharmaceutically acceptable salt thereof:

[0092] In addition to the compounds disclosed herein, the pharmaceutical compositions may contain one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable is selectedon the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21stEd., Gennaro, Ed., Lippencott Williams & Wilkins (2005); Handbook of Pharmaceutical Excipients, 6thEdition, Rowe et al., Eds., Pharmaceutical Press (2009); and the USP / NF (United States Pharmacopeia and the National Formulary).

[0093] In some embodiments, the pharmaceutically acceptable excipient is one or more of an antioxidant, binder, buffer, coloring agent, diluent (e.g., solid or liquid), disintegrant, dispersing agent, dyestuff, filler, emulsifier, flavoring agent, lubricant, pH adjuster, pigment, preservative, stabilizer, solubilizing agent, solvent, suspending agent, sweetener, or wetting agent, or combination thereof.

[0094] Examples of suitable excipients include, without limitation, acacia, alginate, calcium phosphate, calcium carbonate, calcium silicate, carbopol gel, carboxymethyl cellulose, carnauba wax, cellulose, crospovidone, dextrose, diacetylated monoglycerides, ethylcellulose, gelatin, glyceryl monostearate 40-50, gum acacia, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hypromellose phthalate, hypromellose, lactose, lecithin, magnesium stearate, kaolin, methacrylic acid copolymer type C, mannitol, methyl cellulose, methylhydroxybenzoate, microcrystalline cellulose, povidone, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, propylhydroxybenzoate, sodium carboxymethyl cellulose sodium hydroxide, sodium stearyl fumarate, sodium starch glycolate, starch, sorbitan monooleate sorbitol, sorbic acid, sucrose, talc, tragacanth, talc, triethyl citrate, titanium dioxide, yellow ferric oxide, talc, oil medium (e.g., peanut oil, liquid paraffin, mineral oil, olive oil, almond oil, glycerin, propylene glycol), or water,

[0095] When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. As is known in the art, the type of diluent can vary depending upon the intended route of administration.

[0096] The pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21stEd., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Dosage Units

[0097] The disclosure also provides dosage units containing one or more of the compounds disclosed herein or the pharmaceutical compositions disclosed herein. One skilled in the art would be able to select a dosage form for use herein. For example, the dosage unit may be a solid dosage form, liquid dosage form, or solid / liquid dosage form. In certain aspects, the dosage unit is a solid dosage form. In other aspects, the dosage form is a liquid dosage form.

[0098] The dosage unit may be formulated for the delivery that is most useful to the subject. In some embodiments, the dosage unit is for enteral or parenteral administration. Examples of enteral administration include, without limitation, oral, rectal, sublingual, or buccal.

[0099] In other embodiments the dosage unit is for parenteral administration, i.e., a parenteral dosage unit. As used herein, the term “parenteral” refers to routes of administration aside from enteral administration. Examples of parenteral administration include, without limitation, buccal, epicutaneous, epidural, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernous, intracerebral, intracerebroventricular, intradermal, intralesional, intramuscular, intraocular, intraosseous infusion, intraperitoneal, intrapulmonary, intrathecal, intrauterine, intravaginal, intravenous, intravesical, intravitreal, nasal, perivascular, subcutaneous, sublingual, transdermal, topical, transepithelial, or transmucosal. Parenteral administration may be by continuous infusion over a selected period of time. In certain embodiments, the dosage unit is administered intravenously, intraperitoneally, intramuscularly, intradermally, or subcutaneously. In further embodiments, the dosage unit is administered orally, intravenously, intraperitoneally, intramuscularly, intradermally, or subcutaneously. In further embodiments, the dosage unit is administered orally. In yet other embodiments, the dosage unit is administered intradermally, intramuscularly, or subcutaneously.

[0100] Parenteral dosage units are known in the art and include, without limitation, injectable solutions, inhalants, infusions, patches, and suppositories. In certain aspects, the parenteral dosage unit is an injectable solution. In other embodiments, the dosage unit is formulated for oral delivery, i.e., an oral dosage unit. In certain aspects, the oral dosage unit is a pill (e.g., tablet, caplet, capsule (e.g., soft gelatin, hard gelatin, gel capsule)), effervescent dosage form, elixir, film, liquid / solution (e.g., suspension, emulsion), lollipop, lozenge, paste, powder, sachet, or syrup. In further aspects, the oral dosage unit is a pill, tablet, capsule, syrup, liquid solution, powder, paste, patch, pump, or film. In yet other aspects, the oral dosage unit is a dry product for reconstitution with water or other suitable vehicle before use.

[0101] When the dosage form is a solid dosage form, an enteric coating can be applied or the solid dosage form may be scored. An enteric coating can be stable at low pH (e.g., in the stomach) and can dissolve at higher pH (e.g., in the small intestine).

[0102] Regardless of the type of dosage unit, it contains a therapeutically effective amount of the compound disclosed herein. One of skill in the art can determine a suitable amount of the compound disclosed herein to incorporate into the pharmaceutical compositions or dosage units of the disclosure. In certain embodiments, the pharmaceutical composition or dosage unit contains about 0.01 to about 1000 mg of one or more of the compounds disclosed herein. In other embodiments, the pharmaceutical composition or dosage unit contains about 0.01, about 0.1, about 0.5, about 1, about 5, about 10, about 25, about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, 250, about 275, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 mg of one or more of thecompounds disclosed herein. In further embodiments, the pharmaceutical composition or dosage unit contains about 0.01 to about 750, about 0.01 to about 500, about 0.01 to about 250, about 0.01 to about 100, about 0.01 to about 50, about 0.01 to about 25, about 0.01 to about 10, about 0.01 to about 5, about 0.01 to about 0.1, about 0.1 to about 1000, about 0.1 to about 750, about 0.1 to about 500, about 0.1 to about 250, about 0.1 to about 100, about 0.1 to about 50, about 0.1 to about 25, about 0.1 to about 10, about 0.1 to about 5, about 0.1 to about 1, about 1 to about 1000, about 1 to about 750, about 1 to about 500, about 1 to about 250, about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 10, about 1 to about 5, about 5 to about 1000, about 5 to about 750, about 5 to about 500, about 5 to about 250, about 5 to about 100, about 5 to about 50, about 5 to about 25, about 5 to about 10, about 10 to about 1000, about 10 to about 750, about 10 to about 500, about 10 to about 250, about 10 to about 100, about 10 to about 50, about 10 to about 25, about 25 to about 1000, about 25 to about 750, about 25 to about 500, about 25 to about 250, about 25 to about 100, about 25 to about 50, about 50 to about 1000, about 50 to about 750, about 50 to about 500, about 50 to about 250, about 50 to about 100, about 100 to about 1000, about 100 to about 750, about 100 to about 500, about 100 to about 250, about 250 to about 1000, about 250 to about 750, about 250 to about 500, about 500 to about 1000, about 500 to about 750, or about 750 to about 1000 mg of one or more of the compounds disclosed herein. Methods of Use

[0103] The compounds of the disclosure are useful in modulating an inflammatory mediator, e.g., modulating an inflammation response (e.g., in a subject). In some aspects, the compounds can be used in methods of treating inflammation in a subject in need thereof. The methods include administering a compound, pharmaceutical composition or dosage form disclosed herein to the subject in need thereof.

[0104] “Treating” or variations thereof refers ameliorating or reducing the development of a disease or disorder, i.e., delaying the onset of the disease. In certain embodiments, “treating” refers to ameliorating or reducing at least one physical parameter of the disease or disorder. In other embodiments, “treating” is directed to improving the disease or disorder. In further embodiments, “treating” is directed to the cause of the disease or disorder. In yet other embodiments, “treating” is directed to relieving symptoms of the disease or disorder. In still further embodiments, “treating” is directed to treating the disease or disorder as a supplement another therapy.

[0105] The term “inflammation” as used herein refers to a physical condition in which a part of the subject’s body becomes inflamed. Signs of inflammation include, e.g., redness, welling, heat, pain, and / or loss of function. One skilled in the art, e.g., an attending physician, would be able to recognize such signs. In some embodiments, the inflammation is localized, i.e., restricted to one particular area of the subject’s body. In other embodiments, the inflammation is systemic, i.e., in two or more areas of the subject’s body, including the subject’s whole body.

[0106] The disclosure further provides methods of decreasing inflammation in a subject in need thereof. The methods include administering the compounds, pharmaceutical compositions or dosage forms described herein to the subject in need thereof. In doing so, one or more of the signs of inflammation are decreased. In some embodiments, the methods result in decreasing redness. In other embodiments, the methods result in decreasing swelling. In further embodiments, the methods result in decreasing heat. In yet other embodiments, the methods result in decreasing temperature / heat. In still further embodiments, the methods result in decreasing pain. In other embodiments, the methos results in increasing function.

[0107] The disclosure also provides methods of decreasing an inflammatory marker in a subject in need thereof. The methods include administering the compounds, pharmaceutical compositions or dosage forms disclosed herein to the subject in need thereof. The term “inflammatory marker” refers to an internal indication or sign of inflammation in a subject. One skilled in the art would be able to select the particular inflammatory marker to monitor or evaluate. In some embodiment, the inflammatory marker is one or more of a complete blood count (CBC), C reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma viscosity (PV), fibrinogen, ferritin, procalcitonin, or calprotectin, among others. In some embodiments, the inflammatory marker is a CBC. In other embodiments, the inflammatory marker is CRP. In further embodiments, the inflammatory marker is ESR. In yet other embodiments, the inflammatory marker is PV. In still further embodiments, the inflammatory marker is fibrinogen. In other embodiments, the inflammatory marker is ferritin. In further embodiments, the inflammatory marker is procalcitonin. In still other embodiments, the inflammatory marker is calprotectin. One of skill in the art would be able to determine how to measure any one of these markers and what would constitute elevated levels for each marker.

[0108] The methods herein also permit modulating levels of one or more inflammatory regulatory molecules or inflammatory mediators in a subject in need thereof. One of skill in the art would be able to determine the inflammatory regulatory molecules or mediator to modulate. For example, recent studies have shown that the interleukin 1 (IL-1)–interleukin 1 receptor antagonist (IL- 1ra) axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro- inflammatory cytokines (including IL-6).

[0109] In certain examples, the inflammatory regulatory molecule is a cytokine. In some embodiments, the cytokine is an interleukin (IL), tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), or granulocyte-macrophage colony stimulating factor (GM-CSF). In some embodiments, the cytokine is TNF-α. In other embodiments, the cytokine is IFNγ. In further embodiments, the cytokine is GM-CSF. In yet other embodiments, the cytokine is an interleukin. Examples of interleukins include, without limitation, IL-1 (including IL-1α and IL-1β), IL-4, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13,IL-17, IL-19, IL-23, IL-35, and IL-36. In other examples, the inflammatory mediator is a prostaglandin or chemokine. In some embodiments, the inflammatory mediator is a chemokine such as GRO-α. In other embodiments, the inflammatory mediator is a prostaglandin such as prostaglandin E2 (PGE2).

[0110] The compounds or pharmaceutical compositions may be administered as described herein in combination with another pharmaceutical agent. In some embodiments, the another pharmaceutical agent is an anti-inflammatory medication. In some embodiments, the disclosed compound or pharmaceutical composition is administered before the anti-inflammatory medication. In other embodiments, the disclosed compound or pharmaceutical composition is administered after the anti-inflammatory medication. In further embodiments, the disclosed compound or pharmaceutical composition is administered concurrently with the anti-inflammatory medication.

[0111] The anti-inflammatory medication may be selected by one of skill in the art depending on the subject. In some embodiments, the anti-inflammatory medication is a steroid. Examples of steroid useful for treating inflammation include, without limitation, corticosteroids such as cortisone, prednisone or methylprednisolone. In other embodiments, the anti-inflammatory medication is a nonsteroidal anti-inflammatory drug (NSAID). Examples of NSAIDs include, without limitation, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ibuprofen, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, or tolmetin, or combination thereof.

[0112] The disclosure also provides methods of treating inflammatory bowel disease in a subject in need thereof. The methods include administering the compounds, pharmaceutical compositions, or dosage forms disclosed herein to the subject in need thereof. In some embodiments, the methods include administering one or more compound disclosed herein to the subject in need thereof. In other embodiments, the methods include administering one or more pharmaceutical compositions disclosed herein to the subject in need thereof. In further embodiments, the methods include administering one or more dosage units to the subject in need thereof.

[0113] The term “inflammatory bowel disease” or “IBD” as used herein refers to a disorder that involves chronic inflammation of the digestive tract. IBD includes ulcerative colitis and Crohn’s disease. In some embodiments, the IBD is ulcerative colitis. In other embodiments, the IBD is Crohn’s disease. In further embodiments, the IBD includes ulcers in the intestinal lining. In yet other embodiments, the IBD includes inflammation of the intestinal lining. The subject may have inflammatory bowel disease or may at risk of developing inflammatory bowel disease. In some embodiments, the patient has or has been diagnosed with inflammatory bowel disease. In other embodiments, the patient is a risk of developing inflammatory bowel disease.

[0114] The term “at risk for developing inflammatory bowel disease” as used herein refers to a subject who has a genetic predisposition to developing inflammatory bowel disease. In some embodiments, subject have genetic mutations that cause inflammatory bowel disease. In otherembodiments, a subject may have one or more genetic variations that may result in inflammatory bowel disease diagnosis.

[0115] The methods described herein include administering one or more of compound described herein (optionally in a pharmaceutical composition) with an additional agent known to be therapeutically useful. In some embodiments, the additional agent is useful for treating inflammatory bowel disease. In other embodiments, the additional agent is anti-inflammatory drugs, immune system suppressors, biologics, antibiotics, anti-diarrheal medications, pain relievers, or supplements. Examples of anti-inflammatory drugs include, without limitation, corticosteroids and / or aminosalicylates, (e.g., mesalamine, balsalazide, or olsalazine). Examples of immune system suppressors include, without limitation, azathioprine, mercaptopurine, and methotrexate. Examples of biologics include, without limitation, infliximab, adalimumab, golimumab, certolizumab, vedolizumab, and ustekinumab. Examples of antibiotics include, without limitation, ciprofloxacin and metronidazole. Examples of anti- diarrheal medications include fiber supplement (e.g., psyllium powder or methylcellulose) or loperamide. An examples of a pain reliever is acetaminophen.

[0116] In certain embodiments, the additional agent may be a therapy, i.e., non- pharmacological. For example, the subject may require nutritional support, i.e., a special diet, or be administered food enterally (e.g., feeding tube) or parenterally (e.g., injection of nutrients).

[0117] The disclosure also provides methods of treating colorectal cancer in a subject in need thereof. The methods include administering a compound, pharmaceutical composition, or dosage form to the subject in need thereof. In some embodiments, the colorectal cancer is in the colon. In some embodiments, the colorectal cancer is in the rectum.

[0118] The disclosure also provides methods of monitoring the compounds of formula I, X, XX, XXX, X-1 to X-6, XX-1 to XX-4, XXX-1 to XXX-3, I-A, I-B, I-C, I-D, I-E, I-F, I-G, II-A, III-A, IV-A, IV-B, or V-A or metabolites thereof, using techniques known in the art. For example, the compounds, or metabolites thereof, may be traced in vivo after administration. In doing so, the compounds are labelled with an appropriate isotope. Examples of isotopes include deuterium (2H, D), tritium (3H),11C,13C,14C, or18F. Suitable techniques for monitoring the isotopically labeled compounds include, without limitation, mass spectrometry, autoradiography, PET imaging, or combinations thereof.

[0119] In addition, deuterium (2H, D) may be used in place of hydrogen (1H, H) anywhere on the compounds of formula I, X, XX, XXX, X-1 to X-6, XX-1 to XX-4, XXX-1 to XXX-3, I-A, I-B, I-C, I-D, I-E, I-F, I-G, II-A, III-A, IV-A, IV-B, or V-A using techniques known in the art in order to potentially improve pharmaceutical properties, e.g., by reducing metabolism or by shifting the ratio of metabolites formed to favor more prolonged efficacy, greater efficacy, less toxicity or any combination of these outcomes. Aspects Aspect 1. A compound of Formula I:wherein: each A is, independently, C or N, provided that no more than three A moieties are simultaneously N; R1is C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1-20alkylphenyl, or C1-20alkylcycloalkyl, wherein R1is optionally substituted by one or more OH, -C(O)OC1-6alkyl, -C(O)OH, C1-6alkyl, C1-6alkoxy, - C(O)H, C(O), cycloalkyl, CN, or halo;wherein each Z is, independently, C or N, provided that only one Z moiety is N; each E is, independently, CH, N, O, or S; each G is, independently, CH or N, provided that no more than three G moieties are simultaneously N; R3is CH2, NH, N(C1-6alkyl), N(C3-6cycloalkyl), or NCF3; R4and R5are, independently, H, D, -C(O)OH, -C(O)OC1-6alkyl, C1-6alkyl, or combine to form a cycloalkyl; R6and R7are, independently, H, OH, D, C1-6alkyl, halo, or combine to form a cycloalkyl; and R10, R11, R12, R13, and R14are, independently, H, OH, C1-6alkoxy, C1-6alkyl, CN, -C(O)H, -C(O)C1- 6alkyl, halo, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -SO2C1-6alkyl, -CF3, -CHF2, or -SF5, provided that if A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent; or a pharmaceutically acceptable salt thereof.

[0120] Aspect 2. The compound of Aspect 1, wherein when A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent, provided at least one A is N-oxo.

[0121] Aspect 2a. The compound of Aspect 1, wherein when A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent, provided only one A is N-oxo.

[0122] Aspect 3. The compound of Aspect 1 or 2, wherein each A is C.

[0123] Aspect 4. The compound of Aspect 1 or 2, wherein one A is N, or two A are N, or three A are N.

[0124] Aspect 5. The compound of any one of the preceding Aspects, wherein R1is C1- 20alkyl.

[0125] Aspect 6. The compound of any one of Aspects 1-4, wherein R1is C2-20alkenyl.

[0126] Aspect 7. The compound of any one of Aspects 1-4, wherein R1is C2-20alkynyl.

[0127] Aspect 8. The compound of any one of Aspects 1-4, wherein R1is C1-20alkylphenyl.

[0128] Aspect 9. The compound of any one of Aspects 1-4, wherein R1is C1- 20alkylcycloalkyl.

[0129] Aspect 10. The compound of Aspect 1, wherein R1is hexadec-9-enyl.

[0130] Aspect 11. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more OH.

[0131] Aspect 12. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more -C(O)OC1-6alkyl.

[0132] Aspect 13. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more -C(O)OH.

[0133] Aspect 14. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more C1-6alkyl.

[0134] Aspect 15. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more C1-6alkoxy.

[0135] Aspect 16. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more -C(O)H.

[0136] Aspect 17. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more cycloalkyl.

[0137] Aspect 18. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more CN.

[0138] Aspect 19. The compound of any one of the preceding Aspects, wherein R1is substituted by one or more halo.

[0139] Aspect 20. The compound of any one of the preceding Aspects, wherein R2is.

[0140] Aspect 21. The compound of any one of Aspects 1-19, wherein R2is.

[0141] Aspect 22. The compound of any one of Aspects 1-19, wherein R2is.

[0142] Aspect 23. The compound of any one of Aspects 1-19, wherein R2is. Aspect 24. The compound of any one of Aspects 1-19, wherein R2is.

[0144] Aspect 25. The compound of Aspect 24, wherein each Z is C.

[0145] Aspect 26. The compound of Aspect 24, wherein one Z is N.

[0146] Aspect 27. The compound of any one of Aspects 24-26, wherein at least one E is CH.

[0147] Aspect 28. The compound of any one of Aspects 24-26, wherein at least one E is N.

[0148] Aspect 29. The compound of any one of Aspects 24-28, wherein at least one E is O.

[0149] Aspect 30. The compound of any one of Aspects 24-29, wherein at least one E is S;.

[0150] Aspect 31. The compound of any one of Aspects 1-19, wherein R2is.

[0151] Aspect 32. The compound of Aspect 31, wherein at least one G is CH.

[0152] Aspect 33. The compound of Aspect 31 or 32, wherein one G is N, or two G are N, or three are N.

[0153] Aspect 34. The compound of any one of the preceding Aspects, wherein R3is CH2.

[0154] Aspect 35. The compound of any one of Aspects 1-33, wherein R3is NH.

[0155] Aspect 36. The compound of any one of Aspects 1-33, wherein R3is N(C1-6alkyl).

[0156] Aspect 37. The compound of any one of Aspects 1-33, wherein R3is N(C3- 6cycloalkyl).

[0157] Aspect 38. The compound of any one of Aspects 1-33, wherein R3is NCF3.

[0158] Aspect 39. The compound of any one of the preceding Aspects, wherein R4is H.

[0159] Aspect 40. The compound of any one of Aspects 1-38, wherein R4is D.

[0160] Aspect 41. The compound of any one of Aspects 1-38, wherein R4is -C(O)OH.

[0161] Aspect 42. The compound of any one of Aspects 1-38, wherein R4is -C(O)OC1-6alkyl.

[0162] Aspect 43. The compound of any one of Aspects 1-38, wherein R4is C1-6alkyl.

[0163] Aspect 44. The compound of any one of the preceding Aspects, wherein R5is H.

[0164] Aspect 45. The compound of any one of Aspects 1-43, wherein R5is D.

[0165] Aspect 46. The compound of any one of Aspects 1-43, wherein R5is -C(O)OH.

[0166] Aspect 47. The compound of any one of Aspects 1-43, wherein R5is -C(O)OC1-6alkyl.

[0167] Aspect 58. The compound of any one of Aspects 1-43, wherein R5is C1-6alkyl.

[0168] Aspect 49. The compound of any one of Aspects 1-38, wherein R4and R5combine to form a cycloalkyl.

[0169] Aspect 50. The compound of any one of the preceding Aspects, wherein R6is H.

[0170] Aspect 51. The compound of any one of Aspects 1-49, wherein R6is OH.

[0171] Aspect 52. The compound of any one of Aspects 1-49, wherein R6is D.

[0172] Aspect 53. The compound of any one of Aspects 1-49, wherein R6is C1-6alkyl.

[0173] Aspect 54. The compound of any one of Aspects 1-49, wherein R6is halo.

[0174] Aspect 55. The compound of any one of the preceding Aspects, wherein R7is H.

[0175] Aspect 56. The compound of any one of Aspects 1-55, wherein R7is OH.

[0176] Aspect 57. The compound of any one of Aspects 1-55, wherein R7is D.

[0177] Aspect 58. The compound of any one of Aspects 1-55, wherein R7is C1-6alkyl.

[0178] Aspect 59. The compound of any one of Aspects 1-55, wherein R7is halo.

[0179] Aspect 60. The compound of any one of Aspects 1-49, wherein R6and R7combine to form a cycloalkyl.

[0180] Aspect 61. The compound of any one of the preceding Aspects, wherein R10is H.

[0181] Aspect 62. The compound of any one of Aspects 1-60, wherein R10is OH.

[0182] Aspect 63. The compound of any one of Aspects 1-60, wherein R10is C1-6alkoxy.

[0183] Aspect 64. The compound of any one of Aspects 1-60, wherein R10is C1-6alkyl.

[0184] Aspect 65. The compound of any one of Aspects 1-60, wherein R10is CN.

[0185] Aspect 66. The compound of any one of Aspects 1-60, wherein R10is -C(O)H.

[0186] Aspect 67. The compound of any one of Aspects 1-60, wherein R10is -C(O)C1-6alkyl.

[0187] Aspect 68. The compound of any one of Aspects 1-60, wherein R10is halo.

[0188] Aspect 69. The compound of any one of Aspects 1-60, wherein R10is -SO2NH2.

[0189] Aspect 70. The compound of any one of Aspects 1-60, wherein R10is -SO2NHC1-6alkyl.

[0190] Aspect 71. The compound of any one of Aspects 1-60, wherein R10is -SO2N(C1-6alkyl)2.

[0191] Aspect 72. The compound of any one of Aspects 1-60, wherein R10is -SO2C1-6alkyl.

[0192] Aspect 73. The compound of any one of Aspects 1-60, wherein R10is CF3.

[0193] Aspect 74. The compound of any one of Aspects 1-60, wherein R10is CHF2.

[0194] Aspect 75. The compound of any one of Aspects 1-60, wherein R10is SF5.

[0195] Aspect 76. The compound of any one of Aspects 1-60, wherein R10is oxo.

[0196] Aspect 77. The compound of any one of Aspects 1-60, wherein R10is absent.

[0197] Aspect 78. The compound of any one of the preceding Aspects, wherein R11is H.

[0198] Aspect 79. The compound of any one of Aspects 1-77, wherein R11is OH.

[0199] Aspect 80. The compound of any one of Aspects 1-77, wherein R11is C1-6alkoxy.

[0200] Aspect 81. The compound of any one of Aspects 1-77, wherein R11is C1-6alkyl.

[0201] Aspect 82. The compound of any one of Aspects 1-77, wherein R11is CN.

[0202] Aspect 83. The compound of any one of Aspects 1-77, wherein R11is -C(O)H.

[0203] Aspect 84. The compound of any one of Aspects 1-77, wherein R11is -C(O)C1-6alkyl.

[0204] Aspect 85. The compound of any one of Aspects 1-77, wherein R11is halo.

[0205] Aspect 86. The compound of any one of Aspects 1-77, wherein R11is -SO2NH2.

[0206] Aspect 87. The compound of any one of Aspects 1-77, wherein R11is -SO2NHC1- 6alkyl.

[0207] Aspect 88. The compound of any one of Aspects 1-77, wherein R11is -SO2N(C1- 6alkyl)2.

[0208] Aspect 89. The compound of any one of Aspects 1-77, wherein R11is -SO2C1-6alkyl.

[0209] Aspect 90. The compound of any one of Aspects 1-77, wherein R11is CF3.

[0210] Aspect 91. The compound of any one of Aspects 1-77, wherein R11is CHF2.

[0211] Aspect 92. The compound of any one of Aspects 1-77, wherein R11is SF5.

[0212] Aspect 93. The compound of any one of Aspects 1-77, wherein R11is oxo.

[0213] Aspect 94. The compound of any one of Aspects 1-77, wherein R11is absent.

[0214] Aspect 95. The compound of any one of the preceding Aspects, wherein R12is H.

[0215] Aspect 96. The compound of any one of Aspects 1-94, wherein R12is OH.

[0216] Aspect 97. The compound of any one of Aspects 1-94, wherein R12is C1-6alkoxy.

[0217] Aspect 98. The compound of any one of Aspects 1-94, wherein R12is C1-6alkyl.

[0218] Aspect 99. The compound of any one of Aspects 1-94, wherein R12is CN.

[0219] Aspect 100. The compound of any one of Aspects 1-94, wherein R12is C(O)H.

[0220] Aspect 101. The compound of any one of Aspects 1-94, wherein R12is C(O)C1-6alkyl.

[0221] Aspect 102. The compound of any one of Aspects 1-94, wherein R12is halo.

[0222] Aspect 103. The compound of any one of Aspects 1-94, wherein R12is SO2NH2.

[0223] Aspect 104. The compound of any one of Aspects 1-94, wherein R12is SO2NHC1-6alkyl.

[0224] Aspect 105. The compound of any one of Aspects 1-94, wherein R12is SO2N(C1-6alkyl)2.

[0225] Aspect 106. The compound of any one of Aspects 1-94, wherein R12is SO2C1-6alkyl.

[0226] Aspect 107. The compound of any one of Aspects 1-94, wherein R12is CF3.

[0227] Aspect 108. The compound of any one of Aspects 1-94, wherein R12is CHF2.

[0228] Aspect 109. The compound of any one of Aspects 1-94, wherein R12is SF5.

[0229] Aspect 110. The compound of any one of Aspects 1-94, wherein R12is oxo.

[0230] Aspect 111. The compound of any one of Aspects 1-94, wherein R12is absent.

[0231] Aspect 112. The compound of any one of the preceding Aspects, wherein R13is H.

[0232] Aspect 113. The compound of any one of Aspects 1-111, wherein R13is OH.

[0233] Aspect 114. The compound of any one of Aspects 1-111, wherein R13is C1-6alkoxy.

[0234] Aspect 115. The compound of any one of Aspects 1-111, wherein R13is C1-6alkyl.

[0235] Aspect 116. The compound of any one of Aspects 1-111, wherein R13is CN.

[0236] Aspect 117. The compound of any one of Aspects 1-111, wherein R13is C(O)H.

[0237] Aspect 118. The compound of any one of Aspects 1-111, wherein R13is C(O)C1-6alkyl.

[0238] Aspect 119. The compound of any one of Aspects 1-111, wherein R13is halo.

[0239] Aspect 120. The compound of any one of Aspects 1-111, wherein R13is SO2NH2.

[0240] Aspect 121. The compound of any one of Aspects 1-111, wherein R13is SO2NHC1- 6alkyl.

[0241] Aspect 122. The compound of any one of Aspects 1-111, wherein R13is SO2N(C1- 6alkyl)2.

[0242] Aspect 123. The compound of any one of Aspects 1-111, wherein R13is SO2C1-6alkyl.

[0243] Aspect 124. The compound of any one of Aspects 1-111, wherein R13is CF3.

[0244] Aspect 125. The compound of any one of Aspects 1-111, wherein R13is CHF2.

[0245] Aspect 126. The compound of any one of Aspects 1-111, wherein R13is SF5.

[0246] Aspect 127. The compound of any one of Aspects 1-111, wherein R13is oxo.

[0247] Aspect 128.The compound of any one of Aspects 1-111, wherein R13is absent.

[0248] Aspect 129. The compound of any one of the preceding Aspects, wherein R14is H.

[0249] Aspect 130. The compound of any one of Aspects 1-128, wherein R14is OH.

[0250] Aspect 131. The compound of any one of Aspects 1-128, wherein R14is C1-6alkoxy.

[0251] Aspect 132. The compound of any one of Aspects 1-128, wherein R14is C1-6alkyl.

[0252] Aspect 133. The compound of any one of Aspects 1-128, wherein R14is CN.

[0253] Aspect 134. The compound of any one of Aspects 1-128, wherein R14is -C(O)H.

[0254] Aspect 135. The compound of any one of Aspects 1-128, wherein R14is -C(O)C1-6alkyl.

[0255] Aspect 136. The compound of any one of Aspects 1-128, wherein R14is halo.

[0256] Aspect 137. The compound of any one of Aspects 1-128, wherein R14is -SO2NH2.

[0257] Aspect 138. The compound of any one of Aspects 1-128, wherein R14is -SO2NHC1-6alkyl.

[0258] Aspect 139. The compound of any one of Aspects 1-128, wherein R14is -SO2N(C1-6alkyl)2.

[0259] Aspect 140. The compound of any one of Aspects 1-128, wherein R14is -SO2C1-6alkyl.

[0260] Aspect 141. The compound of any one of Aspects 1-128, wherein R14is CF3.

[0261] Aspect 142. The compound of any one of Aspects 1-128, wherein R14is CHF2.

[0262] Aspect 143. The compound of any one of Aspects 1-128, wherein R14is SF5.

[0263] Aspect 144. The compound of any one of Aspects 1-128, wherein R14is oxo.

[0264] Aspect 145. The compound of any one of Aspects 1-128, wherein R14is absent.

[0265] Aspect 146. The compound of any one of Aspects 1, 5-19, or 39-60, or that is of formula I-A, I-B, I-C, I-D, I-E or I-F:

[0266] Aspect 147. The compound of any one of Aspects 1, 5-19, or 39-60 that is of formula I-G:.

[0267] Aspect 148. The compound of any one of Aspects 1, 5-10, or 39-145 that is of formula II-A:wherein R is R10-R14.

[0268] Aspect 149. The compound of any one of Aspects 1, 5-19, or 39-145 that is of formula III-A:wherein R is R10-R14.

[0269] Aspect 150. The compound of any one of Aspects 1, 5-19, or 50-145 that is of formula IV-A:wherein R is R10-R14.

[0270] Aspect 151. The compound of any one of Aspects 1, 5-19, or 50-145 that is of formula IV-B:wherein R is R10-R14.

[0271] Aspect 152. The compound of any one of Aspects 1, 5-19, or 39-145 that is of formula V-A:I-114 I-115 I-116 I-117 I-118 I-119 I-120 I-121 I-122 I-123 I-124

[0273] Aspect 154. A compound that is:acceptable salt thereof.

[0274] Aspect 155. A pharmaceutical composition comprising a compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0275] Aspect 156. A dosage form comprising the compound of any one of Aspects 1-154 or the pharmaceutical composition of Aspect 155.

[0276] Aspect 157. The dosage form of Aspect 156 that is formulated for oral, intravenous, intraperitoneal, intramuscular, intradermal or subcutaneous administration.

[0277] Aspect 158. The dosage form of Aspect 156 that is formulated for intradermal, intramuscular, or subcutaneous administration.

[0278] Aspect 159. A method of treating inflammation in a subject in need thereof, comprising administering the compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or the dosage form of any one of Aspects 156-158 to the subject in need thereof.

[0279] Aspect 160. A method of decreasing inflammation in a subject in need thereof, comprising administering the compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 154, or the dosage form of any one of Aspects 156-158 to the subject in need thereof.

[0280] Aspect 161. A method of decreasing an inflammatory marker in a subject in need thereof, comprising administering the compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or the dosage form of any one of Aspects 156-158 to the subject in need thereof.

[0281] Aspect 162. A method of treating inflammatory bowel disease in a subject in need thereof, comprising administering the compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or the dosage form of any one of Aspects 156-158 to the subject in need thereof.

[0282] Aspect 163. A method of treating colorectal cancer in a subject in need thereof, comprising administering the compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or the dosage form of any one of Aspects 156-158 to the subject in need thereof.

[0283] Aspect 164. A compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or dosage form of any one of Aspects 156-158 for treating inflammation in a subject in need thereof.

[0284] Aspect 165. A compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or dosage form of any one of Aspects 156-158 for decreasing inflammation in a subject in need thereof.

[0285] Aspect 166. A compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or dosage form of any one of Aspects 156-158 for decreasing an inflammatory marker in a subject in need thereof.

[0286] Aspect 167. A compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or dosage form of any one of Aspects 156-158 for treating inflammatory bowel disease in a subject in need thereof.

[0287] Aspect 168. A compound of any one of Aspects 1-154, pharmaceutical composition of Aspect 155, or dosage form of any one of Aspects 156-158 for treating colorectal cancer in a subject in need thereof.

[0288] The following examples, while illustrative individual embodiments, are not intended to limit the scope of the described invention, and the reader should not interpret them in this way. Examples

[0289] Example 1. (Z)-N-[2-(4-hydroxyphenyl)ethyl]hexadec-9-enamide

[0290] To a solution of (Z)-hexadec-9-enoic acid (2.1, 92.7 mg, 3.64 mmol, 1 eq) in dichloromethane (3.0 mL) was added HATU (166.3 mg, 4.37 mmol, 1.2 eq) and TEA (73.7 mg, 7.28 mmol, 101 µL, 2 eq), then 4-(2-aminoethyl)phenol (1.1, 50.0 mg, 3.64 mmol, 1 eq) was added in oneportion and stirred at 25°C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18150*30mm*5µm; mobile phase: [water (0.1%TFA)-ACN]; B%: 60%-90%, 9 min) and lyophilized to afford 40 mg of 1 (29%) as a white solid. I-2: (ES, m / z): [M+1]+374.0.1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (t, J = 5.5 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.3 Hz, 2H), 5.38-5.26 (m, 2H), 3.22-3.12 (m, 2H), 2.56 (t, J = 7.5 Hz, 2H), 2.06-1.93 (m, 6H), 1.45 (quin, J = 7.2 Hz, 2H), 1.36-1.14 (m, 16H), 0.89-0.81 (t, 6.9 Hz, 3H).

[0291] Example 2. (Z)-N-(4-hydroxyphenethyl)hexadec-9-enamide

[0292] Synthesis of I-2. To a solution of (Z)-hexadec-9-enoic acid (2.1, 3 g, 11.79 mmol, 1 eq), HATU (5.38 g, 14.15 mmol, 1.2 eq), TEA (3.58 g, 35.38 mmol, 4.92 mL, 3 eq) in dry THF (70 mL) was stirred at 25°C for 30 mins. Then the mixture was added to a solution of 4-(2-aminoethyl)phenol hydrochloride (1.1, 2.46 g, 14.15 mmol, 1.2 eq, HCl). The mixture was shaken at 25°C for 16 hrs. The mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 15 um); mobile phase: [water (FA)-ACN]; B%: 80%-100%, 20 min) to afford 3.4 g of I-2 (77%) as a white solid. (ES, m / z): [M+1]+374.3. I-2:1H NMR (400 MHz, chloroform-d) δ = 7.03 (d, J = 8.4 Hz, 2H), 6.85-6.75 (m, 2H), 6.42 (br s, 1H), 5.52 (brs, 1H), 5.42-5.28 (m, 2H), 3.56-3.45 (m, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.14 (t, J = 7.6 Hz, 2H), 2.01 (br d, J = 6 Hz, 4H), 1.66-1.54 (m, 2H), 1.28 (br s, 16H), 0.89 (br t, J = 6.8 Hz, 3H)

[0293] Example 3. 1-(4-hydroxyphenethyl)-3-tetradecylurea

[0294] Synthesis of I-4. To a mixture of 1-isocyanatotetradecane (4.2, 100 mg, 0.418 mmol, 1 eq) in DMF (2 mL) was added TEA (169.07 mg, 1.67 mmol, 0.23 mL, 4 eq) in one portion at 25°C under N2. Then 4-(2-aminoethyl)phenol (1.1, 145.06 mg, 0.83 mmol, 2 eq, HCl) was added to the above mixture and stirred at 25°C for 16 hrs. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 75%-100%, 8min) to give 34.18 mg of I-4 (4%) as a white solid. (ES, m / z): [M+1]+377.4. I-4:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.80 (t, J = 5.6 Hz, 1H), 5.68 (t, J = 5.6 Hz, 1H), 3.13 (q, J = 6.4 Hz, 2H), 2.94 (q, J = 6.8 Hz, 2H), 2.57-2.53 (m, 2H), 1.23 (s, 24H), 0.85 (t, J = 6.8 Hz, 3H)

[0295] Example 4. (Z)-N-(4-hydroxyphenethyl)tetradec-9-enamide

[0296] Synthesis of I-5. A mixture of (Z)-tetradec-9-enoic acid (5.1, 100 mg, 441.79 umol, 1 eq), HATU (201.58 mg, 530.14 umol, 1.2 eq), DIEA (171.29 mg, 1.33 mmol, 230.85 uL, 3 eq) in dry DMF (1 mL) was stirred at 25°C for 30 mins. 4-(2-aminoethyl)phenol (1.1, 115.07 mg, 662.68 umol, 1.5 eq, HCl) was added to the above mixture. The mixture was stirred at 25°C for 16 hrs. The combined organic layers were concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (FA)-ACN];B%: 45%-85%, 8min) to afford 87.2 mg of I-5 (57%) as a white solid. (ES, m / z): [M+1]+346.2. I-5:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.38-5.28 (m, 2H), 3.21-3.13 (m, 2H), 2.58-2.53 (m, 2H), 2.04-1.95 (m, 6H), 1.50-1.40 (m, 2H), 1.31-1.19 (m, 12H), 0.89-0.83 (m, 3H)

[0297] Example 5. N-(4-hydroxyphenethyl)pentadecane-1-sulfonamide

[0298] Synthesis of 6.2. A mixture of 1-bromopentadecane (6.1, 1 g, 3.43 mmol, 1 eq) and thiourea (6.1A, 261.31 mg, 3.43 mmol, 1.1 eq) in EtOH (3.5 mL) was refluxed for 1 hr. After removal of the solvent in vacuum and washing with petroleum ether (5 mL x 3), the corresponding s-alkyl isothiourea salt was obtained as a white solid in almost quantitative yield. The product was transferred into a three-necked round-bottom flask equipped with a thermometer and an addition funnel in an ice- bath, followed by addition of H2O (0.3 mL) and MeCN (6.6 mL). To the resulting vigorously stirred mixture was added dropwise a solution of tert-butyl hypochlorite (372.69 mg, 3.43 mmol, 1 eq) in ACN (3.5 mL) while keeping the inner temperature at 0°C. The mixture was then stirred for 30 mins at 25°C. The solvent was removed under vacuum, followed by addition of ethyl acetate (15 mL). The organic phase was washed with H2O (10 mL x 2), dried over Na2SO4, and concentrated under vacuum gave the desired product in high purity. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-4% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 540 mg of 6.2 (50%) as a white solid.

[0299] Synthesis of I-6. A mixture of pentadecane-1-sulfonyl chloride (6.2, 340 mg, 1.06 mmol, 1 eq), 4-(2-aminoethyl)phenol hydrochloride (1.1, 276.44 mg, 1.59 mmol, 1.5 eq), TEA (322.20 mg, 3.18 mmol, 443.19 uL, 3 eq) in DMF (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 16 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5um; mobile phase: [water (FA)-ACN]; gradient: 65%-95% B over 8 min) to give 147.00 mg of I-6 (33%) as a white solid. (ES, m / z): [M+1]+412.3. I-6:1H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 1H), 7.20-6.84 (m, 3H), 6.76-6.54 (m, 2H), 3.15-3.01 (m, 2H), 2.92-2.82 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.69-1.40 (m, 2H), 1.23 (s, 24H), 0.88-0.82 (m, 3H).

[0300] Example 6. 8-(2-hexylphenyl)-N-(4-hydroxyphenethyl)octanamide

[0301] Synthesis of 7.3. To a solution of 1-bromo-2-iodobenzene (7.1, 2 g, 7.07 mmol, 909.09 uL, 1 eq) in TEA (10.97 mL) was added CuI (53.86 mg, 282.78 umol, 0.04 eq) and Pd(PPh3)2Cl2 (99.24 mg, 141.39 umol, 0.02 eq). Then oct-7-yn-1-ol (7.2, 981.36 mg, 7.78 mmol, 1.1 eq) was added and the mixture was stirred at 20°C for 16 hrs. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 47 / 3) to give 2 g of 7.3 (crude) as a yellow oil.

[0302] Synthesis of 7.5. To a solution of 8-(2-bromophenyl)oct-7-yn-1-ol (7.3, 1.87 g, 6.65 mmol, 1 eq) in H2O (3.68 mL) and Tol. (23 mL) was added Cs2CO3(6.50 g, 19.95 mmol, 3 eq) and hexylboronic acid (7.4, 1.04 g, 7.98 mmol, 1.2 eq). The mixture was then degassed and purged with N2for 3 times. Pd(dppf)Cl2(543.09 mg, 665.04 umol, 0.1 eq) was added and the reaction mixture was degassed and purged with N2for 3 times. The mixture was stirred at 100°C for 16 hrs. The reactionmixture was diluted with water 30 mL and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 19 / 1) to give 1.44 g of 7.5 (76%) as a yellow oil.

[0303] Synthesis of 7.6. To a solution of 8-(2-hexylphenyl)oct-7-yn-1-ol (7.5, 1.34 g, 4.68 mmol, 1 eq) in acetone (13 mL) was added Jones reagent (926.58 mg, 4.68 mmol, 1 eq) dropwise at 0°C until the color of the mixture changed from dark green to orange for 10 mins. Then the 2-propanol was added dropwise until the color of the mixture returned to dark green. The reaction mixture was quenched by IPA (1.5 mL) at 20°C and concentrated under reduced pressure to give a residue, and then diluted with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 to 3 / 47) to give 640 mg of 7.6 (46%) as a yellow oil. (ES, m / z): [M-1]- 299.3.

[0304] Synthesis of 7.7. To a solution of 8-(2-hexylphenyl)oct-7-ynoic acid (7.6, 200 mg, 665.70 umol, 1 eq) in THF (2 mL) was added a catalytic amount of Pd / C (665.70 umol, 66.57 uL, 10% purity, 1 eq). The flask was then purged and filled with an H2atmosphere at 20°C. The reaction mixture was stirred for 0.5 hr at 20°C. The reaction mixture was filtered and concentrated under reduced pressure to give 164 mg of 7.7 (crude) as a yellow oil. (ES, m / z): [M+1]+303.3.

[0305] Synthesis of I-7. To a solution of 8-(2-hexylphenyl)octanoic acid (7.7, 160 mg, 525.51 umol, 1 eq) in DMF (2 mL) was added HATU (599.45 mg, 1.58 mmol, 3 eq) and DIEA (339.59 mg, 2.63 mmol, 457.67 uL, 5 eq) was stirred at 20°C for 10 mins. Then 4-(2-aminoethyl)phenol (1.1, 136.87 mg, 788.27 umol, 1.5 eq, HCl) was added. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [water (FA)- ACN]; B%: 65%-95%, 8 min) to give 100 mg of I-7 (45%) as a brown solid. (ES, m / z): [M+1]+424.3. I-7:1HNMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.13-7.05 (m, 4H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.21-3.13 (m, 2H), 2.59-2.52 (m, 6H), 2.01 (t, J = 7.6 Hz, 2H), 1.54-1.41 (m, 6H), 1.36-1.25 (m, 10H), 1.22 (br d, J = 8.0 Hz, 2H), 0.89-0.82 (m, 3H).

[0306] Example 7. N-(4-hydroxyphenethyl)-7-(4-pentylphenyl)heptanamide

[0307] Synthesis of 8.3. To a round-bottomed flask containing a magnetic stir bar and 1- bromo-4-iodo-benzene (8.1, 2 g, 7.07 mmol, 1 eq) was added CuI (53.86 mg, 282.78 umol, 0.04 eq), Pd(PPh3)2Cl2 (99.24 mg, 141.39 umol, 0.02 eq) and TEA (11 mL), and the resulted mixture was thoroughly degassed by argon for 15 mins before hept-6-yn-1-ol (8.2, 872.28 mg, 7.78 mmol, 1.1 eq) was added via syringe. The resulted reaction mixture was allowed to stir at 20°C for 16 hrs. The mixture was quenched by aq.NH4Cl (50 mL), then diluted with ethyl acetate (70 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 3 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give 1.7 g of 8.3 (90%) as a yellow solid. (ES, m / z): [M+1]+267.9

[0308] Synthesis of 8.5. A mixture of 7-(4-bromophenyl) hept-6-yn-1-ol (8.3, 1 g, 3.74 mmol, 1 eq), pentylboronic acid (8.4, 694.51 mg, 5.99 mmol, 1.6 eq), K2CO3 (1.03 g, 7.49 mmol, 2 eq) in Tol. (5 mL) and H2O (2.5 mL) was degassed and purged with N2 for 3 times, then Pd(PPh3)4 (216.27 mg, 187.15 umol, 0.05 eq) was added and the mixture was stirred at 100°C for 16 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 350 mg of 8.5 (36%) as a colorless oil. (ES, m / z): [M+1]+259.3

[0309] Synthesis of 8.6. To a solution of 7-(4-pentylphenyl)hept-6-yn-1-ol (8.5, 350 mg, 1.35 mmol, 1 eq) in MeOH (10 mL) was added Pd / C (1 g, 2.71 mmol, 10% purity, 2 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi.) at 20°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 170 mg of 8.6 (47%) as a colorless oil.

[0310] Synthesis of 8.7. To a solution of 7-(4-pentylphenyl)heptan-1-ol (8.6, 155 mg, 590.64 umol, 1 eq) in acetone (1 mL) was added Jones reagent (2.7 M, 218.75 uL, 1 eq) dropwise at 0°C until the color of the mixture changed from dark green to orange for 10 mins. Then 2-propanol was added dropwise until the color of the mixture returned to dark green, and the mixture was stirred at 20°C for 1 hr. The mixture was poured into 5 mL of water, and extracted with ethyl acetate (6 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 0.5 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give 160 mg of 8.7 (98%) as a white solid. (ES, m / z): [M-1] - 275.1

[0311] Synthesis of I-8. To a solution of 7-(4-pentylphenyl)heptanoic acid (8.7, 100 mg, 361.78 umol, 1 eq) in DMF (2 mL) was added HATU (206.34 mg, 542.67 umol, 1.5 eq) and DIEA (233.79 mg, 1.81 mmol, 315.08 uL, 5 eq), the mixture was stirred at 20°C for 10 mins. Then 4-(2- aminoethyl)phenol; hydrochloride (1.1, 94.23 mg, 542.67 umol, 1.5 eq) was added, and the mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 65%-98% B over 8 min) to give 43.90 mg of I-8 (30%) as a white solid. (ES, m / z): [M+1]+396.3. I-8:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.07 (s, 4H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.21-3.12 (m, 2H), 2.58-2.51 (m, 6H), 2.01 (t, J = 7.6 Hz, 2H), 1.58-1.49 (m, 4H), 1.48-1.41 (m, 2H), 1.32-1.21 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H)

[0312] Example 8. 6-(3-heptylphenyl)-N-(4-hydroxyphenethyl)hexanamide

[0313] Synthesis of 9.3. To a solution of 1-bromo-3-iodo-benzene (9.1, 2 g, 7.07 mmol, 900.90 uL, 1 eq) in TEA (11 mL) was added CuI (53.86 mg, 282.78 umol, 0.04 eq) and Pd(PPh3)2Cl2 (99.24 mg, 141.39 umol, 0.02 eq). Then hex-5-yn-1-ol (9.2, 763.21 mg, 7.78 mmol, 1.1 eq) was added and the mixture was stirred at 25°C for 16 hrs. The mixture was quenched by aq. NH4Cl (50 mL), then diluted with ethyl acetate 210 mL (70 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to give 1.15 g of 9.3 (95%) as a light-yellow oil. (ES, m / z): [M+1]+254.0.

[0314] Synthesis of 9.5. To a solution of 6-(3-bromophenyl)hex-5-yn-1-ol (9.3, 1.15 g, 4.54 mmol, 1 eq), heptylboronic acid (9.4, 785.14 mg, 5.45 mmol, 1.2 eq) and Cs2CO3 (4.44 g, 13.63 mmol, 3 eq) in H2O (2 mL) and Tol. (12 mL) was added Pd(dppf)Cl2 (371.00 mg, 454.30 umol, 0.1 eq). The mixture was stirred at 100°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to give 826.2 mg of 9.5 (39%) as a yellow oil. (ES, m / z): [M+1]+273.2.

[0315] Synthesis of 9.6. To a solution of 6-(3-heptylphenyl)hex-5-yn-1-ol (9.5, 826.2 mg, 3.03 mmol, 1 eq) in acetone (8 mL) was added dropwise the Jones reagent (600.70 mg, 3.03 mmol, 1 eq) at 0°C until the color of the mixture changed from dark green to orange for 10 mins. Then 2-propanol was added dropwise until the color of the mixture returned to dark green, the mixture was stirred at 25°C for 1 hr. The mixture was poured into 10 mL of water, and it was extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and filtered and concentratedunder reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate= 3: 1) to give 292.4 mg of 9.6 (34%) as a light-yellow oil. (ES, m / z): [M-1] - 285.4.

[0316] Synthesis of 9.7. To a solution of 6-(3-heptylphenyl)hex-5-ynoic acid (9.6, 292.4 mg, 1.02 mmol, 1 eq) in EtOH (3 mL) was added a catalytic amount of Pd / C (1.02 mmol, 10% purity, 1 eq). The flask was then purged and filled with an H2atmosphere at 25°C under 15 psi. The reaction mixture was stirred for 1 hr at 25°C. The catalyst Pd / C was removed by filtration over celite with EtOH (5 mL x 3) rinsing. The filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: ethyl acetate = 3: 1) to give 188.2 mg of 9.7 (53%) as a light-yellow oil. (ES, m / z): [M- 1] - 289.4.

[0317] Synthesis of I-9. To a solution of 6-(3-heptylphenyl)hexanoic acid (9.7, 158.20 mg, 544.69 umol, 1 eq) in DMF (1.5 mL) was added HATU (310.66 mg, 817.04 umol, 1.5 eq) and DIEA (211.19 mg, 1.63 mmol, 284.62 uL, 3 eq). The mixture was stirred at 25°C for 10 mins. Then 4-(2- aminoethyl)phenol (1.1, 141.87 mg, 817.04 umol, 1.5 eq, HCl) was added to the mixture and stirred at 25°C for 50 mins. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 8min) to give 111.32 mg of I-9 (50%) as a white solid. (ES, m / z): [M+1]+410.3. I-9:1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 7.79 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.00-6.92 (m, 5H), 6.66 (d, J = 8.4 Hz, 2H), 3.16 (br d, J = 7.6 Hz, 2H), 2.58-2.51 (m, 6H), 2.01 (t, J = 7.6 Hz, 2H), 1.56-1.43 (m, 6H), 1.30-1.18 (m, 10H), 0.88-0.81 (m, 3H)

[0318] Example 9. 9-(3-butylphenyl)-N-(4-hydroxyphenethyl)nonanamide

[0319] Synthesis of 10.3. To a solution of 1-bromo-3-iodo-benzene (10.1, 2 g, 7.07 mmol, 900.90 uL, 1 eq) in TEA (10.97 mL) was added CuI (53.86 mg, 282.78 umol, 0.04 eq) and Pd(PPh3)2Cl2(99.24 mg, 141.39 umol, 0.02 eq). Then non-8-yn-1-ol (10.2, 1.09 g, 7.78 mmol, 1.1 eq) was added to the mixture and stirred at 25°C for 16 hrs. The reaction mixture diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 95 / 5) to give 1.87 g of 10.3 (89%) as a yellow oil. (ES, m / z): [M+1]+297.1.

[0320] Synthesis of 10.5. To a solution of 9-(3-bromophenyl)non-8-yn-1-ol (10.3, 1.87 g, 6.33 mmol, 1 eq), butylboronic acid (10.4, 774.87 mg, 7.60 mmol, 1.2 eq) and Cs2CO3(6.19 g, 18.99 mmol, 3 eq) in H2O (2 mL) and Tol. (23 mL) was added Pd(dppf)Cl2(517.29 mg, 633.00 umol, 0.1 eq). The mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 100°C for 16 hrs under N2atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnchromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 95 / 5) to give 896 mg of 10.5 (crude) as a yellow oil.

[0321] Synthesis of 10.6. To a mixture of 9-(3-butylphenyl)non-8-yn-1-ol (10.5, 869 mg, 3.19 mmol, 1 eq) in acetone (8 mL) was added dropwise the Jones Reagent (631.82 mg, 3.19 mmol, 1 eq) at 0°C until the color of the mixture changed from dark green to orange for 10 mins. Then the 2- propanol was added dropwise to the mixture until the color of the mixture returned to dark green. The reaction mixture was quenched by IPA (8 mL) at 25°C, and then diluted with water 30 mL and extracted with ethyl acetate (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 95 / 5) to give 880 mg of 10.6 (96%) as a yellow oil. (ES, m / z): [M-1]- 285.2.

[0322] Synthesis of 10.7. To a solution of 9-(3-butylphenyl)non-8-ynoic acid (10.6, 880 mg, 3.07 mmol, 1 eq) in THF (8 mL) was added Pd / C (3.07 mmol, 66.57 uL, 10% purity, 1 eq). The mixture was stirred at 25°C for 0.5 hr. The catalyst Pd / C was removed by filtration over celite with THF (5mL × 3) rinsing. The filtrate was concentrated to give 524 mg of 10.7 (crude) as a yellow oil.

[0323] Synthesis of I-10. A mixture of 9-(3-butylphenyl)nonanoic acid (10.7, 150 mg, 516.46 umol, 1 eq), HATU (294.56 mg, 774.69 umol, 1.5 eq), DIEA (200.25 mg, 1.55 mmol, 269.87 uL, 3 eq) in DMF (2 mL) was degassed and purged with N2for 3 times, then 4-(2-aminoethyl)phenol hydrochloride (1.1, 134.52 mg, 774.69 umol, 1.5 eq) was added and the mixture was stirred at 25°C for 1 hr under N2atmosphere. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 8min) to give 114.40 mg of I-10 (54%) as a white solid. (ES, m / z): [M+1]+410.7. I-10:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (s, 1H), 7.18-7.12 (m, 1H), 7.01-6.93 (m, 5H), 6.66 (d, J = 8.4 Hz, 2H), 3.21-3.12 (m, 2H), 2.59- 2.50 (m, 6H), 2.00 (t, J = 7.2 Hz, 2H), 1.60-1.39 (m, 6H), 1.33-1.24 (m, 6H), 1.21 (br s, 4H), 0.88 (t, J = 7.2 Hz, 3H)

[0324] Examples 10 & 11. (R)-N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)palmitamide & (S)-N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)palmitamide

[0325] Synthesis of 11.3. To a solution of palmitic acid (11.1, 1 g, 3.90 mmol, 1.17 mL, 1 eq) in DCM (10 mL) was added HATU (2.22 g, 5.85 mmol, 1.5 eq) and DIEA (1.51 g, 11.70 mmol, 2.04 mL, 3 eq) at 25°C. After stirring for 10 mins, 4-(2-amino-1-hydroxy-ethyl)phenol (11.2, 1.11 g, 5.85 mmol, 1.5 eq, HCl) was added to the above mixture. The mixture was stirred at 25°C for 16 hrs. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NaSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give 1.37 g of 11.3 (90%) as a white solid. (ES, m / z): [M+1]+392.3.

[0326] Synthesis of I-11 & 1-12. 200 mg of 11.3 (mixture of 2 peaks) was separated by SFC to give 87.70 mg of I-11 (43 %, ee value: 100 %, Peak 1) and 87.14 mg of 1-12 (43 %, ee value: 98.26 %, Peak 2) as white solids. (ES, m / z): [M+1]+392.3.

[0327] SFC separation methods:

[0328] Method 1: Instrument: Waters SFC150AP preparative SFC; Column: DAICEL CHIRALCEL OZ (250 mm*30 mm, 10 um); Mobile phase: A for CO2 and B for MeOH (0.1% NH3H2O); Gradient: B%=25% isocratic elution mode; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 40°C; System back pressure: 100 bar. I-11:1H NMR (400 MHz, DMSO-d6) δ = 9.64-8.94 (m, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.71-6.65 (m, 2H), 5.54-4.96 (m, 1H), 4.45 (dd, J = 5.2, 7.5 Hz, 1H), 3.20 (td, J = 5.6, 13.0 Hz, 1H), 3.05 (ddd, J = 5.2, 7.8, 13.1 Hz, 1H), 2.03 (t, J = 7.6 Hz, 2H), 1.43 (td, J = 7.2, 14.1 Hz, 2H), 1.24 (s, 24H), 0.89-0.81 (m, 3H). I-12:1H NMR (400 MHz, DMSO-d6) δ = 9.65-8.83 (m, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.43-5.08 (m, 1H), 4.46 (dd, J = 5.2, 7.5 Hz, 1H), 3.19 (br d, J = 5.6 Hz, 1H), 3.07 (br d, J = 7.6 Hz, 1H), 2.03 (t, J = 7.2 Hz, 2H), 1.48-1.39 (m, 2H), 1.24 (s, 24H), 0.89-0.82 (m, 3H)

[0329] Examples 12 & 13. (S,Z)-N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexadec-9- enamide & (R,Z)-N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexadec-9-enamide

[0330] Synthesis of 13.1. To a solution of (Z)-hexadec-9-enoic acid (2.1, 1 g, 3.93 mmol, 1 eq) in DCM (20 mL) was added HATU (2.24 g, 5.90 mmol, 1.5 eq) and DIEA (3.05 g, 23.58 mmol, 4.11 mL, 6 eq). The mixture was stirred at 20°C for 10 mins, then 4-(2-amino-1-hydroxyethyl)phenol (11.2, 1.12 g, 5.90 mmol, 1.5 eq) was added. The mixture was stirred at 20°C for 16 hrs. The mixture was diluted with DCM (30 mL) and extracted with H2O (30 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 3 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 25% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give 1.26 g of 13.2 (82%) as a white solid. (ES, m / z): [2M+1]+779.7

[0331] Synthesis of I-13 & 1-14. 200 mg of 13.1 (mixture of 2 peaks) was separated by SFC to give 69.71 mg of I-13 (34%, ee value: 99.94 %, Peak 2) and 31.32 mg of 1-14 (43 %, ee value: 99.2 %, Peak 1) as white solids. (ES, m / z): [2M+1]+779.7.

[0332] SFC separation methods:

[0333] Method 1: Instrument: Waters SFC150AP preparative SFC; Column: DAICEL CHIRALPAK IH (250 mm*30 mm, 10 um); Mobile phase: A for CO2and B for IPA (0.1%NH3H2O); Gradient: B%=35% isocratic elution mode; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 40℃; System back pressure: 100 bar. I-13:1H NMR (400 MHz, DMSO-d6) δ = 7.74 (t, J = 5.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.37-5.28 (m, 2H), 4.46 (dd, J = 5.2, 7.6 Hz, 1H), 3.25-3.16 (m, 2H), 3.08-3.01 (m, 1H), 2.07-1.94 (m, 6H), 1.47-1.38 (m, 2H), 1.30-1.15 (m,16H), 0.87-0.82 (m, 3H). I-14:1H NMR (400 MHz, DMSO-d6) δ = 9.24 (s, 1H), 7.74 (br t, J = 5.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.37-5.28 (m, 2H), 5.22 (d, J = 4.4 Hz, 1H), 4.50- 4.42 (m, 1H), 3.24-3.16 (m, 1H), 3.09-3.00 (m, 1H), 2.07-1.94 (m, 6H), 1.43 (quin, J = 7.2 Hz, 2H), 1.33- 1.17 (m, 16H), 0.85 (br t, J = 6.8 Hz, 3H)

[0334] Example 14. 4-(2-((4-tridecylpyrimidin-2-yl)amino)ethyl)phenol

[0335] Synthesis of 15.2. To a mixture of 4-bromo-2-chloropyrimidine (15.1, 0.9 g, 4.65 mmol, 1 eq) and 4-(2-aminoethyl)phenol hydrochloride (1.1, 765.93 mg, 5.58 mmol, 1.2 eq) in dioxane (15 mL) was added TEA (706.23 mg, 6.98 mmol, 971.43 uL, 1.5 eq) at 0°C. The reaction was allowed to stir on the ice-bath for 5 mins and was refluxed for 3 hrs. The mixture was quenched by H2O (20mL), then extracted with ethyl acetate (30 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 15% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 0.3 g of 15.2 (21%) as a white solid.

[0336] Synthesis of 15.4. A pressure bottle containing (E)-4,4,5,5-tetramethyl-2-(tridec-1-en- 1-yl)-1,3,2-dioxaborolane (15.3, 176.09 mg, 571.14 umol, 1.5 eq), 4-(2-((4-bromopyrimidin-2- yl)amino)ethyl)phenol (15.2, 0.112 g, 380.76 umol, 1 eq) and K2CO3(105.25 mg, 761.52 umol, 2 eq) in DME (5 mL) and H2O (0.5 mL) was purged with N2for 5 mins andcyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (15.55 mg, 19.04 umol, 0.05 eq) was added. The reaction mixture was heated at 110°C for 18 hrs. The mixture was quenched by H2O (10 mL), then extracted with ethyl acetate (20 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Ethyl acetate: Petroleum ether = 2: 1) to give 180 mg of 15.4 (crude) as a yellow oil.

[0337] Synthesis of I-15. To a solution of (E)-4-(2-((4-(tridec-1-en-1-yl)pyrimidin-2- yl)amino)ethyl)phenol (15.4, 160 mg, 404.47 umol, 1 eq) in ethyl acetate (3 mL) was added Pd / C (0.1 g, 808.94 umol, 10% purity, 2 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 1.5 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18200*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 55%-95% B over 8 min) to give 101.75 mg of I-15 (63%) as a white solid. (ES, m / z): [M+1]+398.3. I- 15:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 8.12 (br d, J = 3.6 Hz, 1H), 7.03-6.94 (m, 3H), 6.66 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 4.9 Hz, 1H), 3.42-3.35 (m, 2H), 2.72-2.65 (m, 2H), 2.49-2.44 (m, 2H), 1.68-1.56 (m, 2H), 1.30-1.19 (m, 20H), 0.85 (t, J = 6.7 Hz, 3H)

[0338] Example 15. 4-(3-(4-tridecyl-1H-pyrazol-1-yl)propyl)phenol

[0339] Synthesis of 16.5C. To a solution of 1-[dimethoxy(oxido)-λ5-phosphanylidene]-2- oxo-propane-1-diazonium (16.5B, 3.75 g, 19.53 mmol, 1.2 eq), K2CO3(4.50 g, 32.55 mmol, 32.55 mL, 2 eq) in MeOH (244 mL) was added dodecanal (16.5A, 3 g, 16.28 mmol, 1 eq) and purged with N2for 3 times. The mixture was stirred at 20°C for 1.5 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with NaHCO3(250 mL) and extracted with petroleum ether 270 mL (90 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 0) to give 2.11 g of 16.5C (71%) as a colorless oil.

[0340] Synthesis of 16.5. To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 10.81 mmol, 1.57 mL, 1.3 eq) in tridec-1-yne (16.5C, 1.5 g, 8.32 mmol, 1 eq) was added BH3.THF (1 M, 831.81 uL, 0.1 eq). The mixture was stirred at sealed tube at 60°C for 12 hrs. The reaction mixture wasquenched by addition of MeOH (10 mL) at 20°C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 98 / 2) to give 1.19 g of 16.5 (46%) as a colorless oil.

[0341] Synthesis of 16.2. 4-bromo-1H-pyrazole (16.1, 3 g, 20.41 mmol, 1 eq), K2CO3 (3.67 g, 26.54 mmol, 1.3 eq) in DMF (20 mL) were added to 3-bromoprop-1-yne (16.1A, 3.34 g, 22.45 mmol, 2.42 mL, 80% purity, 1.1 eq) and the mixture was stirred at 20°C for 5 hrs. The mixture was quenched by H2O (50 mL), then extracted with ethyl acetate (70 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 130 mL / min) to give 2.54 g of 16.2 (89%) as a colorless oil.

[0342] Synthesis of 16.4. A mixture of 4-bromo-1-(prop-2-yn-1-yl)-1H-pyrazole (16.2, 0.7 g, 3.78 mmol, 1 eq), 1-(benzyloxy)-4-iodobenzene (16.3, 1.41 g, 4.54 mmol, 1.2 eq), dichloropalladium; triphenylphosphane (132.78 mg, 189.17 umol, 0.05 eq), CuI (72.05 mg, 378.34 umol, 0.1 eq) in DMF (5 mL) and TEA (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20°C for 16 hrs under N2atmosphere. The mixture was quenched by H2O (50 mL), then extracted with ethyl acetate (70 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 2% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give 0.9 g of 16.4 (64%) as a red solid.

[0343] Synthesis of 16.6. A pressure bottle containing (E)-4,4,5,5-tetramethyl-2-(tridec-1- en-1-yl)-1,3,2-dioxaborolane (16.5, 503.71 mg, 1.63 mmol, 1.5 eq), 1-(3-(4-(benzyloxy)phenyl)prop-2- yn-1-yl)-4-bromo-1H-pyrazole (16.4, 400 mg, 1.09 mmol, 1 eq) and K2CO3(301.07 mg, 2.18 mmol, 2 eq) in DME (5 mL) and H2O (0.5 mL) was purged with N2for 5 min and cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (44.47 mg, 54.46 umol, 0.05 eq) was added. The reaction mixture was heated at 110°C for 18 hrs. The mixture was quenched by H2O (50 mL), then extracted with ethyl acetate (70 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 5% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give 325 mg of 16.6 (28%) as a red solid.

[0344] Synthesis of I-16. To a solution of (E)-1-(3-(4-(benzyloxy)phenyl)prop-2-yn-1-yl)-4- (tridec-1-en-1-yl)-1H-pyrazole (16.6, 250 mg, 533.42 umol, 1 eq) in ethyl acetate (5 mL) was added Pd / C (0.3 g, 5.33 mmol, 10% purity, 10 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 95%-98% B over 8 min) to give 76 mg of I-16 (37%) as white solid. (ES, m / z): [M+1]+385.6. I-16:1H NMR (400 MHz, DMSO-d6) δ = 9.13 (s, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 6.96 (d, J = 8.4 Hz,2H), 6.68-6.63 (m, 2H), 3.98 (t, J = 6.9 Hz, 2H), 2.38 (q, J = 7.6 Hz, 4H), 1.96 (m, J = 7.2 Hz, 2H), 1.48 (br t, J = 7.2 Hz, 2H), 1.31-1.20 (m, 20H), 0.88-0.82 (m, 3H)

[0345] Example 16. (Z)-N-(2,2-difluoro-2-(4-hydroxyphenyl)ethyl)hexadec-9-enamide

[0346] Synthesis of 17.2. To a solution of 1-(benzyloxy)-4-iodobenzene (16.3, 3 g, 9.67 mmol, 1 eq) and ethyl 2-bromo-2,2-difluoroacetate (17.1, 4.91 g, 24.18 mmol, 3.11 mL, 2.5 eq) in DMSO (10 mL) was added Cu (1.60 g, 25.15 mmol, 178.39 uL, 2.6 eq) under N2. The mixture was stirred at 80°C for 16 hrs. The reaction mixture was quenched by addition aq.NH4Cl (50 mL) at 20°C, and extracted with ethyl acetate 60 mL (20 mL x 3). The combined organic layers were washed with NH4Cl (2 x 50 mL) and brine (2 x 50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 4% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give 1.2 g of 17.2 (40%) as a white solid.

[0347] Synthesis of 17.3. To a solution of ethyl 2-(4-(benzyloxy)phenyl)-2,2-difluoroacetate (17.3, 1.2 g, 3.92 mmol, 1 eq) in NH3 / MeOH (7 M, 559.67 uL, 28% purity, 1 eq) was added NH3.H2O (10 mL). The mixture was quenched by adding a solution of MeOH (19 mL) dropwise until the reaction mixture is clear. The mixture was stirred at 20°C for 48 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was then triturated with H2O (20 mL) at 20oC for 10 mins, filtered and concentrated under reduced pressure to give 960 mg of 17.3 (88%) as a white solid.

[0348] Synthesis of 17.4. To a solution of 2-(4-(benzyloxy)phenyl)-2,2-difluoroacetamide (17.3, 960 mg, 3.46 mmol, 1 eq) in THF (100 mL) was added borane; tetrahydrofuran (1 M, 17.31 mL, 5 eq) at 0°C. The mixture was stirred at 70°C for 12 hrs. The reaction mixture was quenched by 1 M HCl (2 mL) at 50°C for 2 hrs, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; gradient: 15%-45% B over 8 min) to give 240 mg of 17.4 (26%) as a white solid.

[0349] Synthesis of 17.5. To a solution of 2-(4-(benzyloxy)phenyl)-2,2-difluoroethan-1- amine (17.4, 120 mg, 400.34 μmol, 1 eq, HCl) in MeOH (1.2 mL) was added Pd / C (10%, 0.2 g) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 1 hr. It was filtered and concentrated under reduced pressure to give 66 mg of 17.5 (40%) as a white solid.

[0350] Synthesis of I-17. To a solution of (Z)-hexadec-9-enoic acid (2.1, 80.10 mg, 314.85 μmol, 1 eq) in DMF (1 mL) was added HATU (143.66 mg, 377.83 μmol, 1.2 eq) and DIEA (122.08 mg, 944.56 μmol, 164.53 μL, 3 eq). The mixture was shaken at 20°C for 10 mins. Then the mixture was added to 4-(2-amino-1,1-difluoroethyl)phenol (17.5, 66 mg, 314.85 μmol, 1 eq, HCl). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [water (FA)-ACN]; gradient: 40%-80% B over 8 min) to give 10.20 mg of I-17 (7.9%) as a white solid. (ES, m / z): [M+1]+410.4. I-17:1H NMR (400 MHz, chloroform-d) δ = 7.38 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.21-5.92 (m, 1H), 5.73 (br t, J = 5.6 Hz, 1H), 5.42-5.30 (m, 2H), 3.95 (dt, J = 6.4, 14.2 Hz, 2H), 2.19 (t, J = 7.6 Hz, 2H), 2.07-1.94 (m, 4H), 1.66-1.59 (m, 2H), 1.38-1.18 (m, 16H), 0.95-0.82 (m, 3H)

[0351] Example 17. (Z)-N-(2-(4-hydroxyphenyl)ethyl-1,1,2,2-d4)hexadec-9-enamide

[0352] Synthesis of 18.2. To a solution of 1-(benzyloxy)-4-iodobenzene (16.3, 3.88 g, 12.51 mmol, 1 eq) and methyl propiolate (18.1, 5.26 g, 62.55 mmol, 5.21 mL, 5 eq) in DME (77 mL) was added K2CO3(8.65 g, 62.55 mmol, 5 eq), Pd(PPh3)2Cl2(878.14 mg, 1.25 mmol, 0.1 eq) and CuI (238.27 mg, 1.25 mmol, 0.1 eq). The mixture was stirred at 70°C for 12 hrs under N2atmosphere. The residuewas purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1) to give 2.28 g of 18.2 (62%) as a light yellow oil. (ES, m / z): [M+1]+267.0.

[0353] Synthesis of 18.3. To a solution of methyl 3-(4-(benzyloxy)phenyl)propiolate (18.2, 500 mg, 1.88 mmol, 1 eq) in THF (3 mL) and D2O (15 mL) was added diiodosamarium (0.1 M, 225.32 mL, 12 eq). The mixture was stirred at 25°C for 16 hrs. The reaction mixture was quenched by addition 0.1M HCl (50 mL) at 25°C, diluted with H2O (30 mL) and extracted with ethyl acetate (200 mL x 3). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 0 to 10 / 1) to give 362.1 mg of 18.3 (60%) as a light yellow oil. (ES, m / z): [M+1]+275.2

[0354] Synthesis of 18.4. A mixture of methyl 3-(4-(benzyloxy)phenyl)propanoate-2,2,3,3-d4 (18.3, 262 mg, 947.70 umol, 1 eq), NH3 / MeOH (7 M, 1.5 mL) in NH3.H2O (2.5 mL) was stirred at 80°C for 3 hrs in sealed tube. The reaction mixture was diluted with MTBE (5 mL) and concentrated under reduced pressure to give 102 mg of 18.4 (35%) as a white solid. (ES, m / z): [M+1]+260.0

[0355] Synthesis of 18.5. To a solution of 3-(4-(benzyloxy)phenyl)propanamide (18.4, 242.3 mg, 934.31 μmol, 1 eq)) in THF (3 mL) was added a mixture of NaOH (121.46 mg, 3.04 mmol, 3.25 eq) in H2O (3 mL) and [acetoxy(phenyl)-λ3-iodanyl] acetate (300.94 mg, 934.31 μmol, 1 eq) at 0°C. The mixture was stirred at 25°C for 1 hr. HCl (3M) was added to the mixture with pH = 1-2 and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (5 mL), then HCl (12 M) was added to the organic phase and the precipitate was filtered to give 134.1 mg of 18.5 (61%) as a white solid. (ES, m / z): [M+1]+232.1

[0356] Synthesis of 18.6. To a solution of 2-(4-(benzyloxy)phenyl)ethan-1,1,2,2-d4-1-amine (18.5, 134 mg, 579.27 umol, 1 eq) in MeOH (3 mL) was added a catalytic amount of Pd / C (30 mg, 10% purity). The flask was then purged and filled with an H2(15 Psi) atmosphere at 25°C. The reaction mixture was stirred at 25°C for 2 hrs. The catalyst Pd / C was removed by filtration over celite with MeOH (5 mL x 3) rinsing. The filtrate was concentrated to give 69.7 mg of 18.6 (84%) as a white solid. (ES, m / z): [M+1]+142.1

[0357] Synthesis of I-18. To a solution of (Z)-hexadec-9-enoic acid (2.1, 90.09 mg, 354.10 μmol, 1 eq) in DMF (0.5 mL) was added HATU (161.57 mg, 424.92 μmol, 1.2 eq) and DIEA (228.82 mg, 1.77 mmol, 308.38 μL, 5 eq). 4-(2-aminoethyl-1,1,2,2-d4)phenol (18.6, 50 mg, 354.10 μmol, 1 eq) was added to the above mixture. The mixture was stirred at 25°C for 2 hrs. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (FA)-ACN]; gradient: 55%-90% B over 8 min) to give 36.54 mg of I-18 (27%) as a white solid. I-18:1H NMR (400 MHz, chloroform-d) δ = 7.03 (d, J = 8.4 Hz, 2H), 6.85-6.76 (m, 2H), 5.66-5.43 (m, 1H), 5.43-5.27 (m, 2H), 3.46 (br d, J = 5.6 Hz, 1H), 2.71 (s, 1H), 2.14 (t, J = 7.6 Hz, 2H), 2.07-1.95 (m, 4H), 1.65-1.53 (m, 2H), 1.28 (br s, 16H), 0.89 (t, J = 6.8 Hz, 3H)

[0358] Example 18. N-[2-(4-hydroxyphenyl)ethyl]-14-methyl-pentadecanamide

[0359] Synthesis of 19.2. To a solution of 11-bromoundecanoic acid (19.1, 10 g, 37.71 mmol, 1eq) in Tol. (100 mL) was added PPh3 (10.88 g, 41.48 mmol, 1.1 eq). The flask was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20oC for 2 mins under N2 atmosphere. The resulting mixture was refluxed for 8 hrs. The reaction mixture was filtered to obtain solid, which was dried under vacuum to give 19.50 g of 19.2 (95%) as a white solid. (ES, m / z): [M+1]+447.2.

[0360] Synthesis of 19.4. To a solution of 10-carboxydecyl(triphenyl)phosphonium hydrobromide (19.2, 4 g, 7.57 mmol, 1 eq) in THF (40 mL) was added dropwise LiHMDS (1 M, 20.74 mL, 2.74 eq) at -70°C. The mixture was stirred at 20°C for 1 hr, then a solution of the 3-methylbutanal (19.3, 977.88 mg, 11.35 mmol, 1.25 mL, 1.5 eq) in THF (10 mL) was added dropwise to the mixture at - 70°C. The mixture was stirred at 25°C for 16 hrs. HCl (1M) was added to the mixture with pH = 3-5 and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 5% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give 495 mg of 19.4 (98%) as a yellow oil. (ES, m / z): [M-1]- 254.2.

[0361] Synthesis of 19.5. To a solution of (Z)-14-methylpentadec-11-enoic acid (19.4, 0.4950 g, 1.95 mmol, 1 eq) in THF (10 mL) was added Pd / C (0.5 g, 3.89 mmol, 10% purity, 2 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 1.5 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 556.6 mg of 19.5 (97%) as a white solid. (ES, m / z): [M-1] - 256.2.

[0362] Synthesis of I-19. A mixture of 14-methylpentadecanoic acid (19.5, 100 mg, 389.98 μmol, 1 eq), 4-(2-aminoethyl)phenol (1.1, 74.49 mg, 428.98 μmol, 1.1 eq, HCl), HATU (177.94 mg, 467.98 μmol, 1.2 eq), DIEA (252.01 mg, 1.95 mmol, 339.63 μL, 5 eq) and in DMF (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20°C for 2 hrs under N2atmosphere.The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 65%-95% B over 8.0 min) to give 73.3 mg of I-19 (33%) as a white solid. (ES, m / z): [M+1]+375.3. I-19:1H NMR (400 MHz, chloroform-d) δ = 7.05 (br d, J = 8.0 Hz, 2H), 6.79 (br d, J = 8.4 Hz, 2H), 3.49 (q, J = 6.4 Hz, 2H), 2.75 (br t, J = 6.8 Hz, 2H), 2.13 (br t, J = 7.6 Hz, 2H), 1.65-1.50 (m, 3H), 1.38-1.06 (m, 21H), 0.94-0.80 (m, 6H).

[0363] Example 19. N-(4-hydroxyphenethyl)-15-methylhexadecanamide

[0364] Synthesis of 20.2. To a solution of 12-bromododecanoic acid (20.1, 5.56 g, 19.91 mmol, 1 eq) in Tol. (56 mL) was added PPh3 (5.75 g, 21.90 mmol, 1.1 eq). The mixture was refluxed for 24 hrs. The reaction mixture was concentrated to removed Tol. The crude product was triturated with ethyl acetate at 50°C for 40 mins to give 10.11 g of 20.2 (96%) as a white solid.

[0365] Synthesis of 20.4. To a solution of 11-carboxyundecyl(triphenyl)phosphonium bromide (20.2, 5 g, 9.23 mmol, 1 eq) in THF (50 mL) was added dropwise LiHMDS (1 M, 23.80 mL, 2.58 eq) at -70°C. The mixture was stirred at 20°C for 1 hr, then a solution of the 3-methylbutanal (20.3, 1.19 g, 13.85 mmol, 1.52 mL, 1.5 eq) in THF (10 mL) was added dropwise at -70°C. The mixture was stirred at 20°C for 16 hrs. HCl (1M) was added to the mixture with pH = 3-5 and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 3 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 10% Ethyl acetate / Petroleum ether gradient @ 120 mL / min), according to plate1 to give 2.23 g of 20.4 (89%) as a yellow oil. (ES, m / z): [M-1]- 267.3

[0366] Synthesis of 20.5. To a solution of (Z)-15-methylhexadec-12-enoic acid (20.4, 500 mg, 1.86 mmol, 1 eq) in MeOH (5 mL) was added Pd / C (10%, 0.2 g) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 0.6 g of 20.5 (crude) as a white solid. (ES, m / z): [M-1]- 269.3

[0367] Synthesis of I-20. To a solution of 15-methylhexadecanoic acid (20.5, 150 mg, 554.63 μmol, 1 eq) in DMF (2.5 mL) was added HATU (253.07 mg, 665.56 μmol, 1.2 eq) and DIEA (215.05 mg, 1.66 mmol, 289.82 μL, 3 eq). The mixture was shaken at 20°C for 10 mins. Then the mixture was added to 4-(2-aminoethyl)phenol (1.1, 115.57 mg, 665.56 μmol, 1.2 eq, HCl). The mixture was stirred at 20°C for 16 hrs. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 65%-98% B over 8.0 min) to give 117.7 mg of I-20 (54%) as a white solid. (ES, m / z): [M+1]+390.4. I-20:1H NMR (400 MHz, chloroform-d) δ = 7.05 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.43 (br s, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.64-1.45 (m, 4H), 1.26 (s, 21H), 1.16 (br d, J = 6.8 Hz, 2H), 0.87 (d, J = 6.8 Hz, 6H).

[0368] Example 20. (Z)-1-(4-hydroxyphenethyl)-3-(tetradec-7-en-1-yl)urea

[0369] Synthesis of 22.2. To a solution of 8-bromooctanoic acid (22.1, 10 g, 44.82 mmol, 1 eq) and PPh3(12.93 g, 49.30 mmol, 1.1 eq) in Tol (100 mL) was degassed and purged with N2for 3 times, and then the mixture was refluxed for 12 hrs under N2atmosphere. The organic phase was separated, and the remaining residue was triturated with MTBE at 25°C for 60 mins to give 15 g of 22.2 (73%) as a yellow oil. (ES, m / z): [M+1]+405.3.

[0370] Synthesis of 22.4. To a solution of 7-carboxyheptyl(triphenyl)phosphonium bromide (22.2, 5 g, 10.30 mmol, 1 eq) in THF (50 mL) was added dropwise LiHMDS (1 M, 28.22 mL, 2.74 eq) at -70°C. The mixture was stirred at 25°C for 1 hr, a solution of the heptanal (22.3, 1.76 g, 15.45 mmol, 2.16 mL, 1.5 eq) in THF (10 mL) was added dropwise to the mixture at -70°C. The mixture was stirred at 25°C for 16 hrs. HCl (1M) was added to the mixture with pH = 3-5 and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.37 g of 22.4 (25%) as a white solid. (ES, m / z): [M-1] - 239.2.

[0371] Synthesis of I-22. To a solution of (Z)-pentadec-8-enoic acid (22.4, 400 mg, 1.66 mmol, 1 eq) in dry Tol (10 mL) was added TEA (303.09 mg, 3.00 mmol, 416.90 μL, 1.8 eq) and DPPA (503.73 mg, 1.83 mmol, 395.09 μL, 1.1 eq). The solution was stirred at 70°C for 3 hrs. The solution was kept at 0°C and 4-(2-aminoethyl)phenol (22.5, 228.27 mg, 1.66 mmol, 1 eq) was added. The mixture was stirred at 20°C for 12 hrs. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 45%-85% B over 8.0 min) to give 180 mg of I-22 (28%) as a white solid. (ES, m / z): [M+1]+375.5. I-22:1H NMR (400 MHz, chloroform-d) δ = 7.06-7.00 (m, J = 8.4 Hz, 2H), 6.82-6.74 (m, J = 8.4 Hz, 2H), 5.41-5.29 (m, 2H), 4.35 (br s, 1H), 4.25 (br s, 1H), 3.40 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.09-1.94 (m, 4H), 1.54-1.39 (m, 2H), 1.39-1.22 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H)

[0372] Example 21. N-[2-(4-hydroxyphenyl)ethyl]-13-methyl-tetradecanamide

[0373] Synthesis of 23.2. To a solution of10-bromodecanoic acid (23.1, 10 g, 39.82 mmol, 1 eq) and PPh3(11.49 g, 43.80 mmol, 1.1 eq) in Tol. (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25oC for 2 mins under N2atmosphere. The resulting mixture was refluxed for 48 hrs. The reaction liquid is filtered to obtain solid, which was dried under vacuum to give 19.50 g of 23.2 (88%) as a white solid. (ES, m / z): [M+1]+433.2.

[0374] Synthesis of 23.4. To a solution of 9-carboxynonyl(triphenyl)phosphonium bromide (23.2, 5 g, 9.74 mmol, 1 eq) in THF (50 mL) was added dropwise LiHMDS (1 M, 24.35 mL, 2.5 eq) at - 70°C. Then the mixture was stirred at 25°C for 1 hr, a solution of the 3-methylbutanal (23.3, 1.26 g, 14.61 mmol, 1.60 mL, 1.5 eq) in THF (10 mL) was added dropwise at -70°C. The mixture was stirred at 25°C for 16 hrs. HCl (1M) was added to the mixture with pH = 3-5 and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 5% Ethylacetate / Petroleum ether gradient @ 40 mL / min) to give 1.78 g of 23.4 (99%) as a yellow oil. (ES, m / z): [M-1]- 240.2.

[0375] Synthesis of 23.5. To a solution of (Z)-13-methyltetradec-10-enoic acid (23.4, 1.78 g, 7.4 mmol, 1 eq) in MeOH (18 mL) was added Pd / C (500 mg, 74.00 mmol, 10% purity, 10 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(14.92 mg, 7.40 mmol, 1 eq) at 25°C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give 1.66 g of 23.5 (92%) as a white solid. (ES, m / z): [M-1]- 242.2.

[0376] Synthesis of 1-23. To a solution of 13-methyltetradecanoic acid (23.5, 200 mg, 825.10 μmol, 1 eq) in DMF (2.5 mL) was added HATU (409.60 mg, 990.11 μmol, 1.2 eq) and DIEA (319.91 mg, 2.48 mmol, 431.15 μL, 3 eq). The mixture was stirred at 20°C for 10 mins. Then the mixture was added to 4-(2-aminoethyl)phenol (1.1, 157.60 mg, 907.60 μmol, 1.1 eq, HCl). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 65%-95% B over 8.0 min) to give 119.38 mg of 23 (40%) as a white solid. (ES, m / z): [M+1]+361.3. I-23:1H NMR (400 MHz, chloroform-d) δ = 7.02 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.76 (br d, J = 11.2 Hz, 1H), 5.56 (br s, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.14 (t, J = 7.6 Hz, 2H), 1.65-1.56 (m, 2H), 1.52 (td, J = 6.8, 13.3 Hz, 1H), 1.25 (s, 16H), 1.19-1.11 (m, 2H), 0.87 (d, J = 6.8 Hz, 6H).

[0377] Example 22. (Z)-N-phenethyloctadec-11-enamide

[0378] Synthesis of I-24. To a solution of (Z)-octadec-11-enoic acid (24.1, 150 mg, 531.05 μmol, 1 eq) in DCM (2 mL) was added HATU (242.30 mg, 637.26 μmol, 1.2 eq) at 20°C. Then DIPEA (205.90 mg, 1.59 mmol, 277.50 μL, 3 eq) was added and the mixture was stirred at this temperature for 30 mins and then 2-phenylethan-1-amine (21.2, 77.22 mg, 637.26 μmol, 80.02 μL, 1.2 eq) was added at 20°C. The resulting mixture was stirred at 20°C for 12 hrs. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 75%- 95% B over 8.0 min) to give 30.57 mg of I-24 (14%) as a white solid. (ES, m / z): [M+1]+386.5. I-24:1H NMR (400 MHz, chloroform-d) δ = 7.35-7.29 (m, 2H), 7.26-7.17 (m, 3H), 5.43-5.30 (m, 3H), 3.57-3.50 (m, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H), 2.02 (q, J = 6.4 Hz, 4H), 1.63-1.58 (m, 2H), 1.35-1.24 (m, 20H), 0.93-0.85 (m, 3H).

[0379] Example 23. N-(4-hydroxyphenethyl)-15-methylhexadecanamide

[0380] Synthesis of I-25. To a solution of (Z)-octadec-11-enoic acid (24.1, 150 mg, 531.05 μmol, 1 eq) in DCM (2 mL) was added HATU (242.30 mg, 637.26 μmol, 1.2 eq) at 20°C. DIPEA (205.90 mg, 1.59 mmol, 277.49 μL, 3 eq) was added to the mixture and stirred at this temperature for 30 mins and then 4-(2-aminoethyl)phenol (1.1, 110.65 mg, 637.26 μmol, 1.2 eq, HCl) was added at 20°C. The resulting mixture was stirred at 20°C for 4 hrs. The residue was purified by prep-HPLC (H2O (0.2% FA)-ACN]; gradient: 75%-95% B over 8.0 min) to give 53.62 mg of I-25 (25%) as a white solid. (ES, m / z): [M+1]+402.4. I-25:1H NMR (400 MHz, chloroform-d) δ = 7.10-7.02 (m, J = 8.4 Hz, 2H), 6.82- 6.76 (m, J = 8.4 Hz, 2H), 5.39 (br d, J = 3.6 Hz, 1H), 5.38-5.34 (m, 2H), 5.13-4.70 (m, 1H), 3.53-3.45 (m, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H), 2.06-1.97 (m, 4H), 1.59-1.58 (m, 1H), 1.63- 1.58 (m, 1H), 1.36-1.24 (m, 20H), 0.97-0.81 (m, 3H).

[0381] Examples 24 & 25. (Z)-N-(4-hydroxyphenethyl)pentadec-8-ene-1-sulfonamide and (E)-N-(4-hydroxyphenethyl)pentadec-8-ene-1-sulfonamide

[0382] Synthesis of 26.2. To a solution of 8-bromooctan-1-ol (26.1, 4 g, 19.13 mmol, 3.28 mL, 1 eq) in DCM (40 mL) was added DMP (9.74 g, 22.95 mmol, 1.2 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction was quenched by addition of aq.NaHCO3 (90 mL) and extractedwith DCM (3 x 60 mL). The combined organics were washed with aq.Na2SO3 (50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 100 / 1 to 3 / 1) to give 2.7 g of 26.2 (68%) as a colourless oil.

[0383] Synthesis of 26.4. To a solution of heptyl(triphenyl)phosphonium bromide (26.3, 7.48 g, 16.95 mmol, 1.3 eq) in THF (35 mL) was added dropwise LiHMDS (1 M, 19.56 mL, 1.5 eq) at -78°C for 10 mins. After addition, the mixture was stirred at this temperature for 90 mins and then 8- bromooctanal (26.2, 2.7 g, 13.04 mmol, 1 eq) in THF (27 mL) was added dropwise at -78°C. The resulting mixture was stirred at 20°C for 12 hrs. HCl (1M) was added to the mixture with pH = 3 ~ 5. The aqueous phase was extracted with ethyl acetate (80 mL x 5). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give 2.5 g of 26.4 (66%) as a white solid.

[0384] Synthesis of 26.5. A solution of (Z)-15-bromopentadec-7-ene (26.4, 0.5 g, 1.73 mmol, 1 eq) in H2O (15 mL) and EtOH (7.5 mL) was refluxed for 12 hrs. The reaction mixture was allowed to cool to 20°C and was diluted with DCM (17 mL) and water (17 mL). Tetrabutylammonium bisulfate (645.51 mg, 1.90 mmol, 1.1 eq) and NaOH (69.13 mg, 1.73 mmol, 1 eq) were added subsequently and the reaction mixture was stirred at 20°C for 10 mins. The organic layer was separated, dried and concentrated to give 1.1 g of crude, then to the solution of the crude in DCM (7 mL) was added triphosgene (256.44 mg, 864.17 μmol, 0.5 eq) 3 portions at 0°C, the mixture was stirred at 20°C for 72 hrs. Then Triphosgene (256.44 mg, 864.17 μmol, 0.5 eq) in DCM (7 mL) was added to the mixture portions at 0°C. The mixture was stirred at 20°C for 24 hrs. The reaction mixture was concentrated to give a residue oil. The residue was purified by flash silica gel chromatography (ISCO®; 1 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 1% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 0.38 g of 26.5 (71%) as a colourless oil.

[0385] Synthesis of I-26 & I-27. To a solution of 4-(2-aminoethyl)phenol (1.1, 53.96 mg, 310.77 μmol, 1.2 eq, HCl) in DMF (1 mL) was added TEA (78.62 mg, 776.93 μmol, 108.14 μL, 3 eq) and (Z)-pentadec-8-ene-1-sulfonyl chloride (26.5, 80 mg, 258.98 μmol, 1 eq). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue.

[0386] The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 55%-80% B over 8.0 min) to give 15.13 mg of I-26 (14%) and 3.88 mg of I-27 (3.4%) as a purple solid. I-26:1H NMR (400 MHz, chloroform-d) δ = 7.12-7.05 (m, J = 8.4 Hz, 2H), 6.83-6.77 (m, J = 8.4 Hz, 2H), 5.41-5.31 (m, 2H), 4.66 (s, 1H), 4.03 (br t, J = 6.4 Hz, 1H), 3.35 (q, J = 6.6 Hz, 2H), 2.95-2.87 (m, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.02 (q, J = 6.4 Hz, 4H), 1.75-1.66 (m, 2H), 1.38-1.24 (m, 16H), 0.94-0.85 (m, 3H). I-27:1H NMR (400 MHz, chloroform-d) δ = 7.11-7.06 (m, J = 8.4 Hz, 2H), 6.82-6.78 (m, J = 8.4 Hz, 2H), 5.39 (br t, J = 5.6Hz, 2H), 4.64 (s, 1H), 4.02 (br t, J = 6.4 Hz, 1H), 3.35 (q, J = 6.4 Hz, 2H), 2.94-2.88 (m, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.00-1.93 (m, 4H), 1.74-1.66 (m, 2H), 1.39-1.24 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H).

[0387] Example 26. (Z)-4-(2-((4-(tridec-6-en-1-yl)pyrimidin-2-yl)amino)ethyl)phenol

[0388] Synthesis of 29.2. To a solution of hex-5-yn-1-ol (29.17.85 g, 79.99 mmol, 1 eq) in THF (267 mL) was added NaH (4.80 g, 119.98 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 1 hr, then BnBr (13.68 g, 79.99 mmol, 9.50 mL, 1 eq) was added, the mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition NH4Cl (250 mL) at 20°C, and then extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layers were washed with brine 250 mL, dried over Na2SO4filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 15 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 14.32 g of 29.2 (95%) as a light yellow oil.

[0389] Synthesis of 29.3. To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.52 g, 74.36 mmol, 10.79 mL, 2 eq) and ((hex-5-yn-1-yloxy)methyl)benzene (29.2, 7 g, 37.18 mmol, 1 eq) was added BH3.THF (1 M, 3.72 mL, 0.1 eq). The mixture was stirred at 20°C for 48 hrs. The reaction mixture was quenched by addition MeOH 5 mL at 20°C, then diluted with water 15 mL and extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layers were washed with brine 20 mL,dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 11 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 4% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 5 g of 29.3 (42%) as a colorless oil.

[0390] Synthesis of 29.4. To a solution of (E)-2-(6-(benzyloxy)hex-1-en-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (29.3, 5 g, 15.81 mmol, 1 eq) in methanol (50 mL) was added Pd / C (10%, 1 g) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 48 hrs. The reaction mixture was filtered and concentrated under reduced pressure to residue which was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 2.9 g of 29.4 (80%) as a colorless oil.

[0391] Synthesis of 29.5. To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)hexan-1-ol (29.4, 1.4 g, 6.14 mmol, 1 eq) in dichloromethane (35 mL) was added DMP (3.12 g, 7.36 mmol, 1.2 eq)at 0°C for 5 mins. The mixture was stirred at 20°C for 30 mins. The reaction mixture was quenched by addition aq. NaHCO330mL and aq. Na2SO330 mL to adjust pH > 7 at 0°C, then extracted with dichloromethane 90 mL (30 mL x 3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 15 / 1) to give 1.18 g of 29.5 (85%) as a light yellow oil.

[0392] Synthesis of 29.7. To a solution of heptyltriphenylphosphonium bromide (29.6, 2.03 g, 4.60 mmol, 1.3 eq) in THF (20 mL) was added dropwise LiHMDS (1 M, 5.31 mL, 1.5 eq) at -70°C and stirred at 20°C for 1 hr, a solution of the 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanal (29.5, 0.8 g, 3.54 mmol, 1 eq) in THF (4 mL) was added dropwise at -70°C. The mixture was stirred at 20°C for 16 hrs. HCl (1M) was added to the mixture with pH = 3-5 and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0) to give 0.94 g of 29.7 (86%) as a colorless oil.

[0393] Synthesis of 29.7A. To a solution of (Z)-4,4,5,5-tetramethyl-2-(tridec-6-en-1-yl)- 1,3,2-dioxaborolane (29.7, 200 mg, 648.71 μmol, 1 eq) in acetone (4.32 mL) and H2O (2.16 mL) were added ammonium acetate (175.01 mg, 2.27 mmol, 3.5 eq) and sodium periodate (430.13 mg, 2.01 mmol, 111.43 μL, 3.1 eq). The suspension was stirred at 20°C for 16 hrs. Then the suspension was stirred at 40°C for 4 hrs. The reaction mixture was diluted with H2O 30 mL and extracted with ethyl acetate 60 mL (20 mL x 3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.15 g of 29.7A (crude) as a colorless oil.

[0394] Synthesis of I-29. To a mixture of (Z)-tridec-6-en-1-ylboronic acid (29.7A, 0.15 g, 663.24 μmol, 1 eq) and 4-(2-((4-bromopyrimidin-2-yl)amino)ethyl)phenol (29.8, 195.09 mg, 663.24μmol, 1 eq) in Tol. (10 mL) and H2O (2 mL) was added K3PO4 (422.35 mg, 1.99 mmol, 3 eq) followed by the addition of cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium iron (54.16 mg, 66.32 μmol, 0.1 eq). The reaction was stirred at 100°C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with water 30 mL and extracted with ethyl acetate 75 mL (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by rep-HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 40%-80% B over 8.0 min) to give 18.15 mg of I-29 (34%) as a white solid. (ES, m / z): [M+1]+396.3. I-29:1H NMR (400 MHz, chloroform-d) δ = 8.16 (br d, J = 5.2 Hz, 1H), 7.09-7.03 (m, J = 8.4 Hz, 2H), 6.75-6.69 (m, J = 8.4 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 5.41-5.29 (m, 2H), 5.11 (br s, 1H), 3.66 (q, J = 6.4 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.60-2.51 (m, 2H), 2.08-1.95 (m, 4H), 1.74-1.63 (m, 2H), 1.39-1.26 (m, 12H), 0.92-0.85 (m, 3H).

[0395] Example 27. (S)-N-(4-hydroxyphenethyl)-14-methylhexadecanamide

[0396] Synthesis of 30.2. To a solution of dodecane-1,12-diol (30.1, 10 g, 49.42 mmol, 1 eq) in Tol. (60 mL) and DMF (10 mL) was added BnBr (9.30 g, 54.37 mmol, 6.46 mL, 1.1 eq) and Ag2O (17.18 g, 74.14 mmol, 1.5 eq). The mixture was stirred at 110°C for 16 hrs. The reaction mixture was extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 4% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 5.77 g of 30.2 (39%) as a colorless oil.

[0397] Synthesis of 30.3. To a solution of 12-benzyloxydodecan-1-ol (30.2, 5.77 g, 19.73 mmol, 1 eq) in DCM (60 mL) was added dropwise DMP (10.04 g, 23.68 mmol, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. The reaction was quenched by addition of aq.NaHCO3 (150 mL) and extracted with DCM (3 x 100 mL). The combined organics were washed with aq.Na2SO3 (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 3% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 4.32 g of 30.3 (75%) as a yellow oil.

[0398] Synthesis of 30.5. To a solution of [(2S)-2-methylbutyl]-triphenyl-phosphonium iodide (30.4, 1 g, 2.17 mmol, 1 eq) in THF (10 mL) was added dropwise NaHMDS (1 M, 4.34 mL, 2 eq) at -70°C and stirred at -70°C for 1 hr, a solution of the 12-benzyloxydodecanal (30.3, 1.89 g, 6.52 mmol, 3 eq) in THF (2 mL) was added dropwise to the mixture at -70°C. The mixture was stirred at 25°C for 16 hrs. The mixture was quenched by aq.NH4Cl (10 ml) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 2% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 420 mg of 30.5 (56%) as a colorless oil.

[0399] Synthesis of 30.6. To a solution of (S,Z)-(((14-methylhexadec-12-en-1- yl)oxy)methyl)benzene (30.5, 200 mg, 580.43 μmol, 1 eq) in MeOH (10 mL) was added Pd / C (6.18 g, 5.80 mmol, 10% purity, 10 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(1.17 mg, 580.43 μmol, 1 eq) at 25°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 160 mg of 30.6 (crude) as a colorless oil.

[0400] Synthesis of 30.7. To a solution of (14S)-14-methylhexadecan-1-ol (30.6, 160 mg, 623.87 μmol, 1 eq) in acetone (5 mL)was added dropwise Jones reagent (2.7 M, 231.06 μL, 1 eq) at 0°C until the color of the mixture became dark green to orange for 2 hrs. Then 2-propanol was added dropwise until the color of the mixture returned to dark green at 25°C. The mixture was quenched by aq.NH4Cl (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 200 mg of 30.7 (crude) as a yellow oil.

[0401] Synthesis of I-30. A mixture of (14S)-14-methylhexadecanoic acid (30.7, 200 mg, 739.51 μmol, 1 eq), HATU (337.42 mg, 887.41 μmol, 1.2 eq), HOBt (119.91 mg, 887.41 μmol, 1.2 eq) and DIEA (286.72 mg, 2.22 mmol, 386.42 μL, 3 eq) in dry DMF (5 mL) was stirred at 25°C for 30 mins. Then 4-(2-aminoethyl)phenol (1.1, 154.09 mg, 887.41 μmol, 1.2 eq, HCl) was added to the reaction. The mixture was stirred at 25°C for 16 hrs. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WatersXbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 70%- 98% B over 8.0 min) to give 79.95 mg of I-30 (27%) as a white solid. (ES, m / z): [M-1]–388.1. I-30:1H NMR (400 MHz, methanol-d4) δ = 7.02 (d, J = 8.4 Hz, 2H), 6.72-6.68 (m, 2H), 3.36-3.32 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.61-1.52 (m, 2H), 1.34-1.26 (m, 20H), 1.23-1.03 (m, 3H), 0.90-0.83 (m, 6H).

[0402] Example 28. N-phenethyloctanamide

[0403] Synthesis of I-33. To a solution of 2-phenylethan-1-amine (21.2, 745.00 mg, 6.15 mmol, 772.02 μL, 2 eq) in DCM (5 mL) was added TEA (622.11 mg, 6.15 mmol, 855.72 μL, 2 eq) and octanoyl chloride (33.1, 0.5 g, 3.07 mmol, 524.66 μL, 1 eq) at 0°C. The mixture was stirred at 20°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 45%-80% B over 8.0 min) to give 537.80 mg of I-33 (70%) as a white solid. (ES, m / z): [M+1]+248.3. I-33:1H NMR (400 MHz, chloroform-d) δ = 7.35-7.29 (m, 2H), 7.26-7.17 (m, 3H), 5.39 (br s, 1H), 3.54 (q, J = 6.8 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H), 1.63-1.55 (m, 2H), 1.28 (br s, 8H), 0.89 (t, J = 6.8 Hz, 3H).

[0404] Examples 29 & 30. (R)-4-(2-((1,1,1-trifluoroheptadecan-2-yl)amino)ethyl)phenol and (S)-4-(2-((1,1,1-trifluoroheptadecan-2-yl)amino)ethyl)phenol

[0405] Synthesis of 34.6. To the solution of 2-(4-benzyloxyphenyl)ethanol (34.6a, 7 g, 30.66 mmol, 1 eq) in DCM (70 mL) was added DMP (15.61 g, 36.80 mmol, 1.2 eq), and the mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition of aq.NaHCO3 (300 mL) and aq.Na2S2O3 (200 mL), and diluted with water (200 mL) at 20°C, extracted with DCM (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20 ~ 30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 2.88 g of 34.6 (41%) as a yellow oil.

[0406] Synthesis of 34.2. To a solution of hexadecanal (34.1, 4 g, 16.64 mmol, 1 eq) in THF (50 mL) was added trimethyl(trifluoromethyl)silane (3.08 g, 21.63 mmol, 1.3 eq) at 20°C. The mixture was stirred at 0°C for 10 mins. Then tetrabutylammonium fluoride trihydrate (52.49 mg, 166.37 umol, 0.01 eq) was added dropwise at 0°C. The mixture was stirred at 20°C for 6 hrs. The reaction mixture was cooled to 0°C, then H2O (1.65 g, 91.51 mmol, 1.65 mL, 5.5 eq) and tetrabutylammonium fluoride trihydrate (524.92 mg, 1.66 mmol, 0.1 eq) was added to the reaction. The mixture was stirred at 20°C for16 hrs. The mixture was concentrated afford the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give 3.02 g of 34.2 (58%) as a colorless oil.

[0407] Synthesis of 34.3. A solution of 1,1,1-trifluoroheptadecan-2-ol (34.2, 3.02 g, 9.73 mmol, 1 eq) and Py (923.40 mg, 11.67 mmol, 942.25 uL, 1.2 eq) in DCM (20 mL) was cooled to 0°C, then trifluoromethylsulfonyl trifluoromethanesulfonate (3.02 g, 10.70 mmol, 1.77 mL, 1.1 eq) was added. The reaction mixture was stirred at 20°C for 16 hrs. The organic phase was washed with water and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 1 ~ 7% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give 3.5 g of 34.3 (81%) as a colorless oil.

[0408] Synthesis of 34.4. To a mixture of 1,1,1-trifluoroheptadecan-2-yl trifluoromethanesulfonate (34.3, 2.5 g, 5.65 mmol, 1 eq) in DMSO (20 mL) was added NaN3(752.94 mg, 11.58 mmol, 2.05 eq) at 20°C under N2. The mixture was stirred at 40°C for 5 hrs. The mixture was cooled to 20°C and poured into a saturated aq.NaHCO3(20 mL) and H2O (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 1.73 g of 34.4 (91%) as a colorless oil.

[0409] Synthesis of 34.5. To a solution of 2-azido-1,1,1-trifluoro-heptadecane (34.4, 1.73 g, 5.16 mmol, 1 eq) and HCl (522.33 mg, 5.16 mmol, 512.09 μL, 36% purity, 1 eq) in MeOH (17 mL), THF (17 mL) was added Pd / C (0.5 g, 51.57 mmol, 10% purity, 10 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 1.72 g of 34.5 (HCl, 96%) as a colorless oil.

[0410] Synthesis of 34.7. A mixture of 1,1,1-trifluoroheptadecan-2-amine (34.5, 950 mg, 2.75 mmol, 1 eq, HCl) and 2-(4-(benzyloxy)phenyl)acetaldehyde (34.6, 1.86 g, 8.24 mmol, 3 eq) in THF (10 mL) was stirred at 20°C for 1 hr. Then NaBH(OAc)3(1.75 g, 8.24 mmol, 3 eq) was added to the above reaction. The resulting mixture was stirred at 20°C for 16 hrs. The reaction mixture was partitioned in ethyl acetate (15 mL x 3) and a saturated aq.NaHCO3 (20 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 3 ~ 4% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 970 mg of 34.7 (crude) as a colorless oil. (ES, m / z): [M+1]+520.4.

[0411] Synthesis of 34.8. To a solution of N-(4-(benzyloxy)phenethyl)-1,1,1- trifluoroheptadecan-2-amine (34.7, 500 mg, 962.05 μmol, 1 eq) in THF (5 mL) was added Pd / C (0.3 g,9.62 mmol, 10% purity, 10 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, Petroleum ether / Ethyl acetate = 5 / 1) to give 240 mg of 34.8 (58%) as a colorless oil. (ES, m / z): [M+1]+430.4

[0412] Synthesis of 34.9. A mixture of N-(4-hydroxyphenethyl)-4-nitro-N-(1,1,1- trifluoroheptadecan-2-yl)benzenesulfonamide (34.8, 270 mg, 628.49 μmol, 1 eq), 4-nitrobenzenesulfonyl chloride (417.85 mg, 1.89 mmol, 3 eq) and Py (59.66 mg, 754.19 μmol, 60.87 μL, 1.2 eq) in DCM (3 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 20°C for 16 hrs under N2 atmosphere. The residue was diluted with 1M HCl (2 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 300 mg of 34.9 (77%) as a yellow solid. (ES, m / z): [M+1]+615.4

[0413] Synthesis of 34.9A & 34.9B. 300 mg of 34.9 (mixture of 2 peaks) was separated by SFC twice to give 120 mg of 34.9A (31 %, ee value: 100 %, Peak 1) and 100 mg of 34.9B (25 %, ee value: 98.8 %, Peak 2) as white solids.

[0414] SFC separation methods:

[0415] Method 1: Instrument: Waters SFC150AP preparative SFC; Column: DAICEL CHIRALPAK AD (250 mm*30 mm,10 um); Mobile phase: A for CO2and B for MeOH; Gradient: B% = 35% isocratic elution mode; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 40°C； System back pressure: 100 bar.

[0416] Synthesis of I-34. To a solution of rel-(R)-N-(4-hydroxyphenethyl)-4-nitro-N-(1,1,1- trifluoroheptadecan-2-yl)benzenesulfonamide (34.9A, 100 mg, 162.67 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (44.96 mg, 325.33 μmol, 2 eq) and PhSH (53.77 mg, 488.00 μmol, 49.88 μL, 3 eq). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by aq. NaClO (2 mL). The residue was diluted with brine (3 mL) and extracted with ethyl acetate 9 mL (3 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 5 / 1) to give 60 mg of I-34 (crude) and the crude residue was purified by prep-HPLC (column: Xselect CSH C18100*30mm*5um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 55%-95% B over 10.0 min) to give 28.37 mg of I-34 (40%) as a yellow oil. (ES, m / z): [M+1]+430.4. I-34:1H NMR (400 MHz, chloroform-d) δ = 7.09 (d, J = 8.4 Hz, 2H), 6.82-6.73 (m, 2H), 3.13-3.01 (m, 1H), 3.00-2.80 (m, 2H), 2.72 (m, 2H), 1.70-1.59 (m, 1H), 1.45-1.19 (m, 27H), 0.89 (t, J = 6.8 Hz, 3H)

[0417] Synthesis of I-35. To a solution of rel-(R)-4-(2-((1,1,1-trifluoroheptadecan-2- yl)amino)ethyl)phenol (34.9B, 100 mg, 162.67 μmol, 1 eq) in DMF (1 mL) was added PhSH (53 mg, 481.05 μmol, 49.17 μL, 2.96 eq) and K2CO3(44.96 mg, 325.33 μmol, 2 eq). The mixture was stirred at20°C for 16 hrs. The reaction mixture was quenched by aq. NaClO (2 mL). The residue was diluted with brine (2 mL) and extracted with ethyl acetate 9 mL (3 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C1880*40mm*3um; mobile phase: [H2O (0.04%HCl)-ACN]; gradient: 55%-95% B over 8.0 min) to give 38.84 mg of I-35 (57%) as a white solid. (ES, m / z): [M+1]+430.4. I-35:1H NMR (400 MHz, chloroform-d) δ = 7.09 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.68-4.49 (m, 1H), 3.12-3.03 (m, 1H), 2.98-2.82 (m, 2H), 2.79-2.65 (m, 2H), 1.66-1.61 (m, 1H), 1.37 (br d, J = 6.4 Hz, 1H), 1.27 (m, 26H), 0.89 (br t, J = 6.8 Hz, 3H).

[0418] Example 31. N-(4-hydroxyphenethyl)hexanamide

[0419] Synthesis of I-36. To a solution of 4-(2-aminoethyl)phenol (1.1, 1.29 g, 7.43 mmol, 2 eq, HCl) in DCM (10 mL) was added TEA (751.76 mg, 7.43 mmol, 1.03 mL, 2 eq), then hexanoyl chloride (36.1, 500 mg, 3.71 mmol, 518.67 μL, 1 eq) was added to the mixture at 0°C. The mixture was stirred at 20°C for 1 hr. The mixture was diluted with water (30 mL) and DCM (30 mL). The aqueous layer was separated and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to dryness to provide a white solid. The residue was purified by prep-HPLC (FA condition: column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)- ACN]; gradient: 20%-50% B over 8.0 min.) to give 11.21 mg of I-36 (1.2%) as a white solid. (ES, m / z): [M+1]+236.2. I-36:1H NMR (400 MHz, DMSO-d6) δ = 9.28-9.07 (m, 1H), 7.80 (br t, J = 5.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 3.22-3.11 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.01 (t, J = 7.6 Hz, 2H), 1.45 (quin, J = 7.6 Hz, 2H), 1.32-1.12 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H)

[0420] Example 32. (S)-N-(4-hydroxyphenethyl)-4-methylhexanamide

[0421] Synthesis of 39.2. A solution of (S)-4-methylhexan-1-ol (39.2, 300 mg, 2.58 mmol, 1 eq) in acetone (3 mL) was added to dropwise Jones reagent at 0°C until the color of the mixture became dark green to orange for 10 mins. 2-propanol was added dropwise until the color of the mixture returned to dark green. The mixture was poured into 3 mL of water, and extracted with ethyl acetate (5mL x 3). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 50 / 1 to 1 / 1) to give 120 mg of 39.2 (28%) as a colourless oil.

[0422] Synthesis of 39.3. Oxalyl chloride (107.25 mg, 844.96 μmol, 73.97 μL, 1.1 eq) was added to a solution of (S)-4-methylhexanoic acid (39.2, 100 mg, 768.14 μmol, 1 eq) and DMF (2.81 mg, 38.41 μmol, 2.95 μL, 0.05 eq) in DCM (2 mL) at 0°C under N2 atmosphere. The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was used to next step directly.

[0423] Synthesis of I-39. 4-(2-aminoethyl)phenol (1.1, 146.72 mg, 844.96 μmol, 1.1 eq, HCl) was added to a solution of NaOH (107.54 mg, 2.69 mmol, 3.5 eq) in H2O (2 mL) at 0°C until the solution was clear. Then the above prepared (4S)-4-methylhexanoyl chloride (39.3, 114.17 mg, 768.15 μmol, 1 eq) was added dropwise to the mixture while maintaining inner temperature at 0-5°C. The reaction solution becomes turbid from clear solution. Then the mixture was stirred at 20°C for 0.5 hr. The reaction mixture was extracted with DCM (3 mL x 2). The residue was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 25%-60% B over 8.0 min) to give 74.4 mg of I-39 (38%) as a white solid. (ES, m / z): [M+1]+250.2. I-39:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.79 (br t, J = 5.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.23-3.12 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.10-1.95 (m, 2H), 1.56-1.44 (m, 1H), 1.34-1.19 (m, 3H), 1.16-1.04 (m, 1H), 0.87-0.76 (m, 6H)

[0424] Example 33. (S)-N-(1-hydroxy-3-(4-hydroxyphenyl)propan-2-yl)decanamide

[0425] Synthesis of I-40. To a solution of (S)-4-(2-amino-3-hydroxypropyl)phenol (40.2, 640.76 mg, 3.15 mmol, 2eq, HCl) in DCM (6 mL) was added TEA (318.36 mg, 3.15 mmol, 437.91 μL, 2 eq) at 0°C. A solution of decanoyl chloride (32.1, 300 mg, 1.57 mmol, 326.44 μL, 1 eq) in DCM (3 mL) was added dropwise at 0°C, the mixture was stirred at 0°C for 0.5 hr. Then the mixture was stirred at 20°C for 1.5 hrs. The residue was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 30%-65% B over 8.0 min) to give 119.32 mg of I-40 (23%) as a white solid. (ES, m / z): [M+1]+322.3. I-40:1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 7.52 (br d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.68 (t, J = 5.2 Hz, 1H), 3.80 (br d, J = 5.6 Hz, 1H), 3.31-3.28 (m, 1H), 3.27-3.20 (m, 1H), 2.76-2.64 (m, 1H), 2.47-2.41 (m, 1H), 1.98 (t, J = 7.2 Hz, 2H), 1.47-1.33 (m, 2H), 1.30-1.10 (m, 12H), 0.86 (br t, J = 6.8 Hz, 3H)

[0426] Example 34. N-(4-hydroxyphenethyl)-5-methylhexanamide

[0427] Synthesis of 41.2. To a solution of 5-methylhexanoic acid (41.1, 0.52 g, 3.99 mmol, 1 eq) in DCM (5 mL) was added oxalyl dichloride (760.48 mg, 5.99 mmol, 524.47 μL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture of 41.2 (crude) was used directly as a yellow oil.

[0428] Synthesis of I-41. To a solution of NaOH (476.32 mg, 11.91 mmol, 3 eq) in H2O (6 mL) was added 4-(2-aminoethyl)phenol (22.5, 544.54 mg, 3.97 mmol, 1 eq) and 5-methylhexanoyl chloride (41.2, 590 mg, 3.97 mmol, 1 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was diluted with H2O 20mL and extracted with ethyl acetate 60 mL (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C1880 * 40 mm * 3 um; mobile phase: [H2O (0.2%FA) ACN]; gradient: 10%-50% B over 10.0 min) to give 251.84 mg of I-41 (25%) as a colourless oil. (ES, m / z): [M+1]+250.2. I-41:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (br t, J = 5.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.68-6.63 (m, 2H), 3.22-3.14 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.00 (t, J = 7.6 Hz, 2H), 1.53-1.41 (m, 3H), 1.13-1.05 (m, 2H), 0.84 (d, J = 6.8 Hz, 6H).

[0429] Example 35.8-((1R,2S)-2-hexylcyclopropyl)-N-(4-hydroxyphenethyl)octanamide

[0430] Synthesis of 43.1. A solution of (Z)-hexadec-9-enoic acid (2.1, 5 g, 19.65 mmol, 1 eq) and DMF (71.82 mg, 982.68 μmol, 75.60 μL, 0.05 eq) in DCM (50 mL) at 0°C under N2 atmosphere. Oxalyl chloride (2.74 g, 21.62 mmol, 1.89 mL, 1.1 eq) was added dropwise to the above mixture maintained inner temperature 0-5°C. The mixture was stirred at 25°C for 0.5 hr. The reaction mixture of (Z)-hexadec-9-enoyl chloride (100%) was used directly as a colourless oil. (1R)-1-phenylethanol (3.60 g, 29.47 mmol, 3.56 mL, 1.5 eq) was added to a solution of pyridine (7.77 g, 98.22 mmol, 7.93 mL, 5 eq) in DCM (40 mL) at 0°C until the solution was clear. The above prepared (Z)-hexadec-9-enoyl chloride (5.36 g, 19.64 mmol, 1 eq) was added dropwise to the mixture while maintaining inner temperature at 0- 5°C. The reaction solution becomes turbid from clear solution. Then the mixture was stirred at 25°C for 0.5 hr. The reaction mixture was diluted with H2O (20 mL), the phases were separated. The water phases were extracted with DCM (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 5 to 100 / 15) to give 6.17 g of 43.1 (87%) as a yellow oil.

[0431] Synthesis of 43.2. To a solution of diiodomethane (6.57 g, 24.54 mmol, 1.98 mL, 4.4 eq) in DCM (20 mL) was added diethylzinc (1 M, 12.27 mL, 2.2 eq) at 0℃. The mixture was stirred at 0℃ for 10 mins. A solution of (R)-1-phenylethyl (Z)-hexadec-9-enoate (43.1, 2 g, 5.58 mmol, 1 eq) in DCM (10 mL) was added to the previous solution. The mixture was stirred at 25℃ for 16 hrs. The reaction mixture was diluted with aq.NH4Cl (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 3 to 100 / 8) to give 1.9 g of 43.2 (91%) as a colourless oil.

[0432] Synthesis of 43.3A. To a solution of (R)-1-phenylethyl 8-((1R,2S)-2- hexylcyclopropyl)octanoate (43.2, 80 mg, 214.72 μmol, 1 eq) in THF (2 mL) was added Pd / C (540.00 mg, 37.59 μmol, 10% purity, 1.75e-1 eq). The mixture was stirred at 25°C for 2 hrs. The catalyst Pd / C was removed by filtration over celite with THF (3mL x 3) rinsing. The reaction mixture was filtered and concentrated under reduced pressure to give 47 mg of 43.3A (81%) as a colourless oil.

[0433] Synthesis of I-43. To a solution of 8-((1R,2S)-2-hexylcyclopropyl)octanoic acid (43.3A, 20 mg, 74.51 μmol, 1 eq) in DCM (3 mL) was added HATU (34.00 mg, 89.41 μmol, 1.2 eq) and DIPEA (28.89 mg, 223.52 μmol, 38.93 μL, 3 eq) and stirred at 25°C for 0.5 hr, then added 4-(2- aminoethyl)phenol (1.1, 15.52 mg, 89.41 μmol, 1.2 eq, HCl). The mixture was stirred at 25°C for 16 hrs. The reaction mixture was diluted with H2O (2 mL) and the phases were separated. The water phases were extracted with DCM (1 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 40%-95% B over 2.0 min) to give 12.2 mg of I-43 (42%) as a white solid. (ES, m / z): [M+1]+378.52. I-43:1H NMR (400 MHz, chloroform-d) δ = 7.06 (d, J = 8.4 Hz, 2H), 6.83-6.75 (m, 2H), 5.42 (br s, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.66-1.55 (m, 2H), 1.38 (br s, 7H), 1.29 (br s, 10H), 1.14 (br d, J = 3.6 Hz, 2H), 0.93-0.86 (m, 3H), 0.70-0.61 (m, 2H), 0.60-0.53 (m, 1H), -0.29 - -0.36 (m, 1H)

[0434] Example 36. (Z)-N-(4-hydroxyphenethyl)dodec-5-enamide

[0435] Synthesis of 44.3. To a solution of 4-bromobutanoic acid (44.2, 2 g, 11.98 mmol, 1 eq) and HMPA (12.88 g, 71.86 mmol, 12.57 mL, 6 eq) in THF (20 mL) was added n-BuLi (2.5 M, 10.06 mL, 2.1 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hr. A solution of oct-1-yne (44.1, 1.32 g, 11.98 mmol, 1 eq) in THF (10 mL) was added dropwise to the solution, and the reaction mixture was stirred at 25°C for 16 hrs. The reaction mixture was diluted with HCl 50 mL and extracted with ethyl acetate 120 mL (40 mL x 3). The combined organic layers were washed with NaCl 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1) to give 240 mg of 44.3 (10%) as a white solid.

[0436] Synthesis of 44.4. To a solution of dodec-5-ynoic acid (44.3, 0.14 g, 713.25 μmol, 1 eq) in ethyl acetate (50 mL) was added Lindlar catalyst (50 mg, 12.11 μmol, 50.00 μL, 5% purity, 1.70-2 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 25°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 140 mg of 44.4 (crude) as a yellow oil.

[0437] Synthesis of I-44. A mixture of (Z)-dodec-5-enoic acid (44.4, 100 mg, 504.28 μmol, 1 eq), HATU (210.92 mg, 554.71 μmol, 1.1 eq) and DIEA (195.52 mg, 1.51 mmol, 263.51 μL, 3 eq) in dry DCM (2 mL) was stirred at 25°C for 30 mins. Then 4-(2-aminoethyl)phenol hydrochloride (1.1, 105.95 mg, 504.28 μmol, 1 eq, HCl) was added to the reaction. The mixture was stirred at 20°C for 16 hrs. Thereaction mixture was extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min) to give 28.29 mg of I-44 (17%) as a white solid. (ES, m / z): [M+1]+318.3. I-44:1H NMR (400 MHz, chloroform-d) δ = 7.06 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.45-5.27 (m, 3H), 4.73 (s, 1H), 3.54-3.43 (m, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.17-1.96 (m, 6H), 1.73-1.62 (m, 2H), 1.40-1.19 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H)

[0438] Example 37 (R,Z)-4-(2-((1,1,1-trifluoroheptadec-10-en-2-yl)amino)ethyl)phenol and Example 38. (S,Z)-4-(2-((1,1,1-trifluoroheptadec-10-en-2-yl)amino)ethyl)phenol

[0439] Synthesis of 45.8. To a solution of 4-(2-hydroxyethyl)phenol (45.8A, 3 g, 21.71 mmol, 1 eq) in DMSO (24 mL) was added TEA (4.36 g, 43.11 mmol, 6.00 mL, 1.99 eq), SO3.Py (7.00 g, 43.97 mmol, 2.03 eq) in DMSO (24 mL). The mixture was stirred at 20°C for 16 hrs. The reaction was diluted with water (20 mL) at 0°C and extracted with DCM (50 mL). The combined organic phase waswashed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether = 1% to 40%) to give 1.87 g of 45.8 (63%) as a light yellow oil.

[0440] Synthesis of 45.2. (Z)-hexadec-9-enoic acid (2.1, 20 g, 78.61 mmol, 1 eq) was dissolved in THF (100 mL) and added dropwise to LAH (2.5 M, 62.89 mL, 2 eq) at 0°C. The mixture was refluxed for 1 hr and then stirred at 20°C for 16 hrs. 2 M NaOH solution was added to the mixture. The organic phase was washed three times with brine and dried over Na2SO4. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 13.01 g of 45.2 (68%) as a light yellow oil.

[0441] Synthesis of 45.3. To the solution of (Z)-hexadec-9-en-1-ol (45.2, 7 g, 29.12 mmol, 1 eq) in DCM (70 mL) was added TEA (29.46 g, 291.15 mmol, 40.52 mL, 10 eq) and pyridine; sulfur trioxide (13.90 g, 87.35 mmol, 3 eq) in DMSO (11.37 g, 145.58 mmol, 11.37 mL, 5 eq) at 0°C and stirred at 20°C for 2 hrs. The reaction was quenched by HCl (1M) to pH = 3, then extracted with DCM (60 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 20 / 1) to give 5.15 g of 45.3 (crude) as a yellow oil.

[0442] Synthesis of 45.4. To a solution of (Z)-hexadec-9-enal (45.3, 4.5 g, 18.88 mmol, 1 eq) in THF (45 mL) was added TMSCF3(3.49 g, 24.54 mmol, 1.3 eq). The mixture was stirred at 0°C for 10 mins and TBAF (1 M, 188.75 μL, 0.01 eq) was added dropwise at 0°C. The mixture was stirred at 0°C for 10 mins and then stirred at 20°C for 6 hrs. The reaction mixture was cooled to 0°C and TBAF (1 M, 1.89 mL, 0.1 eq) and H2O (1.87 g, 103.81 mmol, 1.87 mL, 5.5 eq) was added to the reaction. The reaction mixture was stirred at 0°C for 10 mins. Then the mixture was stirred at 20°C for 16 hrs. The mixture was concentrated afford the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 20 / 1) to give 6.22 g of 45.4 (crude) as a colourless oil.

[0443] Synthesis of 45.5. A solution of (Z)-1,1,1-trifluoroheptadec-10-en-2-ol (45.4, 6.22 g, 20.14 mmol, 1 eq) in DCM (60 mL) was cooled to 0°C and Py (1.91 g, 24.18 mmol, 1.95 mL, 1.2 eq) was added followed by trifluoromethylsulfonyl trifluoromethanesulfonate (6.25 g, 22.16 mmol, 3.66 mL, 1.1 eq). The reaction mixture was stirred at 20°C for 16 hrs. The reaction mixture was diluted with water 50 mL and extracted with DCM 180 mL (60 mL x 3). The combined organic layer was washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 1% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 6.72 g of 45.5 (74%) as a colourless oil.

[0444] Synthesis of 45.6. To a mixture of (Z)-1,1,1-trifluoroheptadec-10-en-2-yl trifluoromethanesulfonate (45.5, 6.72 g, 15.26 mmol, 1 eq) in DMSO (70 mL) was added NaN3 (2.08 g,32.04 mmol, 2.1 eq) at 20°C under N2. The mixture was stirred at 40°C for 16 hrs. The mixture was cooled to 20°C. The reaction mixture was quenched by addition aq. NaClO 50 mL. The residue was poured into NaHCO3 (50 mL) and H2O (50 mL). The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 100% Petroleum ether gradient @ 100 mL / min) to give 3.89 g of 45.6 (76%) as a colourless oil.

[0445] Synthesis of 45.7. To a solution of (Z)-16-azido-17,17,17-trifluoroheptadec-7-ene (45.6, 3.65 g, 10.95 mmol, 1 eq) in THF (37 mL) was added triphenylphosphane (3.45 g, 13.14 mmol, 1.2 eq) and H2O (36.50 g, 202.61 mmol, 36.5 mL, 10% purity, 18.51 eq) and HCl (12 M, 912.22 μL, 1 eq). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was diluted with ethyl acetate / H2O (1:1, 40 mL). The aqueous layer was extracted with ethyl acetate (2 x 40 mL), the combined organic layers was dried with Na2SO4, concentrated, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 6% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 2.21 g of 45.7 (51%) as a white solid.

[0446] Synthesis of 45.9. A mixture of (Z)-1,1,1-trifluoroheptadec-10-en-2-amine (45.7, 1.21 g, 3.94 mmol, 1 eq) and 2-(4-hydroxyphenyl)acetaldehyde (45.8, 1.61 g, 11.81 mmol, 3 eq) in THF (13 mL) was stirred at 20°C for 1 hr. NaBH(OAc)3(2.50 g, 11.81 mmol, 3 eq) was added the reaction. The resulting mixture was stirred at 20°C for 16 hrs. The reaction mixture was partitioned between ethyl acetate (15 mL x 3) and aq.NaHCO3(20 mL). The combined organic layers was dried with Na2SO4, concentrated, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether = 1% to 4%) to give 864 mg of 45.9 (51%) as a yellow oil. (ES, m / z): [M+1]+428.4

[0447] Synthesis of 45.10. A mixture of (Z)-4-(2-((1,1,1-trifluoroheptadec-10-en-2- yl)amino)ethyl)phenol (45.9, 864 mg, 2.02 mmol, 1 eq), 4-nitrobenzenesulfonyl chloride (895.63 mg, 4.04 mmol, 2 eq), and Py (191.80 mg, 2.42 mmol, 195.71 μL, 1.2 eq) in DCM (9 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0°C for 5 hrs under N2atmosphere, then the mixture was stirred at 20°C for 16 hrs under N2atmosphere. The residue was diluted with HCl (1M) 5mL and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C1100 * 30 mm * 5 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 40%-80% B over 20.0 min) to give 800 mg of 45.10 (64%) as a white solid. (ES, m / z): [M+1]+613.5

[0448] Synthesis of 45.10A & 45.10B. 500 mg of 45.10 (mixture of 2 peaks) was separated by Chiral HPLC separation to give 190 mg of 45.10A (38 %, ee value: 100 %, Peak 1) and 140 mg of 45.10B (28 %, ee value: 100 %, Peak 2) as white solids. The two isomers were confirmed by NOE.

[0449] SFC separation methods:

[0450] Method 1: Instrument: Waters SFC150Mgm preparative SFC; Column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Mobile phase: A for CO2 and B for MeOH (0.1%NH3H2O); Gradient: B% = 15% isocratic elution mode; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar.

[0451] Chiral HPLC separation methods:

[0452] Method 2: Instrument: GX-281; Column: DAICEL CHIRALPAK IH (30 * 250 mm, 10 um); Mobile phase: A for Heptane and B for IPA; Gradient: B% = 5%; Flow rate: 50 ml / min; Wavelength: 220 nm.

[0453] Synthesis of I-45. To a solution of (R,Z)-N-(4-hydroxyphenethyl)-4-nitro-N-(1,1,1- trifluoroheptadec-10-en-2-yl)benzenesulfonamide (45.10A, 190 mg, 310.08 μmol, 1 eq) in DMF (2 mL) was added benzenethiol (0.5 g, 4.54 mmol, 463.82 μL, 14.64 eq) and K2CO3(85.71 mg, 620.16 μmol, 2 eq). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition aq. NaClO 10 mL. The residue was diluted with brine 5 mL and extracted with ethyl acetate 15 mL (5mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: X-Select CSH Phenyl- Hexyl 100 * 305u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 40%-85% B over 10.0 min) to give 43.0 mg of I-45 (32%) as a white solid. (ES, m / z): [M+1]+428.4.

[0454] Synthesis of I-46. To a solution of (S,Z)-N-(4-hydroxyphenethyl)-4-nitro-N-(1,1,1- trifluoroheptadec-10-en-2-yl)benzenesulfonamide (45.10B, 140 mg, 228.48 μmol, 1 eq) in DMF (3 mL) was added K2CO3(63.16 mg, 456.96 μmol, 2 eq) and PhSH (75.52 mg, 685.44 μmol, 70.06 μL, 3 eq). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition aq. NaClO. The residue was diluted with brine 5 mL and extracted with ethyl acetate 15 mL (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100 * 30 5u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 50%-90% B over 8.0 min) to give 36.83 mg of I-46 (36%) as a white solid. (ES, m / z): [M+1]+428.4. I-45:1H NMR (400 MHz, chloroform-d) δ = 7.09 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 5.42-5.31 (m, 2H), 4.76-4.56 (m, 1H), 3.13-3.04 (m, 1H), 3.01- 2.82 (m, 2H), 2.81-2.66 (m, 2H), 2.03 (q, J = 6.8 Hz, 4H), 1.70-1.59 (m, 1H), 1.38-1.23 (m, 19H), 0.93- 0.84 (m, 3H). I-46:1H NMR (400 MHz, chloroform-d) δ = 7.09 (d, J = 8.4 Hz, 2H), 6.83-6.72 (m, 2H), 5.46-5.28 (m, 2H), 4.75-4.51 (m, 1H), 3.18-3.04 (m, 1H), 2.94 (br d, J = 8.4 Hz, 1H), 2.87 (td, J = 7.2, 11.2 Hz, 1H), 2.79-2.65 (m, 2H), 2.03 (q, J = 6.8 Hz, 4H), 1.62 (br dd, J = 4.6, 10.4 Hz, 2H), 1.42-1.22 (m, 19H), 0.89 (t, J = 6.8 Hz, 3H)

[0455] Example 39. (S)-N-(4-hydroxyphenethyl)-12-methyltetradecanamide

[0456] Synthesis of 47.4b. Imidazole (28.96 g, 425.42 mmol, 1.5 eq) and iodine (93.58 g, 368.70 mmol, 74.27 mL, 1.3 eq) were added sequentially to a solution of PPh3 (89.27 g, 340.34 mmol, 1.2 eq) in DCM (1250 mL) at 25°C. A solution of (S)-2-methylbutan-1-ol (47.4a, 25 g, 283.61 mmol, 30.53 mL, 1 eq) in DCM (250 mL) was added to the resulting fine suspension and stirred for 4 hrs at 25°C. The reaction was diluted with CH2Cl2 (500 mL), and quenched with aq. Na2S2O3 (1000 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was distilled in vacuum (105°C, 0.09 Psi pressure / oil pump) to give 36.8 g of 47.4b (65%) as a yellow oil.

[0457] Synthesis of 47.4. A solution of (S)-1-iodo-2-methylbutane (47.4b, 36.8 g, 185.82 mmol, 1 eq) and PPh3 (146.22 g, 557.44 mmol, 3 eq) in Tol. (200 mL) was stirred at 105°C for 48 hrs in four 100 mL of sealed tube. After the reaction was finished, the upper toluene solution was poured out and the left gum oil was triturated with ethyl acetate (50 mL x 2), the ethyl acetate layer was poured out and the gum was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 mm * 100 mm * 10 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 20%-42% B over 18.0 min) to give 10.96 g of 47.4 (12%) as a yellow solid.

[0458] Synthesis of 47.2. To a solution of decane-1,10-diol (47.1, 5 g, 28.69 mmol, 1 eq) in CHCl3(140 mL) and DCM (140 mL) was added Ag2O (10.04 g, 43.32 mmol, 1.51 eq). The resultingmixture was stirred for 1 hr at 35°C. BnBr (5.40 g, 31.56 mmol, 3.75 mL, 1.1 eq) was then added and the reaction mixture was stirred for 16 hrs under nitrogen atmosphere. The suspension was filtered on Celite and the filtrate was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 10-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 4.05 g of 47.2 (53%) as a colourless oil.

[0459] Synthesis of 47.3. To a mixture of 10-benzyloxydecan-1-ol (47.2, 3.5 g,13.24 mmol, 1 eq) in DCM (35 mL) was added DMP (6.18 g, 14.56 mmol, 1.1 eq) in portions at 20°C under N2. The mixture was stirred at 20°C for 2 hrs. Then aq. NaHCO3 (50 mL) was added to the mixture until pH = 9 at 0°C, quenched by aq. Na2S2O3 (50 mL) and extracted with DCM (30 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 3% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 2.59 g of 47.3 (74%) as a colourless oil.

[0460] Synthesis of 47.5. To a solution of (S)-(2-methylbutyl)triphenylphosphonium iodide (47.4, 2.92 g, 6.35 mmol, 1 eq) in THF (35 mL) was added NaHMDS (1 M, 9.53 mL, 1.5 eq) slowly at - 70°C, the mixture was stirred at -70°C for 1 hr, then a solution of 10-benzyloxydecanal (47.3, 2.5 g, 9.53 mmol, 1.5 eq) in THF (10 mL) was added to the solution slowly at -70°C and the mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition aq. NH4Cl (20ml) at 0°C, and then diluted with H2O (25 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-2% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1.78 g of 47.5 (88%) as a yellow oil.

[0461] Synthesis of 47.6. To a solution of (S, Z)-(((12-methyltetradec-10-en-1- yl)oxy)methyl)benzene (47.5, 1.78 g, 5.62 mmol, 1 eq) in MeOH (5 mL) was added Pd / C (1.78 g, 1.67 mmol, 10% purity, 2.97e-1eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 1.27 g of 47.6 (98%) as a white solid.

[0462] Synthesis of 47.7. (S)-12-methyltetradecan-1-ol (47.6, 1.27 g, 5.56 mmol, 1 eq) was added to acetone (20 mL), then Jones reagent (2.5 M, 2.22 mL, 1 eq) was slowly added dropwise to the above mixture at 0°C. The reaction solution was stirred at 20°C for 16 hrs. The reaction mixture was quenched by addition H2O (10 mL) at 20°C. The combined organic layers were washed with ethyl acetate (20 mL x 3), the organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.31 g of 47.7 (97%) as a green oil.

[0463] Synthesis of 47.8. To a solution of (S)-12-methyltetradecanoic acid (47.7, 310 mg, 1.28 mmol, 1 eq) in DCM (3 mL) and DMF (9.35 mg, 127.89 μmol, 9.84 μL, 0.1 eq) was added oxalyl dichloride (243.49 mg, 1.92 mmol, 167.92 μL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hr.The reaction mixture was concentrated under reduced pressure to give 333.59 mg of 47.8 (100%) as a yellow oil.

[0464] Synthesis of I-47. To a solution of NaOH (51.15 mg, 1.28 mmol, 1 eq) in H2O (3 mL) was added 4-(2-aminoethyl)phenol (1.1, 266.48 mg, 1.53 mmol, 1.2 eq, HCl). The mixture was stirred at 20°C for 15 mins, then (S)-12-methyltetradecanoyl chloride (47.8, 333.59 mg, 1.28 mmol, 1 eq) in THF (3 mL) was added dropwise at 0°C and stirred at 20°C for 16 hrs. HCl (1 M) was added to the mixture until pH = 3-4 and extracted with ethyl acetate (5mL x 3). The organic phase was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C1880 * 40 mm * 3 um; mobile phase: [H2O (0.04%HCl)-ACN]; gradient: 55%-100% B over 8.0 min) to give 59.10 mg of I-47 (12%) as a white solid. (ES, m / z): [M+1]+362.3. I-47:1H NMR (400 MHz, chloroform -d) δ = 7.05 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.41 (br s, 1H), 5.22 (br s, 1H), 3.54-3.45 (m, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.36-1.19 (m, 19H), 1.18-1.06 (m, 2H), 0.89-0.82 (m, 6H)

[0465] Example 40. 2-(2-hexylcyclopropyl)-N-(2-phenylethyl) acetamide

[0466] Synthesis of 48.1. To a solution of 2-[rac-(1S,2S)-2-hexylcyclopropyl]ethanol (17.8, 150 mg, 880.85 μmol, 1 eq) in acetone (2 mL) was added dropwise Jones reagent (2.5 M, 352.34 μL, 1 eq) at 0°C, the mixture was stirred at 20°C for 30 mins. The reaction mixture was quenched by addition H2O (3 mL) at 20°C, and then diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 150 mg of 48.1 (crude) as a blue oil. (ES, m / z): [M-1]- 183.3.

[0467] Synthesis of 48.2. To a solution of 2-[rac-(1S, 2S)-2-hexylcyclopropyl] acetic acid (48.1, 100 mg, 542.67 μmol, 1 eq) in DCM (1 mL) was added DMF (1.98 mg, 27.13 μmol, 2.09 μL, 0.05 eq) and (COCl)2(75.77 mg, 596.94 μmol, 52.25 μL, 1.1 eq) at 0°C, the mixture was stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure to give 110 mg of 48.2 (crude) as a blue oil.

[0468] Synthesis of I-48. To a solution of 2-phenylethan-1-amine (21.2, 72.33 mg, 596.88 μmol, 74.95 μL, 1.1 eq) and TEA (164.72 mg, 1.63 mmol,226.58 μL, 3 eq) in DCM (2 mL) was added 2- [rac-(1S,2S)-2-hexylcyclopropyl]acetyl chloride (48.2, 110 mg, 542.62μmol, 1 eq) at 0°C, the mixturewas stirred at 20°C for 1 hr. The mixture was filtered and purified by prep-HPLC (column: Phenomenex Luna C18100 * 30 mm * 3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 12 mg of I-48 (22%) as a colorless oil of mixture. I-48:1H NMR (400 MHz, chloroform-d) δ = 7.36-7.19 (m, 5H), 5.91 (br s, 1H), 3.65-3.49 (m, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.39-2.27 (m, 1H), 2.17-2.05 (m, 1H), 1.61-1.56 (m, 2H), 1.39-1.18 (m, 8H), 1.16-1.03 (m, 1H), 0.93-0.83 (m, 3H), 0.77 (tq, J = 5.6, 8.4 Hz, 1H), 0.72-0.65 (m, 1H), -0.20 (q, J = 5.2 Hz, 1H)

[0469] Example 41. 2-((1S,2S)-2-hexylcyclopropyl)-N-(4-hydroxyphenethyl)acetamide & 2-((1R,2R)-2-hexylcyclopropyl)-N-(4-hydroxyphenethyl)acetamide

[0470] Synthesis of 49.2. A mixture of dec-3-yn-1-ol (49.1, 2 g, 12.97 mmol, 1 eq), Lindlar catalyst (2.68 g, 648.30 μmol, 2.68 mL, 5% purity, 0.05 eq) in ethyl acetate (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 3 hrs under H2(15 Psi) atmosphere. The reaction mixture was filtered and the filter was concentrated to give 2 g of 49.2 (98%) as a yellow oil.

[0471] Synthesis of 49.3. To a solution of diiodomethane (7.54 g, 28.16 mmol, 2.27 mL, 4.4 eq) in DCM (20 mL) was added diethylzinc (1 M, 14.08 mL, 2.2 eq) at 0°C, the mixture was stirred at 0°C for 10 mins. A solution of (Z)-dec-3-en-1-ol (49.2, 1 g, 6.40 mmol, 1 eq) in DCM (20 mL) was added to the previous solution. The mixture was stirred at 25°C for 16 hrs. The reaction mixture was diluted with aq.NH4Cl (6 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 8% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 1.66 g of 49.3 as a colourless oil.

[0472] Synthesis of Int 4_set 60. A solution of 2-((1S,2S)-2-hexylcyclopropyl)ethan-1-ol & 2-((1R,2R)-2-hexylcyclopropyl)ethan-1-ol (49.3, 520 mg, 3.05 mmol, 1 eq) in acetone (5 mL) wasslowly added dropwise to Jones reagent (2.5 M, 1.22 mL, 1 eq) at 0°C. The reaction solution was stirred at 25°C for 16 hrs. The reaction solution was concentrated by evaporation under reduced pressure, diluted with ethyl acetate, and washed with water then the organic layer was concentrated to give 255 mg of Int 4_set 60 (45%) as a yellow oil.

[0473] Synthesis of 49.4. To a solution of 2-((1S,2S)-2-hexylcyclopropyl)acetic acid & 2- ((1R,2R)-2-hexylcyclopropyl)acetic acid (Int 4set 60,150 mg, 814.00 μmol, 1 eq) in DCM (1.5 mL) was added DMF (2.97 mg, 40.70 μmol, 3.13 μL, 0.05 eq) and (COCl)2(113.65 mg, 895.40 μmol, 78.38 μL, 1.1 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 165.01 mg of 49.4 (crude) as a yellow oil.

[0474] Synthesis of I-49. To a solution of 4-(2-aminoethyl)phenol hydrochloride (1.1, 155.46 mg, 895.32 μmol, 1.1 eq) in DCM (1.65 mL) was added TEA (329.44 mg, 3.26 mmol, 453.15 μL, 4 eq) and 2-((1S,2S)-2-hexylcyclopropyl)acetyl chloride & 2-((1R,2R)-2-hexylcyclopropyl)acetyl chloride (49.4, 165 mg, 813.93 μmol, 1 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: X-Select CSH Phenyl-Hexyl 100*305u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 35%-70% B over 8.0 min) to give 7.84 mg of I-49 (3.1%) as a light yellow gum. I-49:1H NMR (400 MHz, chloroform-d) δ = 7.08 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.92 (br d, J = 1.2 Hz, 1H), 5.08-4.78 (m, 1H), 3.53 (br dd, J = 2.4, 6.2 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.32 (dd, J = 6.4, 16.6 Hz, 1H), 2.11 (dd, J = 8.4, 16.6 Hz, 1H), 1.42-1.20 (m, 10H), 1.16-1.04 (m, 1H), 0.89 (t, J = 6.8 Hz, 4H), 0.83-0.65 (m, 2H), -0.18 (q, J = 5.2 Hz, 1H)

[0476] Synthesis of 50.1. To a solution of (Z)-dec-3-en-1-ol (int.4_S60, 550 mg, 3.52 mmol, 1 eq) in acetone (10 mL) was added Jones reagent (2.5 M, 2.11 mL, 1.5 eq) dropwise at 0°C. The reaction solution was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition H2O 10 mL at 20°C. The combined organic layers were washed with ethyl acetate 60 mL (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified byflash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 3% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 432 mg of 50.1 (crude) as a white solid.

[0477] Synthesis of 50.2. To a solution of (Z)-dec-3-enoic acid (50.1, 283 mg, 1.66 mmol, 1 eq) in DCM (3 mL) was added DMF (6.08 mg, 83.11 μmol, 6.39 μL, 0.05 eq). Then oxalyl dichloride (232.09 mg, 1.83 mmol, 160.06 μL, 1.1 eq) was added to above mixture at 0°C. The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 300 mg of 50.2 (crude) as a white solid.

[0478] Synthesis of I-50. To a solution of 4-(2-aminoethyl)phenol (1.1, 552.13 mg, 3.18 mmol, 2 eq, HCl) and TEA (321.76 mg, 3.18 mmol, 442.58 μL, 2 eq) in DCM (3 mL) was added (Z)- dec-3-enoyl chloride (50.2, 300 mg, 1.59 mmol, 1 eq) at 0°C. The mixture was stirred at 20°C for 16 hrs. The reaction was quenched with H2O (1 mL). The mixture was extracted with ethyl acetate (2 mL x 3), dried over Na2SO4and filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C1880 * 40 mm * 3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 35%-65% B over 8.0 min) to give 21.22 mg of I-50 (4.6%) as a white solid. (ES, m / z): [M+1]+290.2. I-50:1H NMR (400 MHz, chloroform-d) δ = 7.05 (br d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.78-5.57 (m, 2H), 5.54-5.39 (m, 1H), 3.48 (q, J = 6.4 Hz, 2H), 2.99 (br d, J = 7.2 Hz, 2H), 2.74 (br t, J = 6.8 Hz, 2H), 1.99 (q, J = 6.8 Hz, 2H), 1.41-1.19 (m, 8H), 0.89 (t, J = 6.4 Hz, 3H)

[0479] Example 43. 10-hydroxy-N-phenethyldecanamide

[0480] Synthesis of I-51. To a solution of 10-hydroxydecanoic acid (51.1, 0.5 g, 2.66 mmol, 1 eq) in DMF (5 mL) was added DIEA (1.03 g, 7.97 mmol, 1.39 mL, 3 eq) and HATU (1.11 g, 2.92 mmol, 1.1 eq) at 0°C, the mixture was stirred at 0°C for 0.5 hr. Then 2-phenylethanamine (21.2, 321.83 mg, 2.66 mmol, 333.51 μL, 1 eq) was added to the above mixture under ice-cooling while stirring, the mixture was stirred at 20°C for 0.5 hr. The residue was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0 min) to give 429.60 mg of I-51 (46%) as a white solid. (ES, m / z): [M+1]+292.2. I-51:1H NMR (400 MHz, DMSO-d6) δ = 7.82 (br t, J = 5.2 Hz, 1H), 7.31-7.16 (m, 5H), 3.41-3.39 (m, 1H), 3.37 (br t, J = 6.8 Hz, 3H), 3.28-3.22 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.01 (t, J = 7.6 Hz, 2H), 1.50-1.35 (m, 4H), 1.23 (br s, 10H).

[0481] Example 44. (Z)-1-phenethyl-3-(tetradec-7-en-1-yl)urea

[0482] Synthesis of 53.2. To a solution of oct-1-yne (44.1, 650 mg, 5.90 mmol, 1 eq) and HMPA (6.34 g, 35.39 mmol, 6.19 mL, 6 eq) in THF (3 mL) was added n-BuLi (2.5 M, 4.95 mL, 2.1 eq) at -78°C. The mixture was stirred at -78°C for 0.5 hr. A solution of 7-bromoheptanoic acid (53.1, 1.23 g, 5.90 mmol, 1 eq) in THF (3 mL) was added dropwise to the solution, the reaction mixture was stirred at 20°C for 4 hrs. HCl (1M) 5 mL was added to the reaction mixture until pH = 3 ~ 4, and extracted with ethyl acetate 60 mL (20 mL x 3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Titank C18 Bulk 250 * 70 mm 10u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 40%-85% B over 20.0 min) to give 440 mg of 53.2 (31%) as a colorless oil. (ES, m / z): [M-1]+237.3.

[0483] Synthesis of 53.3. MeOH (8 mL) was charged to the three-necked round bottom flask, then pentadec-8-ynoic acid (53.2, 390 mg, 1.64 mmol, 1 eq) was added to the mixture at 20°C for 10 mins. The calcium palladium carbonate (202.73 mg, 49.08 μmol, 202.73 μL, 5% purity, 0.03 eq) was added dropwise to the reaction mixture at 20°C within 5 mins. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20°C for 3 hrs. The catalyst calcium palladium carbonate (202.73 mg, 49.08 μmol, 202.73 μL, 5% purity, 0.03 eq) was removed by filtration over celite with MeOH (20 mL x 3) rinsing. The reaction mixture was filtered and concentrated under reduced pressure to give 470 mg of 53.3 (crude) as a colorless oil. (ES, m / z): [M-1]+241.3.

[0484] Synthesis of I-53. To a solution of (Z)-pentadec-8-enoic acid (53.4, 200 mg, 832.01 μmol, 1 eq) in Tol. (3 mL) was added TEA (92.61 mg, 915.22 μmol, 127.39 μL, 1.1 eq) and DPPA (251.87 mg, 915.22 μmol, 197.54 μL, 1.1 eq). The mixture was stirred at 20°C for 1 hr, then the mixture was heated to 90°C, and stirred for 2 hrs. After allowing the mixture to cool down, a solution of 2- phenylethan-1-amine (21.2, 100.82 mg, 832.01 μmol, 104.48 μL, 1 eq) in Tol. (1 mL) was added dropwise under ice-cooling while stirring. The reaction solution was stirred at 20°C for 12 hrs. The reaction mixture was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 55%-85% B over 15.0 min) to give 96.9 mg of I-53 (32%) as a white solid. (ES, m / z): [M+1]+359.3. I-53:1H NMR (400 MHz, chloroform-d) δ = 7.34-7.28 (m, 2H), 7.25-7.17 (m, 3H), 5.41-5.30 (m, 2H), 4.41-4.28 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 3.10 (q, J = 6.8 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.06-1.97 (m, 4H), 1.49-1.41 (m, 2H), 1.30 (br d, J = 9.2 Hz, 14H), 0.89 (br t, J = 6.8 Hz, 3H)

[0485] Example 45. N-(4-fluorophenethyl)-10-hydroxydecanamide

[0486] Synthesis of I-54. To a solution of 10-hydroxydecanoic acid (54.1, 300 mg, 1.59 mmol, 1 eq) in DMF (3 mL) was added HATU (727.08 mg, 1.91 mmol, 1.2 eq) and DIEA (617.84 mg, 4.78 mmol, 832.66 μL, 3 eq) at 0°C, and the mixture was stirred at 0°C for 0.5 hr. Then 2-(4- fluorophenyl)ethan-1-amine (52.1A, 243.95 mg, 1.75 mmol, 229.92 μL, 1.1 eq) was added to above mixture at 0°C. The mixture was stirred at 25°C for 0.5 hr. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 * 30 mm * 3um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 35%-65% B over 8.0 min) to give 97 mg of I-54 (20%) as a white solid. (ES, m / z): [M+1]+310.2. I-54:1H NMR (400 MHz, chloroform-d) δ = 7.19-7.10 (m, 2H), 7.05-6.94 (m, 2H), 5.48 (br s, 1H), 3.64 (t, J = 6.8 Hz, 2H), 3.54-3.45 (m, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H), 1.59-1.52 (m, 4H), 1.36-1.25 (m, 10H)

[0487] Example 46. 10-((4-hydroxyphenethyl)amino)-10-oxodecanoic acid

[0488] Synthesis of 55.2. To a solution of 10-tert-butoxy-10-oxo-decanoic acid (55.1, 1 g, 3.87 mmol, 1 eq) in DMF (10 mL) was added HATU (1.62 g, 4.26 mmol, 1.1 eq) and DIEA (1.50 g, 11.61 mmol, 2.02 mL, 3 eq). The mixture was stirred at 20°C for 30 mins. 4-(2-aminoethyl)phenol (22.5,, 530.97 mg, 3.87 mmol, 1 eq) was added to above mixture. The mixture was stirred at 20°C for 1 hr. The reaction mixture was diluted with H2O and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250 * 50 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 35%-65% B over 10.0 min) to give 0.9 g of 55.2 (61%) as a white solid. (ES, m / z): [M-1]- 376.4.

[0489] Synthesis of I-55. A mixture of tert-butyl 10-[2-(4-hydroxyphenyl)ethylamino]-10- oxo-decanoate (55.2, 100 mg, 264.89 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 15.10 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C1880 * 30 mm * 3 um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 10%-45% B over 8.0 min) to give 34.47 mg of I-55 (40%) as a white solid. (ES, m / z): [M+1]+322.1. I-55:1H NMR (400 MHz, DMSO-d6) δ = 11.95 (s, 1H), 9.14 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 6.99-6.94 (m, J = 8.4 Hz, 2H), 6.68-6.64 (m, 2H), 3.21-3.14 (m, 2H), 2.59-2.52 (m, 2H), 2.18 (t, J = 7.2 Hz, 2H), 2.07-1.97 (m, 2H), 1.53-1.40 (m, 4H), 1.23 (br s, 8H)

[0490] Example 47. 10-oxo-10-(2-phenylethylamino)decanoic acid

[0491] Synthesis of 56.2. To a solution of 10-tert-butoxy-10-oxo-decanoic acid (56.1, 1 g, 3.87 mmol, 1 eq) in DMF (10 mL) was added HATU (2.21 g, 5.81 mmol, 1.5 eq) and DIEA (1.50 g, 11.61 mmol, 2.02 mL, 3 eq) at 0°C, and the mixture was stirred at 0°C for 0.5 hr. Then 2-phenylethan-1- amine (21.2, 515.95 mg, 4.26 mmol, 534.66 μL, 1.1 eq) was added to above mixture, and the mixture was stirred at 20°C for 1 hr. The mixture was purified by prep-HPLC (Phenomenex luna C18250 * 50 mm * 10 um; mobile phase: [H2O (0.05%HCl)-ACN]; gradient: 40%-80% B over 10.0 min) to give 1.05 g of 56.2 (75%) as a pink solid. (ES, m / z): [M+1]+362.3

[0492] Synthesis of I-56. A mixture of tert-butyl 10-oxo-10-(2-phenylethylamino)decanoate (56.2, 0.1 g, 276.61 μmol, 1 eq) in HCl / dioxane (4 M, 69.15 μL, 1 eq) was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (Phenomenex Luna PFP(2) 100 * 30 mm * 5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 35%-70% B over 8.0 min) to give 34.39 mg of I-56 (40%) as a white solid. (ES, m / z): [M+1]+306.2. I-56:1H NMR (400 MHz, DMSO-d6) δ = 11.97 (br s, 1H), 7.82 (br t, J = 5.6 Hz, 1H), 7.31-7.24 (m, 2H), 7.21-7.16 (m, 3H), 3.28-3.21 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.18 (t, J = 7.2 Hz, 2H), 2.01 (t, J = 7.6 Hz, 2H), 1.50-1.41 (m, 4H), 1.22 (br s, 8H)

[0493] Example 48. 10-((4-fluorophenethyl)amino)-10-oxodecanoic acid

[0494] Synthesis of 57.2. To a solution of 10-(tert-butoxy)-10-oxodecanoic acid (57.1, 900 mg, 3.59 mmol, 1 eq) in DMF (3 mL) was added DIEA (1.39 g, 10.78 mmol, 1.88 mL, 3 eq) and HATU (1.37 g, 3.59 mmol, 1 eq) at 0°C, and the mixture was stirred at 0°C for 0.5 hr. Then 2-(4- fluorophenyl)ethan-1-amine (52.1A, 500.00 mg, 3.59 mmol, 471.25 μL, 1 eq) was added to above mixture under ice-cooling while stirring the mixture was heated to 20°C for 0.5 hr. The mixture was purified by prep-HPLC (neutral condition: column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 10.0 min to give 700 mg of 57.2 (51%) as a colorless oil. (ES, m / z): [M+1]+380.2.

[0495] Synthesis of I-57. A mixture of tert-butyl 10-((4-fluorophenethyl)amino)-10- oxodecanoate (57.2, 200 mg, 527.00 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 7.59 eq) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20°C for 2 hrs under N2atmosphere. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex Luna PFP(2) 100 * 30 mm * 5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient:15%-50% B over 8.0 min) to give 109.67 mg of I-57 (64%) as a white solid. (ES, m / z): [M+1]+324.1. I-57:1H NMR (400 MHz, DMSO-d6) δ = 12.02-11.90 (m, 1H), 7.84-7.76 (m, 1H), 7.21 (dd, J = 5.6, 8.4 Hz, 2H), 7.12-7.05 (m, 2H), 3.28-3.19 (m, 2H), 2.70-2.65 (m, 2H), 2.18 (t, J = 7.6 Hz, 2H), 2.00 (t, J = 7.2 Hz, 2H), 1.53-1.37 (m, 4H), 1.30-1.11 (m, 8H)

[0496] Example 49. 10-hydroxy-N-(4-hydroxyphenethyl)decanamide

[0497] Synthesis of I-58. To a solution of 10-hydroxydecanoic acid (58.1, 500 mg, 2.66 mmol, 1 eq) in DMF (3 mL) was added DIEA (1.03 g, 7.97 mmol, 1.39 mL, 3 eq) and HATU (1.06 g, 2.79 mmol, 1.05 eq) at 0°C, the mixture was stirred at 0°C for 0.5 hr. Then 4-(2-aminoethyl)phenol (22.5, 364.33 mg, 2.66 mmol, 1 eq) was added to above mixture under ice-cooling while stirring, and the mixture was stirred at 20°C for 0.5 hr. The residue was purified by prep-HPLC (column: Phenomenex luna C18100 * 40 mm * 5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 10%-50% B over 8.0 min) to give 465 mg of I-58 (54%) as a yellow solid. (ES, m / z): [M+1]+308.2. I-58:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.74-6.57 (m, 2H), 3.39- 3.36 (m, 2H), 3.23-3.13 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.06-1.96 (m, 2H), 1.53-1.34 (m, 4H), 1.24 (br s, 10H)

[0498] Example 50. 4-[3-[4-[(Z)-tridec-6-enyl]pyrazol-1-yl]propyl]phenol

[0499] Synthesis of 59.2. To a solution of 4-(3-hydroxypropyl)phenol (59.1, 9 g, 59.14 mmol, 1 eq) in DCM (90 mL) and DMF (5 mL) was added PPh3(23.27 g, 88.70 mmol, 1.3 eq) and CBr4(29.42 g, 88.70 mmol, 1.3 eq) at 0°C. The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 80 / 20 to 50 / 50) to give 12 g of 59.2 (89%) as a white oil.

[0500] Synthesis of 59.4. Amino 4-(3-bromopropyl)phenol (59.2, 12.5 g, 58.12 mmol, 1 eq), 4-bromo-1H-pyrazole (59.3, 12.81 g, 87.17 mmol, 1.5 eq) and K2CO3(11.24 g, 81.36 mmol, 1.4 eq) was dissolved in DMF (150 mL). The mixture was stirred at 20°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (Phenomenex luna c18250 mm * 100 mm * 10 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 28%-58% B over 20.0 min) to give 16 g of 59.4 (65%) as a yellow solid. (ES, m / z): [M+1]+281.0

[0501] Synthesis of 59.6. To a solution of hex-5-yn-1-ol (59.5, 20 g, 203.79 mmol, 1 eq) in THF (200 mL) was added NaH (12.23 g, 305.68 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr, then BnBr (34.85 g, 203.79 mmol, 24.20 mL, 1 eq) was added at 0°C, the mixture was stirred at 20°C for 16 hrs. The reaction was cooled to 0°C and quenched by the addition ofsaturated aqueous ammonium chloride (30 mL) then diluted with water (30 mL). The mixture was extracted with ethyl acetate (150 mL x 2), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 11 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 6% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 28 g of 59.6 (2.9%) as a white solid. (ES, m / z): [M+1]+189.1

[0502] Synthesis of 59.7. To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.02 g, 106.23 mmol, 15.89 mL, 2 eq) and hex-5-ynoxymethylbenzene (59.6, 10 g, 53.12 mmol, 1 eq) was added BH3.THF (1 M, 5.31 mL, 0.1 eq) at 0°C. The mixture was stirred at 20°C for 48 hrs. The reaction mixture was quenched by addition MeOH 50 mL at 20°C, and then diluted with water 150 mL and extracted with ethyl acetate 300 mL (100 mL x 3). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 3.37 g of 59.7 (20%) as a white solid. (ES, m / z): [M+1]+317.3

[0503] Synthesis of 59.8. To a solution of 2-[(E)-6-benzyloxyhex-1-enyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (59.7, 3.37 g, 10.66 mmol, 1 eq) and 4-[3-(4-bromopyrazol-1- yl)propyl]phenol (59.4, 3.00 g, 10.66 mmol, 1 eq) in Tol. (36 mL) and H2O (7.2 mL) was added K3PO4(6.79 g, 31.97 mmol, 3 eq) and Pd(dppf)Cl2(779.73 mg, 1.07 mmol, 0.1 eq). The mixture was refluxed for 16 hrs. The reaction mixture was quenched by addition H2O 12 mL at 20°C. The combined organic layers were washed with ethyl acetate 120 mL (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 9% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 2.07 g of 59.8 (49%) as a white solid. (ES, m / z): [M+1]+391.2

[0504] Synthesis of 59.9. MeOH (5 mL) was charged to the 100 mL three-necked round bottom flask, then 4-[3-[4-[(E)-6-benzyloxyhex-1-enyl]pyrazol-1-yl]propyl]phenol (59.8, 1 g, 1.28 mmol, 1 eq) was added at 20°C within 1 min at 20°C inner temperature, Pd / C (1.36 g, 1.28 mmol, 10% purity, 1 eq) was added to the reaction mixture at 20°C within 1 min. After the addition, the mixture was stirred at 20°C for 1 hr under H2(15 Psi) atmosphere. The suspension was filtered through a pad of Celite and the pad cake was washed with EtOH (500 ml x 5). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was used directly for the next step without purification to give 700 mg of 59.9 (90%) as a yellow oil. (ES, m / z): [M+1]+303.2

[0505] Synthesis of 59.10. The amino ester 4-[3-[4-(6-hydroxyhexyl)pyrazol-1- yl]propyl]phenol (59.9, 550 mg, 1.82 mmol, 1 eq) and PPh3 (524.73 mg, 2.00 mmol, 1.1 eq) was dissolved in DCM (9 mL) and DMF (2 mL). CBr4 (663.45 mg, 2.00 mmol, 1.1 eq) was added to the above mixture at 0°C. The mixture was stirred at 20°C for 16 hrs. The reaction mixture wasconcentrated under reduced pressure to remove DCM (9 mL) to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 595 mg of 59.10 (89%) as a white solid. (ES, m / z): [M+1]+365.1

[0506] Synthesis of 59.11. 4-[3-[4-(6-bromohexyl)pyrazol-1-yl]propyl]phenol (59.10, 0.51 g, 1.40 mmol, 1 eq) was dissolved in ACN (5 mL). Then K2CO3 (385.89 mg, 2.79 mmol, 2 eq) was added, and BnBr (405.92 mg, 2.37 mmol, 281.89 μL, 1.7 eq) was slowly added dropwise. The mixture was stirred at 40°C for 16 hrs. The solids in the reaction solution were filtered and then the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 88 / 12 to 50 / 50) to give 610 mg of 59.11 (95%) as a colorless oil. (ES, m / z): [M+1]+455.2

[0507] Synthesis of 59.13. To a solution of hept-1-yne (158.37 mg, 1.65 mmol, 215.47 μL, 15 eq) and HMPA (1.18 g, 6.59 mmol, 1.15 mL, 60 eq) in THF (10 mL) was added n-BuLi (2.5 M, 922.21 μL, 21 eq) at -70°C under N2atmosphere. The mixture was stirred at -70°C for 1 hr. A solution of 1-[3-(4-benzyloxyphenyl)propyl]-4-(6-bromohexyl)pyrazole (59.11, 0.05 g, 109.79 μmol, 1 eq) in THF (1 mL) was added dropwise to the solution at -78°C in N2atmosphere, and the reaction mixture was stirred at 20°C for 3 hrs. The reaction mixture was diluted with NH4Cl 3 mL and extracted with ethyl acetate 12 mL (4 mL x 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 96 : 4 to 90 : 10) to give 0.12 g of 59.13 (58%) as a yellow oil.

[0508] Synthesis of 59.14. MeOH (2 mL) was charged to the 10 mL three-necked round bottom flask, then 1-[3-(4-benzyloxyphenyl)propyl]-4-tridec-6-ynyl-pyrazole (59.13, 100 mg, 212.46 μmol, 1 eq) was added at 20°C within 1 min. At 20°C inner temperature, lindlar catalyst (43.87 mg, 10.62 μmol, 43.87 μL, 5% purity, 0.05 eq) was added dropwise in portions to the reaction mixture at 20°C within 1 min. After the addition, the mixture was stirred at 20°C for 1 hr under H2(15 Psi) atmosphere. The suspension was filtered through a pad of Celite and the pad cake was washed with MeOH (10 ml x 5). The reaction mixture was concentrated under reduced pressure to give 110 mg of 59.14 (99%) as a yellow oil. (ES, m / z): [M+1]+473.3

[0509] Synthesis of I-59. DCM (2 mL) was charged to the 10 mL three-necked round bottom flask, then1-[3-(4-benzyloxyphenyl)propyl]-4-[(Z)-tridec-6-enyl]pyrazole (59.14, 40 mg, 84.62 μmol, 1 eq) was added at 20°C within 1 min. Then BCl3(1 M, 423.10 μL, 5 eq) was added dropwise to the reaction mixture at -78°C within 1 min. After the addition, the mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by MeOH 2 mL at 0°C, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Xselect CSH C18100 * 30 mm * 5 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 50%-100% B over 8.0 min) to give 12.73 mg of I-59 (crude) as a yellow oil, and the crude was purified by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm,10 um);mobile phase: [CO2-MeOH (0.1%NH3H2O)]; B%: 23%, isocratic elution mode) to give 5.81 mg of I-59 (8.9%) as a white oil. (ES, m / z): [M+1]+383.3 I-59:1H NMR (400 MHz, chloroform-d) δ = 7.37 (s, 1H), 7.15 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.39-5.32 (m, 2H), 4.11 (br t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.45 (t, J = 7.6 Hz, 2H), 2.20-2.14 (m, 2H), 2.06-1.98 (m, 4H), 1.36- 1.27 (m, 14H), 0.89 (t, J = 7.2 Hz, 3H)

[0510] Example 51. (Z)-16-methoxy-16-oxohexadec-9-enoic acid, ((R)-4-(2-amino-1- hydroxyethyl)phenol, and (S)-4-(2-amino-1-hydroxyethyl)phenol

[0511] Synthesis of 2. To a solution of 8-bromooctan-1-ol (26.1, 9 g, 43.04 mmol, 7.38 mL, 1 eq) in DCM (135 mL) was added TBSCl (7.14 g, 47.34 mmol, 5.82 mL, 1.1 eq) and imidazole (3.52 g, 51.64 mmol, 1.2 eq) at 15°C. The mixture was stirred at 15°C for 16 hrs. The residue was diluted with H2O (120 mL x 2). The organic phase was separated, washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 50 / 1) to give 12.7 g of 2 (91%) as a yellow oil.

[0512] Synthesis of 4. To a solution of oct-7-ynoic acid (3, 4.37 g, 30.92 mmol, 1 eq) and HMPA (33.24 g, 185.54 mmol, 32.46 mL, 6 eq) in THF (100 mL) was added n-BuLi (2.5 M, 25.98 mL, 2.1 eq) at -65°C. The mixture was stirred at -65°C for 3 hrs. To a solution of ((8-bromooctyl)oxy)(tert- butyl)dimethylsilane (2, 5 g, 15.46 mmol, 1 eq) in THF (25 mL) was added dropwise to the solution, and the reaction mixture was stirred at 15°C for 13 hrs. The reaction mixture was diluted with HCl (150 mL, 1 M) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine 150 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 30 / 1) to give 4.7 g of 4 as a yellow oil.

[0513] Synthesis of 5. THF (260 mL) was charged to the round bottom flask, then 16-((tert- butyldimethylsilyl)oxy)hexadec-7-ynoic acid (4, 4.3 g, 11.24 mmol, 1 eq) and Lindlar catalyst 2.15 g, 520.56 μmol, 2.15 mL, 5% purity, 4.63e-2 eq) was added to the mixture at 0°C. After the addition, the mixture was stirred at 20°C for 5 hrs under H2balloon. The reaction mixture was filtered and the filter was concentrated to give 4.06 g of 5 (93%) as a light-yellow oil.

[0514] Synthesis of 6. A mixture of (Z)-16-((tert-butyldimethylsilyl)oxy)hexadec-7-enoic acid (5, 2.3 g, 5.98 mmol, 1 eq), DMF (21.85 mg, 298.96 μmol, 23.00 μL, 0.05 eq) in DCM (23 mL) was degassed and purged with N2for 3 times, and oxalyl dichloride (834.81 mg, 6.58 mmol, 575.73 μL, 1.1 eq) was added to the reaction at 0°C, then the mixture was stirred at 20°C for 30 mins under N2atmosphere. The reaction was used next step directly without purification.

[0515] Synthesis of 7. The reaction mixture of 6 was added to MeOH (10 mL), and then the mixture was stirred at 24°C for16 hrs under N2atmosphere. The mixture was concentrated afford the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 11 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 0.92 g of 7 as a yellow oil.

[0516] Synthesis of Int 8_set 64. To a solution of methyl (Z)-16-hydroxyhexadec-7-enoate (7, 920 mg, 3.23 mmol, 1 eq) in acetone (15 mL) was slowly added Jones reagent (2.5 M, 1.55 mL, 1.2 eq) dropwise at 0°C. The reaction solution was stirred at 25°C for 2 hrs. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc (10 mL), and washed with water (5 mL). The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 570 mg of Int 8_set 64 (59%) as a yellow oil.

[0517] Synthesis of 8C & 8D. 4-(2-amino-1-hydroxyethyl)phenol (8A, 1 g, HCl) was purified by prep-HPLC (column: Daicel ChiralPak IG (250 * 30 mm, 10 um); mobile phase: [Heptane- EtOH(0.1% IPAm)]; gradient:20%-40% B over 15.0 min) and twice SFC separation (Method 1 followed by Method 2) to give 80 mg of 8C and 110 mg of 8D.

[0518] Method 1&2: Instrument: GX-281; Column: DAICEL CHIRALPAK IG (250 mm * 30 mm,10 um); Mobile phase: A for HEP and B for EtOH (0.1%IPA); Gradient: B% = 20-40% ; Flow rate:45 ml / min; Wavelength:220 nm

[0519] Example 52. (Z)-16-oxo-16-(phenethylamino)hexadec-7-enoic acid

[0520] Synthesis of 60.1. A mixture of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (int 8_set 64, 200 mg, 502.65 μmol, 1 eq), oxalyl dichloride (70.18 mg, 552.92 μmol, 48.40 μL, 1.1 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and DMF (1.84 mg, 25.13 μmol, 1.93 μL, 0.05 eq) was added to the reaction at 0°C, then the mixture was stirred at 20°C for 30 mins under N2 atmosphere. The mixture was concentrated to give 213 mg of 60.1 (crude) as a brown solid.

[0521] Synthesis of 60.2. A mixture of 2-phenylethan-1-amine (21.2, 72.97 mg, 602.15 μmol, 75.62 μL, 1.2 eq), TEA (152.33 mg, 1.51 mmol, 209.53 μL, 3 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times. Then methyl (Z)-16-chloro-16-oxohexadec-7-enoate (60.1, 159 mg, 501.80 μmol, 1 eq) in DCM (5 mL) was added to the reaction. Then the mixture was stirred at 0°C for 2 hrs under N2 atmosphere. The reaction mixture was diluted H2O 3 mL with and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 200 mg of 60.2 (crude) as a yellow oil. (ES, m / z): [M+1]+402.3

[0522] Synthesis of I-60. A mixture of methyl (Z)-16-oxo-16-(phenethylamino)hexadec-7- enoate (60.2, 50 mg, 124.51 μmol, 1 eq) in THF (0.7 mL) was degassed and purged with N2 for 3 times, and LiOH.H2O (10.45 mg, 249.02 μmol, 2 eq) in H2O (0.3 mL) was added to the reaction. Then the mixture was stirred at 20°C for 2 hrs under N2 atmosphere. LiOH.H2O (10.45 mg, 249.02 μmol, 2 eq) was added to the above mixture and the mixture was stirred at 20°C for 2 hrs under N2 atmosphere. The reaction was filtered and the filter cake was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 20%-50% B over 12.0 min) to give 40 mg of I-60 (31%) as a white solid. (ES, m / z): [M+1]+388.3. I-60:1H NMR (400 MHz, DMSO-d6) δ = 7.92-7.82 (m, 1H), 7.31-7.23 (m, 2H), 7.22-7.14 (m, 3H), 5.32 (t, J = 4.8 Hz, 2H), 3.25-3.21 (m, 2H), 2.72-2.64 (m, 2H), 2.14 (t, J = 7.2 Hz, 2H), 2.07-1.91 (m, 6H), 1.53-1.38 (m, 4H), 1.35-1.14 (m, 12H)

[0523] Example 53. (Z)-16-((4-fluorophenethyl)amino)-16-oxohexadec-7-enoic acid

[0524] Synthesis of 61.1. To a solution of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (int 8_set 64, 300 mg, 1.00 mmol, 1 eq) in THF (1.25 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1- amine (268.65 mg, 2.01 mmol, 0.266 mL, 2 eq). The mixture was stirred at 25°C for 0.5 hr. Then a solution of 2-(4-fluorophenyl)ethan-1-amine (52.1A, 137.5 mg, 988.0 μmol, 1 eq) in THF (2 mL) was added DIEA (383.07 mg, 2.97 mmol, 516.27 μL, 3 eq) and added dropwise to the above reaction mixture. The mixture was stirred at 25°C for 0.5 hr. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna C1880 * 40 mm * 3 um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 110 mg of 61.1 (66%) as a white solid. (ES, m / z): [M+1]+420.3.

[0525] Synthesis of I-61. To a solution of methyl (Z)-16-((4-fluorophenethyl)amino)-16- oxohexadec-7-enoate (61.1, 60 mg, 143.00 μmol, 1 eq) in THF (0.7 mL) was added LiOH.H2O (12.00 mg, 286.01 μmol, 2 eq) in H2O (0.3 mL). The mixture was stirred at 25°C for 2 hrs. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.05%HCl)-ACN]; gradient: 40%-100% B over 8.0 min) to give 25.06 mg of I-61 (43%) as a white solid. (ES, m / z): [M+1]+406.2. I-61:1H NMR (400 MHz, DMSO-d6) δ = 11.98 (br s, 1H), 7.80 (br t, J = 5.6 Hz, 1H), 7.22 (dd, J = 5.6, 8.4 Hz, 2H), 7.14-7.03 (m, 2H), 5.37-5.28 (m, 2H), 3.27-3.21 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.17 (t, J = 7.2 Hz, 2H), 2.03-1.95 (m, 6H), 1.52-1.40 (m, 4H), 1.30-1.14 (m, 12H)

[0526] Example 54. (Z)-16-hydroxy-N-phenethylhexadec-9-enamide

[0527] Synthesis of 62.1. To a solution of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (int 8_set 64, 150 mg, 502.65 μmol, 1 eq) in THF (2 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1- amine (134.33 mg, 1.01 mmol, 133.00 μL, 2 eq). The mixture was stirred at 25°C for 0.5 hr. Then a solution of 2-phenylethan-1-amine (21.2, 60.91 mg, 502.65 μmol, 63.12 μL, 1 eq), DIEA (194.89 mg, 1.51 mmol, 262.66 μL, 3 eq) in THF (1 mL) at 25°C. The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was diluted with H2O (3 mL) and extracted with ethyl acetate 15 mL (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 200 mg of 62.1 (74%) as a yellow oil. (ES, m / z): [M+1]+402.3.

[0528] Synthesis of I-62. THF (2 mL) was charged to the 50 ml three-necked round bottom flask, then LiAlH4(2.5 M, 298.82 μL, 3 eq) was added dropwise to the reaction mixture at 0°C within 0.5 hr. Then a solution of methyl (Z)-16-oxo-16-(2-phenylethylamino)hexadec-7-enoate (62.1, 100 mg, 249.02 μmol, 1 eq) in THF (1 mL) was added dropwise to the reaction mixture at 0°C within 5 mins. After the addition, the mixture was stirred at 25°C for 2 hrs. After 2 hrs, the reaction mixture was quenched by H2O (0.5 mL), followed by NaOH (15%, 0.5 mL) and H2O (1.5 mL) at 0°C within 30 mins. The mixture was filtered and the residue were washed with THF 15 mL (5 mL x 3), the combined solution was washed with brine (15 mL), dried over Na2SO4. The residue was purified by prep-HPLC (column: Xselect CSH C18100 * 30 mm * 5 um; mobile phase: [H2O (0.225%FA)-ACN]; gradient:40%-70% B over 8.0 min) to give 31.40 mg of I-62 (33%) as a white solid. (ES, m / z): [M+1]+374.3. I- 62:1H NMR (400 MHz, DMSO-d6) δ = 7.82 (br t, J = 5.2 Hz, 1H), 7.31-7.24 (m, 2H), 7.22-7.15 (m, 3H), 5.38-5.28 (m, 1H), 4.32 (t, J = 5.2 Hz, 1H), 3.39-3.35 (m, 2H), 3.25 (q, J = 6.8 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.04-1.95 (m, 6H), 1.48-1.35 (m, 4H), 1.32-1.18 (m, 14H).

[0529] Example 55. (Z)-N-(4-fluorophenethyl)-16-hydroxyhexadec-9-enamide

[0530] Synthesis of I-63. THF (2 mL) was charged to the 50 mL three-necked round bottom flask, then LiAlH4(2.5 M, 286.01 μL, 3 eq) was added at 0°C within 0.5 hr. Then a solution of methyl (Z)-16-((4-fluorophenethyl)amino)-16-oxohexadec-7-enoate (61.1, 100 mg, 238.34 μmol, 1 eq) in THF (1 mL) was added dropwise to the reaction mixture at 0°C within 5 mins. After the addition, the mixture was stirred at 25°C for 2 hrs. The reaction mixture was quenched by H2O (1 mL), followed by 15% NaOH (1 mL) and H2O (3 mL) at 0°C within 30 mins. The mixture was filtered and the residue were washed with THF 30 mL (10 mL x 3), the combined solution was washed with brine (15 mL), dried over Na2SO4. The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 10.0 min) to give 9.39 mg of I-63 (10%) as a white solid. (ES, m / z): [M+1]+392.3. I-63:1H NMR (400 MHz, DMSO-d6) δ = 7.80 (br t, J = 5.6 Hz, 1H), 7.25-7.18 (m, 2H), 7.12-7.05 (m, 2H), 5.33 (t, J = 4.8 Hz, 2H), 4.32 (br s, 1H), 3.36 (br d, J = 4.0 Hz, 2H), 3.27-3.21 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.06-1.94 (m, 6H), 1.50-1.36 (m, 4H), 1.32-1.14 (m, 14H)

[0531] Example 56. (S,Z)-16-((2-hydroxy-2-(4-hydroxyphenyl)ethyl)amino)-16- oxohexadec-7-enoic acid

[0532] Synthesis of 64.9. To a solution of (Z)-16-methoxy-16-oxo-hexadec-9-enoic acid (Int 8 set 64, 70 mg, 234.57 μmol, 1 eq) in THF (0.7 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1- amine (47.02 mg, 351.86 μmol, 46.55 μL, 1.5 eq). The mixture was stirred at 20°C for 1 hr. The mixture was concentrated to give 74.3 mg of methyl (Z)-16-chloro-16-oxo-hexadec-7-enoate (crude) as a brown solid. To a solution of (S)-4-(2-amino-1-hydroxyethyl)phenol (8C, 35.93 mg, 234.58 μmol, 1 eq) in H2O (0.7 mL) was added NaOH (28.15 mg, 703.74 μmol, 3 eq) and methyl (Z)-16-chloro-16-oxo-hexadec-7- enoate (74.33 mg, 234.58 μmol, 1 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hr. The mixture was concentrated to give 100 mg of 64.9 (crude) as a white solid.

[0533] Synthesis of I-64. To a solution of methyl (S,Z)-16-((2-hydroxy-2-(4- hydroxyphenyl)ethyl)amino)-16-oxohexadec-7-enoate (64.9, 100 mg, 230.64 μmol, 1 eq) in THF (0.8 mL) and H2O (0.8 mL) was added LiOH.H2O (9.68 mg, 230.64 μmol, 1 eq). The mixture was stirred at 20°C for 2 hrs. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30 mm * 3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-50% B over 8.0 min) to give 18.09 mg of I- 64 (18%) as a white solid. I-64:1H NMR (400 MHz, DMSO-d6) δ = 8.52-8.33 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.42-5.25 (m, 2H), 4.47 (dd, J = 4.4, 7.9 Hz, 1H), 3.22-3.17 (m, 1H), 3.01 (ddd, J = 4.8, 8.0, 13.0 Hz, 1H), 2.08-1.92 (m, 8H), 1.45 (qd, J = 7.6, 15.3 Hz, 4H), 1.35-1.13 (m, 12H)

[0534] Example 57. (R,Z)-16-((2-hydroxy-2-(4-hydroxyphenyl)ethyl)amino)-16- oxohexadec-7-enoic acid

[0535] Synthesis of 65.9. A mixture of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (Int 8_set 64, 100 mg, 335.10 μmol, 1 eq), oxalyl dichloride (46.79 mg, 368.61 μmol, 32.27 μL, 1.1 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times, and DMF (612.32 μg, 8.38 μmol, 6.45e-1 μL, 0.05 eq) was added to the reaction at 0°C, then the mixture was stirred at 20°C for 30 mins under N2 atmosphere. The mixture was concentrated afford the crude product to give 106 mg of methyl (Z)-16- chloro-16-oxo-hexadec-7-enoate (crude) as a brown solid. To a solution of 4-[(1R)-2-amino-1-hydroxy- ethyl]phenol (8D, 51.24 mg, 334.53 μmol, 1 eq) and NaOH (40.14 mg, 1.00 mmol, 3 eq) in H2O (1 mL) was added methyl (Z)-16-chloro-16-oxo-hexadec-7-enoate (106 mg, 334.53 μmol, 1 eq) in THF (2 mL) at 0°C. And the mixture was stirred at 20°C for 1 hr under N2 atmosphere. The crude product was triturated with H2O at 20°C for 10 mins. The filter cake was purified by prep-HPLC (column: X-Select CSH Phenyl-Hexyl 100 * 305u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 30%-70% B over 10.0 min) to give 60 mg of 65.9 (41%) as a white solid.

[0536] Synthesis of I-65. A mixture of methyl (R,Z)-16-((2-hydroxy-2-(4- hydroxyphenyl)ethyl)amino)-16-oxohexadec-7-enoate (65.9, 50 mg, 115.32 μmol, 1 eq) in THF (0.7 mL) was degassed and purged with N2for 3 times, and LiOH.H2O (9.68 mg, 230.64 μmol, 2 eq) in H2O (0.3 mL) was added to the reaction. Then the mixture was stirred at 25°C for 2 hrs under N2atmosphere. The mixture was concentrated afford the crude product. The residue was purified by prep-HPLC (column: X- Select CSH Phenyl-Hexyl 100 * 305u; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 25%-55% B over 8.0 min) to give 35.72 mg of I-65 (73%) as a white solid. I-65:1H NMR (400 MHz, DMSO-d6) δ = 7.76 (br t, J = 5.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.40-5.26 (m, 2H), 4.46 (dd, J =5.2, 7.3 Hz, 1H), 3.22-3.17 (m, 1H), 3.10-3.02 (m, 1H), 2.17 (t, J = 7.2 Hz, 2H), 2.10-1.92 (m, 6H), 1.55- 1.38 (m, 4H), 1.34-1.13 (m, 12H).

[0537] Example 58. methyl 16-((4-hydroxyphenethyl)amino)-16-oxohexadecanoate and 16-((4-hydroxyphenethyl)amino)-16-oxohexadecanoic acid

[0538] Synthesis of I-65A. To a solution of 16-methoxy-16-oxohexadecanoic acid (65.1, 0.2 g, 665.71 μmol, 1 eq) in THF (5 mL) was added 1-chloro-N, N, 2-trimethyl-prop-1-en-1-amine (106.74 mg, 798.85 μmol, 105.68 μL, 1.2 eq). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was used to next step directly. To a solution of 4-(2-aminoethyl)phenol (65.2, 86.04 mg, 627.20 μmol, 1 eq) in THF (5 mL) was added DIEA (243.18 mg, 1.88 mmol, 327.74 μL, 3 eq), then the above prepared methyl 16-chloro-16-oxohexadecanoate (0.2 g, 627.20 μmol, 1 eq) was added dropwise. The mixture was stirred at 25°C for 0.5 hr. The mixture was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 50%-80% B over 10.0 min] to give 150 mg of I-65A (57%) as a white solid. (ES, m / z): [M+1]+420.4. I-65A:1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.68-6.63 (m, 2H), 3.57 (s, 3H), 3.23-3.12 (m, 2H), 2.56 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 2.01 (t, J = 7.4 Hz, 2H), 1.56-1.41 (m, 4H), 1.23 (s, 20H)

[0539] Synthesis of I-65C. A mixture of methyl 16-((4-hydroxyphenethyl)amino)-16- oxohexadecanoate (I-65A, 50 mg, 119.16 μmol, 1 eq) in THF (0.7 mL) was degassed and purged with N2for 3 times and LiOH.H2O (7.50 mg, 178.74 μmol, 1.5 eq) in H2O (0.3 mL) was added to the reaction. Then the mixture was stirred at 25°C for 2 hrs under N2atmosphere. The mixture was concentrated afford the crude product. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 20%-50% B over 10.0 min) to give 35.22 mg of I-65C (72%) as a white solid. (ES, m / z): [M+1]+406.4. I-65C:1H NMR (400 MHz, DMSO-d6) δ = 7.78 (t, J = 5.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 3.18- 3.14 (m, 2H), 2.56 (t, J = 7.4 Hz, 2H), 2.13 (t, J = 7.3 Hz, 2H), 2.01 (t, J = 7.3 Hz, 2H), 1.51-1.37 (m, 4H), 1.23 (s, 20H)

[0540] Example 59. N-(4-hydroxyphenethyl)-8-phenyloctanamide

[0541] Synthesis of I-65B. To a solution of 8-phenyloctanoic acid (65B.1250 mg, 1.13 mmol, 1 eq) in THF (0.5 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (227.44 mg, 1.70 mmol, 225.19 μL, 1.5 eq). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was used to next step directly. To a solution of 4-(2-aminoethyl) phenol (65B.2140 mg, 1.02 mmol, 1 eq) in THF (0.5 mL) was added DIEA (395.70 mg, 3.06 mmol, 533.29 μL, 3 eq) and the above prepared 8- phenyloctanoyl chloride was added dropwise. The mixture was stirred at 25°C for 0.5hr. The mixture was purified by prep-HPLC (column: Xselect CSH C18100*30mm*5um; mobile phase: [H2O (0.2%FA)-ACN]; gradient: 40%-70% B over 12.0 min to give 80.21 mg of I-65B (23%) as a white solid. (ES, m / z): [M-1]+340.3. I-65B:1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.28-7.23 (m, 2H), 7.19-7.13 (m, 3H), 6.96 (d, J = 8.4 Hz, 2H), 6.68-6.64 (m, 2H), 3.21-3.13 (m, 2H), 2.58-2.53 (m, 4H), 2.01 (t, J = 7.4 Hz, 2H), 1.54 (quin, J = 7.2 Hz, 2H), 1.44 (quin, J = 7.2 Hz, 2H), 1.29-1.23 (m, 4H), 1.22-1.15 (m, 2H).

[0542] Example 60. methyl (Z)-16-((4-hydroxyphenethyl)amino)-16-oxohexadec-7- enoate and (Z)-16-((4-hydroxyphenethyl)amino)-16-oxohexadec-7-enoic acid

[0543] Synthesis of I-65D. To a solution of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (int 8_Set 64, 0.06 g, 201.06 μmol, 1 eq) in THF (1 mL) was added Ghosez's reagent (53.73 mg, 402.12 μmol, 53.20 μL, 2 eq). The mixture was stirred at 0°C for 0.5 hr. The mixture was used to the next step directly. To a solution of 4-(2-aminoethyl)phenol (65D.1, 27.71 mg, 201.98 μmol, 1.00 eq) in THF (2 mL) was added DIEA (78.31 mg, 605.94 μmol, 105.54 μL, 3 eq) and methyl (Z)-16-chloro-16-oxo- hexadec-7-enoate (64 mg, 201.98 μmol, 1 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). Thecombined organic layers were washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 26.72 mg of I-65D (31%) as a white solid. (ES, m / z): [M+1]+418.2. I-65D:1H NMR (400 MHz, methanol-d4) δ = 7.04 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 5.43-5.29 (m, 2H), 3.66 (s, 3H), 3.39-3.35 (m, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 2.15 (t, J = 7.4 Hz, 2H), 2.10- 2.02 (m, 4H), 1.67-1.53 (m, 4H), 1.40-1.29 (m, 12H).

[0544] Synthesis of I-65E. To a solution of methyl (Z)-16-((4-hydroxyphenethyl)amino)-16- oxohexadec-7-enoate (I-65D, 36 mg, 86.21 μmol, 1 eq) in THF (0.7 mL) was added LiOH.H2O (5.43 mg, 129.31 μmol, 1.5 eq) in H2O (0.3 mL). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition; column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to give 14.53 mg of I-65E (60%) as a white solid. (ES, m / z): [M+1]+404.2. I-65E:1H NMR (400 MHz, methanol-d4) δ = 7.02 (d, J = 8.4 Hz, 2H), 6.74-6.67 (m, 2H), 5.35 (t, J = 4.7 Hz, 2H), 3.39-3.33 (m, 2H), 2.68 (t, J = 7.3 Hz, 2H), 2.24 (t, J = 7.4 Hz, 2H), 2.13 (t, J = 7.4 Hz, 2H), 2.04 (br s, 4H), 1.58 (td, J = 7.5, 15.4 Hz, 4H), 1.40-1.26 (m, 12H).

[0545] Example 61. (Z)-16-((3,4-dihydroxyphenethyl)amino)-16-oxohexadec-7-enoic acid

[0546] Synthesis of 65F.2. To a solution of 4-(2-aminoethyl)benzene-1,2-diol (65F.1, 0.45 g, 2.94 mmol, 1 eq) in DCM (10 mL) was added imidazole (800.01 mg, 11.75 mmol, 4 eq) and TBSCl (1.11 g, 7.34 mmol, 903.64 μL, 2.5 eq). The mixture was stirred at 25°C for 12 hrs. The mixture was filtered and the filtrate was extracted with DCM 60 mL (20 mL x 3). The combined organic layers were washed with aq. NH4Cl 90 mL (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 94 / 6 to 90 / 10) to give 1 g of 65F.2 (89%) as a brown oil.

[0547] Synthesis of 65F.3. To a solution of (Z)-16-methoxy-16-oxo-hexadec-9-enoic acid (Int.8-Set 64, 80 mg, 268.08 μmol, 1 eq) in THF (1 mL) was added Ghosez's reagent (53.74 mg, 402.12 μmol, 53.20 μL, 1.5 eq). The mixture was stirred at 25°C for 0.5 hr. The mixture was used to the next step directly. To a solution of 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)ethan-1-amine (65F.2, 101.18 mg, 265.10 μmol, 1 eq) in THF (2 mL) was added TEA (80.48 mg, 795.3 μmol, 110.70 μL, 3 eq). Then the above prepared Methyl (Z)-16-chloro-16-oxohexadec-7-enoate (84 mg, 265.10 μmol, 1 eq) in THF (2 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 130 mg of 65F.3 (74%) as a yellow oil. (ES, m / z): [M+1]+662.6.

[0548] Synthesis of 65F.4. To a solution of methyl (Z)-16-((3,4-bis((tert- butyldimethylsilyl)oxy)phenethyl)amino)-16-oxohexadec-7-enoate (65F.3, 20 mg, 30.21 μmol, 1 eq) in THF (2 mL) was added hydroxy(trimethyl)stannane (54.62 mg, 302.07 μmol, 10 eq) at 25°C. The mixture was stirred at 50°C for 96 hrs. The reaction mixture was diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine 3 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give 40 mg of 65F.4 (crude) as a white solid. (ES, m / z): [M+1]+648.5.

[0549] Synthesis of I-65F. A mixture of (Z)-16-((3,4-bis((tert- butyldimethylsilyl)oxy)phenethyl)amino)-16-oxohexadec-7-enoic acid (65F.4, 40 mg, 61.72 μmol, 1 eq) in HCl (1 M, 1.5 mL, 24.30 eq) was degassed and purged with N2for 3 times, then the mixture was stirred at 70°C for 16 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O(0.04% HCl)-ACN];gradient:20%-60% B over 8.0 min) to give 2.55 mg of I-65F (20%) as a white solid. (ES, m / z): [M+1]+420.4. I-65F:1H NMR (400 MHz, methanol-d4) δ = 6.67 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 2.0, 8.0 Hz, 1H), 5.38- 5.33 (m, 2H), 3.36-3.32 (m, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.27 (t, J = 7.4 Hz, 2H), 2.14 (t, J = 7.4 Hz, 2H), 2.09-2.00 (m, 4H), 1.59 (quind, J = 7.0, 13.9 Hz, 4H), 1.38-1.34 (m, 4H), 1.30 (br s, 8H)

[0550] Example 62. (Z)-N-(4-fluorophenethyl)hexadec-9-enamide

[0551] Synthesis of I-65H. To a solution of (Z)-hexadec-9-enoic acid (65H.1, 300 mg, 1.18 mmol, 1 eq) in THF (3 mL) was added 1-chloro-N, N, 2-trimethyl-prop-1-en-1-amine (236.35 mg, 1.77 mmol, 234.01 μL, 1.5 eq). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was used tonext step directly. To a solution of 2-(4-fluorophenyl)ethan-1-amine (65H.2, 163.22 mg, 1.17 mmol, 153.84 μL, 1 eq) in THF (3 mL) was added DIEA (454.73 mg, 3.52 mmol, 612.84 μL, 3 eq), then the mixture was cooled to 0°C and the above prepared (Z)-hexadec-9-enoyl chloride (0.2 g, 627.20 μmol, 1 eq) was added dropwise. The mixture was stirred at 25°C for 1 hr. The mixture was purified by prep- HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)- ACN]; gradient: 65%-95% B over 12.0 min] to give 96.67 mg of I-65H (22%) as a white solid. (ES, m / z): [M+1]+376.3. I-65H:1H NMR (400 MHz, methanol-d4) δ = 7.25-7.18 (m, 2H), 6.99 (t, J = 8.8 Hz, 2H), 5.40-5.30 (m, 2H), 3.39 (t, J = 7.3 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 2.13 (t, J = 7.4 Hz, 2H), 2.07-2.00 (m, 4H), 1.59-1.51 (m, 2H), 1.37-1.25 (m, 16H), 0.94-0.86 (m, 3H)

[0552] Example 63. (Z)-16,16,16-trifluoro-N-(4-hydroxyphenethyl)hexadec-9-enamide

[0553] Synthesis of 65I.2. To a solution of dec-9-yn-1-ol (65I.1, 3 g, 19.45 mmol, 1 eq) in Tol. (30 mL) was added 3, 4-dihydro-2H-pyran (1.96 g, 23.34 mmol, 2.13 mL, 1.2 eq) and TFA (221.76 mg, 1.94 mmol, 144.47 μL, 0.1 eq). The mixture was stirred at 110°C for 2 hrs. Then 3, 4-dihydro-2H- pyran (817.99 mg, 9.72 mmol, 889.12 μL, 0.5 eq) was added and the mixture was stirred at 110°C for 14 hrs. The mixture was concentrated under reduced pressure to give a residue which was purified bycolumn chromatography (SiO2, Petroleum ether / Ethyl acetate = 98 / 2 to 3 / 1) to give 3.5 g of 65I.2 (75%) as a colorless oil.

[0554] Synthesis of 65I.4. THF (10 mL) was charged to the three-necked round bottom flask, then 2-(dec-9-yn-1-yloxy)tetrahydro-2H-pyran (65I.2, 1 g, 4.20 mmol, 1 eq) was added to the mixture at 20°C. Then n-BuLi (2.5 M, 2.52 mL, 1.5 eq) was added dropwise to the reaction mixture at -40°C within 5 mins, the mixture was stirred at -40°C for 1 hr. Then the mixture was warmed to -10°C, HMPA (1.50 g, 8.39 mmol, 1.47 mL, 2 eq) was added to the reaction mixture and a solution of 6-bromo-1,1,1- trifluorohexane (65I.3, 1.38 g, 6.29 mmol, 1.5 eq) in THF (5 mL) was added dropwise to the solution at - 10°C. The reaction mixture was stirred at 20°C for 24 hrs. Aq. NH4Cl (40 mL) was added to the reaction mixture at 0°C and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 99 / 1 to 98 / 2) to afford 1.4 g of 65I.4 (88%) as a colorless oil.

[0555] Synthesis of 65I.5. To a solution of 2-((16,16,16-trifluorohexadec-9-yn-1- yl)oxy)tetrahydro-2H-pyran (65I.4, 800 mg, 2.12 mmol, 1 eq) in acetone (10 mL) was added Jones reagent (2.5 M, 3.00 mL, 3.53 eq) dropwise at 0°C within 10 mins. The mixture was stirred at 25°C for 2 hrs. The mixture was diluted with H2O (20 mL) and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with sat. NaHCO3(10 mL), brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 96 / 4 to 94 / 6) to afford 500 mg of 65I.5 (76%) as a white solid. (ES, m / z): [M-1]- 305.1

[0556] Synthesis of 65I.6. To a solution of 16, 16, 16-trifluorohexadec-9-ynoic acid (65I.5, 100 mg, 326.41 μmol, 1 eq) in THF (1 mL) was added Lindlar (67.41 mg, 16.32 μmol, 3.26e-1 μL, 5% purity, 0.05 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred at 0°C for 10 mins under H2(15 Psi). The suspension was filtered and the filter cake was washed with THF (3mL x 3). The combined filtrates were concentrated under reduced pressure to give 80 mg of 65I.6 (crude) as a yellow oil. (ES, m / z): [M-1]- 307.1

[0557] Synthesis of 65I.7. To a solution of (Z)-16, 16, 16-trifluorohexadec-9-enoic acid (65I.6, 80 mg, 259.42 μmol, 1 eq) in THF (1 mL) was added 1-chloro-N,N,2-trimethyl-prop-1-en-1- amine (69.33 mg, 518.84 μmol, 68.64 μL, 2 eq). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was used to next step directly.

[0558] Synthesis of I-65I. To a solution of 4-(2-aminoethyl)phenol (65I.8, 35.59 mg, 259.44 μmol, 1 eq) in THF (0.5 mL) was added DIEA (100.59 mg, 778.31 μmol, 135.56 μL, 3 eq) and (Z)- 16,16,16-trifluorohexadec-9-enoyl chloride (65I.7, 84.79 mg, 259.44 μmol, 1 eq). The mixture was stirred at 25°C for 1 hr. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 55%-85% B over 8.0min) to give 15 mg of product (SFC shows only ~20% (Z)-alkene and ~80% (E)-alkene). The residue was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [CO2-MeOH (0.1%NH3H2O)]; B%:15%, isocratic elution mode) to give 3.0 mg of I-65I (2.7%) as a yellow oil. (ES, m / z): [M+1]+428.4. I-65I:1H NMR (400 MHz, MeOD). δ = 7.02 (d, J = 8.4 Hz, 2H), 6.73-6.67 (m, 2H), 5.42-5.30 (m, 2H), 3.37-3.33 (m, 2H), 2.71-2.65 (m, 2H), 2.20-2.09 (m, 4H), 2.09- 2.00 (m, 4H), 1.63-1.51 (m, 4H), 1.42-1.27 (m, 12H).19FNMR (376.5 MHz, MeOD) δ = 67.99 (s).

[0559] Example 64. (S,Z)-2-(heptadec-9-enamido)-3-phenylpropanoic acid

[0560] Synthesis of 152.2. To a solution of 9-bromononanoic acid (152.1, 20 g, 84.34 mmol, 1 eq) in toluene (200 mL) was added PPh3(22.12 g, 84.34 mmol, 1 eq). The mixture was stirred at 140°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give 33 g of 152.2 (78%) as a white solid. (ES, m / z): [M+1]+420.2.

[0561] Synthesis of 152.4. To a solution of (8-carboxyoctyl)triphenylphosphonium bromide (152.2, 0.6 M, 33.37 mL, 2 eq) in THF (5 mL) was added dropwise KOtBu (1 M, 40.05 mL, 4 eq) at 0°C. The mixture was warm to 20°C and stirred for 0.5 h, then a solution of the octanal (2 M, 5.01 mL, 1 eq) in THF (2 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 20°C for 12 hrs. The mixture was quenched with 1M HCl, diluted with H2O (50 mL x 3) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 2.2 g of 152.4 (34%) as a white solid. (ES, m / z): [M+1]+269.2.

[0562] Synthesis of 152.6. To a solution of (Z)-heptadec-9-enoic acid (152.4, 30 mg, 111.76 umol, 1 eq) in DCM (2 mL) was added HATU (50.99 mg, 134.11 umol, 1.2 eq) and TEA (39.58 mg, 391.16 umol, 54.44 uL, 3.5 eq). Then (S)-methyl 2-amino-3-phenylpropanoate (152.5, 36.16 mg, 167.64 umol, 1.5 eq, HCl) was added to the reaction and stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10:1 to 1:1) to give 28 mg of 152.6 (58%) as a yellow oil. (ES, m / z): [M+1]+430.3.

[0563] Synthesis of I-66. To a solution of (S,Z)-methyl 2-(heptadec-9-enamido)-3- phenylpropanoate (152.6, 18 mg, 41.90 umol, 1 eq) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.11 mg, 50.28 umol, 1.2 eq). The mixture was stirred at 20°C for 12 hrs. The mixture was adjusted pH = 5 with HCl aq. (1M) and solids precipitated out of the solution. The suspension was filtered and the filter cake was dissolved with methanol and concentrated under reduced pressure to give 7 mg of I-66 (26%) as a white solid. (ES, m / z): [M+1]+416.2. I-66:1H NMR (400 MHz, chloroform-d) δ = 7.36-7.27 (m, 3H), 7.21-7.16 (d, J = 6.8 Hz, 2H), 5.79 (br d, J = 7.2 Hz, 1H), 5.40-5.32 (m, 2H), 4.89-4.80 (q, J = 6.8 Hz, 1H), 3.31-3.23 (m, 1H), 3.18-3.11 (m, 1H), 2.22-2.14 (t, J = 8.4 Hz, 2H), 2.06- 1.98 (m, 4H), 1.63-1.52 (m, 3H), 1.37-1.22 (m, 18H), 0.92-0.86 (t, J = 6.8 Hz, 3H).

[0564] Example 65. (S,Z)-2-(heptadec-14-enamido)-3-phenylpropanoic acid

[0565] Synthesis of 157.2. To a solution of (Z)-heptadec-14-enoic acid (Acid 4, 60 mg, 223.52 umol, 1 eq) in DMF (1 mL) was added DIPEA (72.22 mg, 558.80 umol, 97.33 uL, 2.5 eq), EDCI (51.42 mg, 268.22 umol, 1.2 eq), HOBt (36.24 mg, 268.22 umol, 1.2 eq) and (S)-methyl 2-amino-3- phenylpropanoate (157.1, 57.85 mg, 268.22 umol, 1.2 eq). The reaction mixture was stirred at 20°C for 4 hrs. The mixture was poured into 5 mL of water and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4and filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10:1 to 1:1, according to TLC) to give 60 mg of 157.2 (62%) as an off-white solid. (ES, m / z): [M+1]+430.3.

[0566] Synthesis of I-67. To a solution of (S,Z)-methyl 2-(heptadec-14-enamido)-3- phenylpropanoate (157.2, 50 mg, 116.38 umol, 1 eq) in THF (0.75 mL) was added a solution of LiOH.H2O (6.35 mg, 151.29 umol, 1.3 eq) in H2O (0.75 mL) at 20°C. The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (0.5 mL) and adjusted to pH = 5 with HCl aq. (1M), the solids precipitated out of the solution. The suspension was filtered and the filter cake was dried to give the product. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 35%-75%, 8min) to give 12.2 mg of I-67 (24%) as a white solid. (ES, m / z): [M+1]+416.2. I-67:1H NMR (400 MHz, chloroform-d) δ = 7.35-7.28 (m, 3H), 7.20-7.15 (d, J = 6.4 Hz, 2H),5.88 (br d, J = 7.2 Hz, 1H), 5.44-5.29 (m, 2H), 4.87 (q, J = 6.8 Hz, 1H), 3.31-3.22 (m, 1H), 3.18-3.10 (m, 1H), 2.24-2.13 (m, 2H), 2.09-1.97 (m, 4H), 1.62-1.53 (m, 2H), 1.37-1.23 (m, 18H), 1.02-0.92 (t, J = 7.2 Hz, 3H).

[0567] Example 66.1-(7-(3-butylphenyl)heptyl)-3-phenethylurea.

[0568] Synthesis of 73.3. To a solution of 1-bromo-3-butylbenzene (73.1, 1.5 g, 7.04 mmol, 1 eq) Pd(PPh3)2Cl2(247.01 mg, 351.93 μmol, 0.05 eq) and CuI (67.02 mg, 351.92 μmol, 0.05 eq) in TEA (10 mL) was added oct-7-ynoic acid (73.2, 1.48 g, 10.56 mmol, 1.5 eq) at 25°C. The mixture was heated to 60°C and stirred for 2 hrs. The mixture was adjusted to pH = 2 with HCl (1M), then extracted with ethyl acetate 25 mL. The combined organic layers were washed with brine 20 mL dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (FA condition: column: Phenomenex Titank C18 Bulk 250*70mm 10u;mobile phase: [H2O (0.2%FA)-ACN];gradient:45%-85% B over 20.0 min) to give 300 mg of 73.3 (15%) as yellow oil. (ES, m / z): [M+1] + 273.2.

[0569] Synthesis of 73.4. To a solution of 8-(3-butylphenyl) oct-7-ynoic acid (73.3, 280 mg, 1.03 mmol, 1 eq) in MeOH (5 mL) was added Pd / C (280.00 mg, 263.11 μmol, 10% purity, 2.56e-1 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi.) at 25°C for 12hrs. The mixture was filtered through celite pad. The filter cake was rinsed with MeOH (5 ml x 3) and the filtrate was concentrated under reduced pressure to give 200 mg of 73.4 (crude) as yellow oil. (ES, m / z): [M-1]- 275.2

[0570] Synthesis of I-73. To a solution of 8-(3-butylphenyl) octanoic acid (73.4, 200 mg, 723.56 μmol, 1 eq) in Tol. (3 mL) was added TEA (80.54 mg, 795.91 μmol, 110.78 μL, 1.1 eq) and DPPA (219.03 mg, 795.91 μmol, 171.79 μL, 1.1 eq). The mixture was stirred at 25°C for 1 hr, then the mixture was heated to 90°C, and stirred for 2 hrs. After allowing the mixture to cool, a solution of 2- phenylethan-1-amine (73.5, 87.68 mg, 723.56 μmol, 90.86 μL, 1 eq) in Tol. (3 mL) was added dropwise under ice-cooling while stirring. The reaction solution was returned slowly to room temperature and stirred for 12 hrs. The mixture was concentrated under reduced pressure to give a residue which was purified prep-HPLC (neutral condition: column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 60%-90% B over 15.0 min) to give 93.39 mg of I-73(32%) as white solid. (ES, m / z): [M+1] +395.3. I-73:1H NMR (400 MHz, chloroform-d) δ = 7.35-7.28 (m, 2H), 7.26-7.15 (m, 4H), 7.02-6.97 (m, 3H), 4.21-4.06 (m, 2H), 3.50-3.42 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.58 (dt, J = 6.0, 7.6 Hz, 4H), 1.65-1.57 (m, 4H), 1.49-1.41 (m, 2H), 1.40-1.26 (m, 8H), 0.93 (t, J = 7.2 Hz, 3H)

[0571] Example 67. methyl (Z)-16-((3,4-dihydroxyphenethyl)amino)-16-oxohexadec-7- enoate).

[0572] Synthesis of 74.2. To a solution of 8-bromooctan-1-ol (74.1, 9 g, 43.04 mmol, 7.38 mL, 1 eq) in DCM (135 mL) was added TBSCl (7.14 g, 47.34 mmol, 5.82 mL, 1.1 eq) and imidazole (3.52 g, 51.64 mmol, 1.2 eq) at 15°C. The mixture was stirred at 15°C for 16 hrs. The residue was diluted with H2O (120 mL x 2). The organic phase was separated, washed with brine 100 mL, dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 50 / 1) to give 12.7 g of 74.2 (91%) as yellow oil.

[0573] Synthesis of 74.4. To a solution of oct-7-ynoic acid (74.3, 4.37 g, 30.92 mmol, 1 eq) and HMPA (33.24 g, 185.54 mmol, 32.46 mL, 6 eq) in THF (100 mL) was added n-BuLi (2.5 M, 25.98 mL, 2.1 eq) at -65°C. The mixture was stirred at -65°C for 3 hrs. A solution of ((8- bromooctyl)oxy)(tert-butyl)dimethylsilane (74.2, 5 g, 15.46 mmol, 1 eq) in THF (25 mL) was added dropwise to the solution above, and the reaction mixture was stirred at 15°C for 13 hrs. The reaction mixture was diluted with HCl (150 mL, 1 M) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine 150 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 30 / 1) to give 4.7 g of 74.4 as a yellow oil.

[0574] Synthesis of 74.5. THF (260 mL) was charged to the round bottom flask, then 16- ((tert-butyldimethylsilyl)oxy)hexadec-7-ynoic acid (74.4, 4.3 g, 11.24 mmol, 1 eq) and LINDLAR CATALYST (2.15 g, 520.56 μmol, 2.15 mL, 5% purity, 4.63e-2 eq) was added to the mixture at 0°C. After the addition, the mixture was stirred at 20°C for 5 hrs under H2balloon. The reaction mixture was filtered and the filtrate was concentrated to give 4.06 g of 74.5 (93%) as a light-yellow oil.

[0575] Synthesis of 74.6. A mixture of (Z)-16-((tert-butyldimethylsilyl)oxy)hexadec-7-enoic acid (74.5, 2.3 g, 5.98 mmol, 1 eq), DMF (21.85 mg, 298.96 μmol, 23.00 μL, 0.05 eq) in DCM (23 mL) was degassed and purged with N2for 3 times, and oxalyl dichloride (834.81 mg, 6.58 mmol, 575.73 μL, 1.1 eq) was added to the reaction at 0°C, then the mixture was stirred at 20°C for 30 mins under N2atmosphere. The reaction was used to next step directly.

[0576] Synthesis of 74.7. The reaction mixture of 74.6 was added to MeOH (10 mL), and then the mixture was stirred at 24°C for 16 hrs under N2atmosphere. The mixture was concentrated to afford the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 11 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) to give 0.92 g of 74.7 as a yellow oil.

[0577] Synthesis of Int 8_set 64. To a solution of methyl (Z)-16-hydroxyhexadec-7-enoate (74.7, 920 mg, 3.23 mmol, 1 eq) in acetone (15 mL) was slowly added Jones reagent (2.5 M, 1.55 mL, 1.2 eq) dropwise at 0°C. The reaction solution was stirred at 25°C for 2 hrs. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc (10 mL), and washed with water (5 mL). The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) to give 570 mg of Int 8_set 64 (59%) as a yellow oil.

[0578] Synthesis of I-74. To a solution of (Z)-16-methoxy-16-oxo-hexadec-9-enoic acid (Int 8_set 64, 100 mg, 335.10 μmol, 1 eq) in DMF (2 mL) was added 4-(2-aminoethyl)benzene-1,2-diol(74.8, 76.26 mg, 402.12 μmol, 1.2 eq, HCl), HOBt (54.34 mg, 402.12 μmol, 1.2 eq), TEA (40.69 mg, 402.12 μmol, 55.97 μL, 1.2 eq) and EDCI (96.36 mg, 502.65 μmol, 1.5 eq) and the mixture was stirred at 25°C for 16 hrs under N2. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 40%-80% B over 8.0 min) to give 92 mg of I-74 (63%, ee value: 85.66%) as a white solid. The residue was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-MeOH]; B%:30%, isocratic elution mode) to give 48 mg of I-74 (52%, ee value: 87.06%) as a white solid. Another batch (about 77 mg) was combined with this batch (48 mg) and was separated again by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D.10um; mobile phase: [Heptane-EtOH]; B%:40%, isocratic elution mode) to give 50.17 mg of I-74 (63%) as a white solid. (ES, m / z): [M+1] +434.4.

[0579] SFC separation methods:

[0580] Method 1: Instrument: Waters SFC150AP Preparative SFC System; Column: DAICEL CHIRALPAK AD(250mm*30mm,10um); Mobile phase: A for CO2 and B for MeOH; Gradient: B%=30.00% isocratic elution mode; Flow rate: 70.00g / min; Monitor wavelength: 220&254nm; Column temperature: 40°C; System back pressure: 100 bar

[0581] Method 2: Instrument: Gilson 281 Semi-preparative HPLC system; Column: DAICEL CHIRALCEL OZ 250*25 mm I.D.10um; Mobile phase: A for CO2 and B for EtOH; Gradient: B%=40.00% isocratic elution mode; Flow rate: 50.00g / min; Monitor wavelength: 220&254nm; Column temperature: 40°C; System back pressure: 100 bar

[0582] I-74:1H NMR (400 MHz, DMSO-d6) δ = 8.72 (s, 1H), 8.62 (s, 1H), 7.77 (br t, J = 5.6 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.41 (dd, J = 2.0, 8.0 Hz, 1H), 5.39-5.26 (m, 2H), 3.57 (s, 3H), 3.19-3.09 (m, 2H), 2.47 (s, 2H), 2.28 (t, J = 7.2 Hz, 2H), 2.05-1.93 (m, 6H), 1.57-1.41 (m, 4H), 1.36-1.13 (m, 12H)

[0583] Example 68. (Z)-16-hydroxy-N-(4-hydroxyphenethyl)hexadec-9-enamide)

[0584] Synthesis of 75.2. To a solution of (Z)-16-methoxy-16-oxohexadec-9-enoic acid (int 8_Set 64, 0.1 g, 335.10 μmol, 1 eq) in THF (1 mL) was added Ghosez's reagent (89.55 mg, 670.20 μmol, 88.67 μL, 2 eq). The mixture was stirred at 0°C for 0.5 hr. The mixture was used to the next stepdirectly. The resulting mixture was added to a solution of 4-(2-aminoethyl)phenol (75.1, 45.97 mg, 335.10 μmol, 1.00 eq) and DIEA (129.92 mg, 1.01 mmol, 175.10 μL, 3 eq) in THF (4 mL) at 0°C. The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 50%-85% B over 8.0 min) to give 70 mg of 75.2 (46%) as a white solid. (ES, m / z): [M+1] + 418.2.

[0585] Synthesis of I-75. Equip a 25 ml three-necked round bottom flask, thermometer and N2 balloon. THF (2 mL) was charged to the 25 ml three-necked round bottom flask, and then LiAlH4 (2.5 M, 172.42 μL, 3 eq) was added at 0°C. Then methyl (Z)-16-((4-hydroxyphenethyl)amino)-16- oxohexadec-7-enoate (75.2, 60 mg, 143.69 μmol, 1 eq) in THF (1 mL) was added dropwise to the reaction mixture at 0°C. After the addition, the mixture was stirred at 25°C for 1.5 hrs. The reaction mixture was quenched by addition of MeOH 2 mL at 0°C and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18 100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN];gradient:40%-70% B over 8.0 min) to give 24.92 mg of I-75 (44%) as a white solid. (ES, m / z): [M+1] + 390.4. I-75:1H NMR (400 MHz, methanol- d4) δ = 7.02 (d, J = 8.4 Hz, 2H), 6.75-6.67 (m, 2H), 5.42-5.28 (m, 2H), 3.54 (t, J = 6.8 Hz, 2H), 3.38-3.34 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 2.08-2.00 (m, 4H), 1.54 (td, J = 7.2, 14.4 Hz, 4H), 1.39-1.26 (m, 14H)

[0586] Example 69. (Z)-N-(4-hydroxyphenethyl)-16-oxohexadec-9-enamide

[0587] Synthesis of 77.2. To a solution of oxalyl chloride (14.02 g, 110.45 mmol, 9.67 mL, 2 eq) in DCM (120 mL) was added dropwise DMSO (17.26 g, 220.91 mmol, 17.26 mL, 4 eq) at -70°C and the mixture was stirred at -70°C for 30 min, then 6-bromohexan-1-ol (77.1, 10 g, 55.23 mmol, 7.23 mL, 1 eq) was added dropwise to the solution at -70°C and stirred at -20°C for 0.5 hr. After that, the solution was cooled to -65°C and TEA (33.53 g, 331.36 mmol, 46.12 mL, 6 eq) was added dropwise to the solution. The solution was warmed to 25°C and stirred at 25°C for 0.5 hr. The reaction mixture was quenched by addition of H2O 100 mL at 25°C, and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 11 g of 77.2 (crude) as a yellow oil.

[0588] Synthesis of 77.3. To a solution of 6-bromohexanal (77.2, 11 g, 61.43 mmol, 1 eq) in MeOH (150 mL) was added trimethoxymethane (77.2A, 13.04 g, 122.87 mmol, 13.47 mL, 2 eq) and TsOH (21.16 g, 122.87 mmol, 2 eq) and the mixture was stirred at 70°C for 16 hrs. The reaction mixture was dropwise to NaHCO3 (aq.) (500 mL) at 25°C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1) to give 8.4 g of 77.3 (60%) as a yellow oil.

[0589] Synthesis of 77.4. Equip a 100 mL three-necked round bottom flask, addition funnel and thermometer, N2 balloon etc. THF (120 mL) was charged to the three-necked round bottom flask, then dec-9-ynoic acid (77.3A, 1.95 g, 11.59 mmol, 1 eq) and HMPA (30.72 g, 171.43 mmol, 30.00 mL, 14.79 eq) was added to the solution at 25°C. At -60°C (inner temperature), n-BuLi (2.5 M, 10.66 mL, 2.3 eq) was added dropwise to the reaction mixture and stirred at 0°C for 2 hrs. A solution of 6-bromo- 1,1-dimethoxyhexane (77.3, 3 g, 13.33 mmol, 1.15 eq) in THF (30 mL) was added dropwise to the solution at -60°C. The reaction mixture was warm to 15°C slowly and stirred at 15°C for 16 hrs. The reaction mixture was quenched by addition of HCl (1M) 30 mL at 25°C, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to give 1.4 g of 77.4 (28%) as a yellow oil.

[0590] Synthesis of 77.5. To a solution of 16,16-dimethoxyhexadec-9-ynoic acid (77.4, 0.2 g, 640.12 μmol, 1 eq) in EtOAc (10 mL) was added LINDLAR CATALYST (400.00 mg, 96.85 μmol, 400.00 μL, 5% purity, 1.51e-1 eq) at 0°C and the mixture was stirred at 0°C for 10 min under H2(15 Psi).The reaction mixture was filtered and concentrated under reduced pressure to give 190 mg of 77.5 (92%, crude) as a colorless oil.

[0591] Synthesis of I-77 To a solution of (Z)-16,16-dimethoxyhexadec-9-enoic acid (5.5, 190 mg, 604.21 μmol, 1 eq) in DMF (5 mL) was added HATU (229.74 mg, 604.21 μmol, 1 eq) and DIEA (234.27 mg, 1.81 mmol, 315.73 μL, 3 eq) at 15°C and the mixture was stirred at 15°C for 0.5 hr, then 4- (2-aminoethyl)phenol (77.5A, 82.89 mg, 604.21 μmol, 1 eq) was added to the solution at 15°C and the mixture was stirred at 15°C for 0.5 hr. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 55%-85% B over 8.0 min) to give product 200mg (ee value: 76.5%). 200 mg and another 23mg batch was purified together by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2- MeOH]; B%:30%, isocratic elution mode) to give 140 mg of I-77 (53%) as a colorless oil. (ES, m / z): [M-31] +402.3.

[0592] SFC separation methods:

[0593] Method 1: Instrument: Waters SFC150AP Preparative SFC System; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: A for CO2 and B for MeOH; Gradient: B%=30.00% isocratic elution mode; Flow rate: 50.00g / min; Monitor wavelength: 220&254nm; Column temperature: 40°C; System back pressure: 100 bar. I-77:1H NMR (400 MHz, DMSO-d6) δ = 9.15 (br s, 1H), 7.78 (br t, J = 5.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 5.39-5.26 (m, 2H), 4.30 (t, J = 5.6 Hz, 1H), 3.23-3.12 (m, 8H), 2.56 (t, J = 7.6 Hz, 2H), 2.04-1.95 (m, 6H), 1.52-1.40 (m, 4H), 1.33-1.17 (m, 14H).

[0594] Example 70. (Z)-N-(4-hydroxyphenethyl)-16-oxohexadec-9-enamide

[0595] Synthesis of 78.2. To a solution of oxalyl chloride (14.02 g, 110.45 mmol, 9.67 mL, 2 eq) in DCM (120 mL) was added dropwise DMSO (17.26 g, 220.91 mmol, 17.26 mL, 4 eq) at -70°C and the mixture was stirred at -70°C for 30 min, then 6-bromohexan-1-ol (78.1, 10 g, 55.23 mmol, 7.23 mL, 1 eq) was added dropwise to the solution at -70°C and stirred at -20°C for 0.5 hr. After that, the solution was cooled to -65°C and TEA (33.53 g, 331.36 mmol, 46.12 mL, 6 eq) was added dropwise to the solution and the solution was warmed to 25°C, then the mixture was stirred at 25°C for 0.5 hr. The reaction mixture was quenched by addition of H2O 100 mL at 25°C, and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 11 g of 78.2 (crude) as a yellow oil.

[0596] Synthesis of 78.3. To a solution of 6-bromohexanal (78.2, 11 g, 61.43 mmol, 1 eq) in MeOH (150 mL) was added trimethoxymethane (78.2A, 13.04 g, 122.87 mmol, 13.47 mL, 2 eq) and TosOH (21.16 g, 122.87 mmol, 2 eq) and the mixture was stirred at 70°C for 16 hrs. The reaction mixture was dropwise to NaHCO3 (aq.) (500 mL) at 25°C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1) to give 8.4 g of 78.3 (60%) as a yellow oil.

[0597] Synthesis of 78.4. Equip a 100 mL three-necked round bottom flask, addition funnel and thermometer, N2balloon etc. THF (120 mL) was charged to the three-necked round bottom flask, then dec-9-ynoic acid (78.3A, 1.95 g, 11.59 mmol, 1 eq) and HMPA (30.72 g, 171.43 mmol, 30.00 mL, 14.79 eq) was added to the solution at 25°C. At -60°C (inner temperature), n-BuLi (2.5 M, 10.66 mL, 2.3 eq) was added dropwise to the reaction mixture and stirred at 0°C for 2 hrs. A solution of 6-bromo- 1,1-dimethoxyhexane (78.3, 3 g, 13.33 mmol, 1.15 eq) in THF (30 mL) was added dropwise to the solution at -60°C. The reaction mixture was warm to 15°C slowly and stirred at 15°C for 16 hrs. The reaction mixture was quenched by addition of HCl (1 M) 30 mL at 25°C, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnchromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to give 1.4 g of 78.4 (28%) as a yellow oil.

[0598] Synthesis of 78.5. Five batches in parallel. To a solution of 16,16-dimethoxyhexadec- 9-ynoic acid (78.4, 0.2 g, 640.12 μmol, 1 eq) in EtOAc (10 mL) was added Lindlar catalyst (400.00 mg, 96.85 μmol, 400.00 μL, 5% purity, 1.51e-1 eq) at 0°C and the mixture was stirred at 0°C for 10 min under H2(15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give a 190 mg of 78.5 (crude) as a colorless oil.

[0599] Synthesis of 78.6. To a solution of (Z)-16,16-dimethoxyhexadec-9-enoic acid (78.5, 190 mg, 604.21 μmol, 1 eq) in DMF (5 mL) was added HATU (229.74 mg, 604.21 μmol, 1 eq) and DIEA (234.27 mg, 1.81 mmol, 315.73 μL, 3 eq) at 15°C and the mixture was stirred at 15°C for 0.5 hr, then 4-(2-aminoethyl)phenol (78.5A, 82.89 mg, 604.21 μmol, 1 eq) was added to the solution at 15°C and the mixture was stirred at 15°C for 0.5 hr. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 55%-85% B over 8.0 min) to give 200 mg of 78.6 (ee value: 76.5%). 200 mg and another 23 mg batch was purified together by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CO2-MeOH]; B%: 30%, isocratic elution mode) to give 140 mg of 78.6 (53%) as a colorless oil. (ES, m / z): [M-31] +402.3.

[0600] SFC separation methods:

[0601] Method 1: Instrument: Waters SFC150AP Preparative SFC System; Column: DAICEL CHIRALPAK AD(250 mm x 30 mm, 10 um); Mobile phase: A for CO2 and B for MeOH; Gradient: B%=30.00% isocratic elution mode; Flow rate: 50.00 g / min; Monitor wavelength: 220 & 254 nm; Column temperature: 40℃; System back pressure: 100 bar

[0602] Synthesis of I-78. A solution of (Z)-N-(4-hydroxyphenethyl)-16, 16- dimethoxyhexadec-9-enamide (78.6, 70 mg, 161.43 μmol, 1 eq) in HCl / dioxane (3.5 mL) was stirred at 15°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ACN (3 mL) and 10 mL H2O and then lyophilization to give 41.05 mg of I-78 (65%) as an off-white solid. (ES, m / z): [M+1] + 388.3. I-78:1H NMR (400 MHz, DMSO-d6) δ = 9.70- 9.60 (m, 1H), 9.20-9.09 (m, 1H), 7.77 (br t, J = 5.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.39-5.25 (m, 2H), 3.20-3.14 (m, 2H), 2.59-2.53 (m, 2H), 2.40 (dt, J = 1.6, 7.2 Hz, 2H), 2.07-1.92 (m, 6H), 1.58-1.38 (m, 4H), 1.33-1.17 (m, 12H).

[0603] Example 71. (Z)-15-hydroxy-N-(4-hydroxyphenethyl)-15-methylhexadec-9- enamide.

[0604] Synthesis of 79.2. To a solution of methyl 5-bromopentanoate (79.1, 3 g, 15.38 mmol, 2.20 mL, 1 eq) in THF (18 mL) was added dropwise MeMgBr (3 M, 15.38 mL, 3 eq) at 0°C over 15 mins. After addition, the mixture was stirred for 15 mins at 0°C, then stirred for 5 hrs at 15°C. The reaction mixture was quenched by addition of sat. NH4Cl (30 mL) at 0°C, then diluted with H2O (30 mL) and extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was combined with the batch 2 scale (3 g) for further purification. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 7% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 8 g of 79.2 (88%) as a yellow oil.

[0605] Synthesis of 79.3. To a solution of 6-bromo-2-methylhexan-2-ol (79.2, 8 g, 41.01 mmol, 1 eq) in DCM (80 mL) was added [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (179.93 g, 680.69 mmol, 156.33 mL, 16.6 eq) and 2,6-dimethylpyridine (102.38 g, 955.42 mmol, 111.28 mL, 23.3 eq) at 0°C. The mixture was stirred at 15°C for 2 hrs. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM 300 mL (100 mL x 3). The combined organic layers were washed with HCl (0.1 M, 50 mL), brine (50 mL), NaHCO3(50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0) to give 7 g of 79.3 (55%) as a white solid.

[0606] Synthesis of 79.4. Equip a 500 mL three-necked round bottom flask, addition funnel and thermometer, N2 balloon. THF (80 mL) was charged to the three-necked round bottom flask, then dec-9-ynoic acid (79.3A, 945.76 mg, 5.62 mmol, 1 eq) and HMPA (21.41 g, 119.46 mmol, 20.91 mL, 21.25 eq) was added to the solution at 15°C. n-BuLi (2.5 M, 5.17 mL, 2.3 eq) was added dropwise to the reaction mixture at -60°C and stirred at 0°C for 2 hrs. A solution of ((6-bromo-2-methylhexan-2-yl)oxy)(tert-butyl)dimethylsilane (79.3, 2 g, 6.47 mmol, 1.15 eq) in THF (20 mL) was added dropwise to the solution at -60°C. The reaction mixture was warm to 15°C slowly and stirred at 15°C for 14 hrs. The reaction mixture was quenched by addition of HCl (1 M) 30 mL at 15°C, then extracted with ethyl acetate 360 mL (120 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 5% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) to give 1.5 g of 79.4 (70%) as a yellow oil. (ES, m / z): [M-1]- 395.3.

[0607] Synthesis of 79.5. To a solution of 15-((tert-butyldimethylsilyl)oxy)-15- methylhexadec-9-ynoic acid (79.4, 700 mg, 1.76 mmol, 1 eq) in THF (7 mL) was added Lindlar Catalyst (364.42 mg, 88.23 μmol, 364.42 μL, 5% purity, 0.05 eq) under N2atmosphere. The suspension was degassed and purged with H2(15 Psi) for 3 times. The mixture was stirred at 0°C for 0.5 hr under H2(15 Psi). The reaction mixture was filtered and the filter was concentrated to give 650 mg of 79.5 (85%) as a yellow oil. (ES, m / z): [M-1]- 397.4.

[0608] Synthesis of 79.6. To a solution of (Z)-15-[tert-butyl(dimethyl)silyl]oxy-15-methyl- hexadec-9-enoic acid (7.5, 600 mg, 1.50 mmol, 1 eq) in THF (6 mL) was added 1-chloro-N,N,2- trimethyl-prop-1-en-1-amine (201.09 mg, 1.50 mmol, 199.10 μL, 1 eq). The mixture was stirred at 15°C for 0.5 hr. The resulting solution was used directly. To a solution DIEA (583.50 mg, 4.51 mmol, 786.39 μL, 3 eq) in THF (5 mL) was added 4-(2-aminoethyl)phenol (79.5A, 206.44 mg, 1.50 mmol, 1 eq) and the solution of acyl chloride above at 0°C. The mixture was stirred at 15°C for 0.5 hr. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 95%-100% B over 8.0 min) to give 280 mg of 79.6 (35%) as a yellow oil. (ES, m / z): [M-1]- 516.4.

[0609] Synthesis of I-79. A mixture of (Z)-15-((tert-butyldimethylsilyl)oxy)-N-(4- hydroxyphenethyl)-15-methylhexadec-9-enamide (79.6, 280 mg, 540.69 μmol, 1 eq) in HCl / dioxane (10 mL, 4 M) was degassed and purged with N2for 3 times, then the mixture was stirred at 15°C for 16 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40mm x 10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:60%-90% B over 8.0 min) to give desired compound (200 mg, yield 91%) as a yellow solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD(250 m x 30 mm, 10 um); mobile phase: [CO2-MeOH]; B%: 30%, isocratic elution mode) to give 40.26 mg of I-79 (18%) as a white solid. (ES, m / z): [M-17] + 386.3.

[0610] SFC separation methods:

[0611] Method 1: Instrument: Waters SFC80 Preparative SFC System; Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); Mobile phase: A for CO2 and B for MeOH; Gradient:B%=30.00% isocratic elution mode; Flow rate: 55.00 g / min; Monitor wavelength: 220 & 254 nm; Column temperature: 40℃; System back pressure: 100 bar.

[0612] I-79:1H NMR (400 MHz, methanol-d4) δ = 7.96-7.87 (m, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.42-5.31 (m, 2H), 3.37-3.33 (m, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 2.10-2.02 (m, 4H), 1.77-1.69 (m, 2H), 1.61-1.46 (m, 10H), 1.42-1.27 (m, 10H)

[0613] Example 72. (Z)-14-hydroxy-N-(4-hydroxyphenethyl)-14-methylpentadec-9- enamide.

[0614] Synthesis of 80.2. To a solution of 5-bromo-2-methyl-pentan-2-ol (80.1, 2 g, 11.05 mmol, 1 eq) in DCM (20 mL) was added TBSOTf (48.47 g, 183.35 mmol, 42.11 mL, 16.6 eq) and 2,6- dimethylpyridine (27.58 g, 257.36 mmol, 29.97 mL, 23.3 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. The reaction mixture was diluted with H2O 30 mL at 0°C and extracted with DCM 20 mL. The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0) to give 800 mg of 80.2 (24%) as a colorless oil.

[0615] Synthesis of 80.3. To a solution of dec-9-ynoic acid (80.2A, 396.27 mg, 2.36 mmol, 1 eq) in THF (32 mL) was added HMPA (8.97 g, 50.05 mmol, 8.76 mL, 21.25 eq) at 20°C. At -65°C inner temperature, n-BuLi (2.5 M, 2.17 mL, 2.3 eq) was added dropwise to the reaction mixture and stirred at 0°C for 2 hrs. A solution of ((5-bromo-2-methylpentan-2-yl)oxy)(tert-butyl)dimethylsilane (80.2, 800 mg, 2.71 mmol, 1.15 eq) in THF (8 mL) was added dropwise to the solution at -65°C. The reaction mixture was warmed to 20°C slowly and stirred at 20°C for 10 hrs. The reaction mixture was quenched by addition of HCl (1 M) 8 mL, and then extracted with ethyl acetate 15 mL. The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give 500 mg of 80.3 (55%) as a colorless oil. (ES, m / z): [M-1]- 381.3

[0616] Synthesis of 80.4. To a solution of (Z)-14-((tert-butyldimethylsilyl)oxy)-14- methylpentadec-9-enoic acid (80.3, 500 mg, 1.31 mmol, 1 eq) in THF (5 mL) was added Lindlar catalyst (161.90 mg, 39.20 μmol, 3.89 mL, 5% purity, 0.03 eq). The suspension was degassed and purged with H2(15 Psi) for 3 times. The mixture was stirred under H2(15 Psi) at 0 °C for 0.5 hr. The suspension was filtered through Celite and the filter cake was washed with THF (3 mL x 3). The filtrate was concentrated under reduced pressure to remove THF to give 400 mg of 80.4 (79%) as a yellow oil. (ES, m / z): [M-1]- 383.3

[0617] Synthesis of 80.5. To a solution of (Z)-14-[tert-butyl(dimethyl)silyl]oxy-14-methyl- pentadec-9-enoic acid (80.4, 400 mg, 1.04 mmol, 1 eq) in THF (4 mL) was added 1-chloro-N,N,2- trimethyl-prop-1-en-1-amine (138.95 mg, 1.04 mmol, 137.57 μL, 1 eq) at 20°C. The mixture was stirred at 20°C for 0.5 hr. The resulting solution was used directly. To a solution of DIEA (403.18 mg, 3.12 mmol, 543.37 μL, 3 eq) in THF (4 mL) was added 4-(2-aminoethyl) phenol (142.65 mg, 1.04 mmol, 1 eq) and the above prepared undecanoyl chloride (419.18 mg, 1.04 mmol, 1 eq) was added dropwise into the solution at 20°C and stirred for 1 hr. The reaction mixture was partitioned between H2O 8 mL and EtOAc 6 mL. The organic phase was separated, washed with brine 8 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give 380 mg of 80.5 (72%) as a yellow oil. (ES, m / z): [M-1]- 502.4.

[0618] Synthesis of I-80. To (Z)-14-[tert-butyl(dimethyl)silyl]oxy-N-[2-(4- hydroxyphenyl)ethyl]-14-methyl-pentadec-9-enamide (80.6, 380 mg, 754.22 μmol, 1 eq) was added a solution of HCl / dioxane (3.8 mL, 4 M) at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 55%-85% B over 8.0 min) to give 56.06 mg of I-80 (19%) as a colorless oil. (ES, m / z): [M-OH] + 372.3.

[0619] SFC separation methods:

[0620] Method 1: Instrument: Waters SFC80 Preparative SFC System; Column: column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CO2-MeOH]; B%:30%, isocratic elution mode; Flow rate: 58.00g / min; Monitor wavelength: 220 & 254 nm; Column temperature: 35℃; System back pressure: 100 bar.

[0621] I-80:1H NMR (400 MHz, DMSO-d6) δ = 8.01-7.87 (m, 1H), 7.93 (br s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.39 (q, J = 6.0 Hz, 2H), 3.39-3.36 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.15 (t, J = 7.2 Hz, 2H), 2.08 (J = 6.8 Hz, 4H), 1.80-1.72 (m, 2H), 1.61-1.52 (m, 9H), 1.41-1.27 (m, 8H)

[0622] Example 73. (Z)-16-hydroxy-N-(4-hydroxyphenethyl)-16-methylheptadec-9- enamide

[0623] Synthesis of 81.2 To a solution of 7-bromo-2-methylheptan-2-ol (81.1, 10 g, 47.82 mmol, 1 eq) in DCM (100 mL) was added 2,6-dimethylpyridine (119.39 g, 1.11 mol, 129.77 mL, 23.3 eq) and TBSOTf (209.83 g, 793.79 mmol, 182.30 mL, 16.6 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue wasdiluted with H2O 50 mL and extracted DCM 60 mL. The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Hexanes / Petroleum ether = 1 / 0 to 0 / 1) to give 10 g of 81.2 (64%) as colorless oil.

[0624] Synthesis of 81.4 To a solution of dec-9-ynoic acid (81.3, 1.36 g, 8.07 mmol, 1 eq) in THF (120 mL) was added HMPA (30.72 g, 171.43 mmol, 30.00 mL, 21.25 eq) at 25°C. At -60°C (inner temperature), n-BuLi (2.5 M, 7.42 mL, 2.3 eq) ...

Claims

1. What is Claimed Is:

1. A compound of Formula X, XX, or XXX:wherein: - - - is a single or double bond; each A is, independently, C or N, provided that no more than three A moieties are simultaneously N; R1is C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1-20alkylphenyl, C1-20alkylcycloalkyl, or C2- 20alkynyldiazirinyl, wherein R1is optionally substituted by one or more D, OH, NH2, -C(O)OC1- 6alkyl, -C(O)OH, C1-6alkyl, C1-6alkoxy, -C(O)H, C(O), cycloalkyl, CN, or halo;wherein each Z is, independently, C or N, provided that only one Z moiety is N; each E is, independently, CH, N, O, or S; each G is, independently, CH or N, provided that no more than three G moieties are simultaneously N; R3is CH2, NH, N(C1-6alkyl), N(C3-6cycloalkyl), or NCF3;R4and R5are, independently, H, D, CH2OH, -C(O)OH, -C(O)OC1-6alkyl, C1-6alkyl, or combine to form a cycloalkyl or oxo; R6and R7are, independently, H, OH, D, C1-6alkyl, halo, or combine to form a cycloalkyl or oxo; or R4and R6are joined, together with the atoms to which they are attached to form cyclopropyl; R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are, independently, H, C(O)OH, OH,N3, , O-(optionally substituted tetrahydropyranyl), C1-6alkoxy, C1-6alkyl, CN, -C(O)H, - C(O)C1-6alkyl, halo, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -SO2C1-6alkyl, -CF3, -CHF2, or -SF5, provided that if A is N, then R10, R11, R12, R13, and R14are, independently, oxo (to form an N-oxide) or absent; or R10and R11, or R11and R12, or R12and R13, or R13and R14, or R15and R16, or R16and R17, or R17and R18, or R19and R20, or R21and R22are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl; and m and n are, independently, 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, that is of Formula X:.

3. The compound of claim 1, that is of Formula XX:.

4. The compound of claim 1, that is of Formula XXX:.

5. The compound of claim 1 or 3, wherein - - is a single bond.

6. The compound of claim 1 or 3, wherein - - is a double bond.

7. The compound of any one of the preceding claims, wherein each A is, independently, C.

8. The compound of any one of the preceding claims, wherein each A is, independently, N.

9. The compound of any one of the preceding claims, wherein R1is C1-20alkyl.

10. The compound of any one of claims 1-8, wherein R1is C2-20alkenyl.

11. The compound of any one of claims 1-8, wherein R1is C2-20alkynyl.

12. The compound of any one of claims 1-8, wherein R1is C1-20alkylphenyl.

13. The compound of any one of claims 1-8, wherein R1is C1-20alkylcycloalkyl.

14. The compound of any one of the preceding claims, wherein R2is.

15. The compound of any one of claims 1-14, wherein R2i.

16. The compound of any one of claims 1-14, wherein R2is.

17. The compound of any one of claims 1-14, wherein R2is.

18. The compound of any one of claims 1-14, wherein R2is.

19. The compound of claim 15, wherein each E is, independently, CH, N, O, or S, such as CH, or such as N, or such as S.

20. The compound of claim 15 or 16, wherein each Z is, independently, C or N, provided that only one Z moiety is N, such as Z is C, or such as Z is N.

21. The compound of any one of claims 1-8, wherein R2is.

22. The compound of claim 21, wherein each G is, independently, CH.

23. The compound of claim 21, wherein each G is, independently, N.

24. The compound of any one of the preceding claims, wherein R3is CH2.

25. The compound of any one of claims 1-23, wherein R3is NH.

26. The compound of any one of claims 1-23, wherein R3is N(C1-6alkyl).

27. The compound of any one of claims 1-23, wherein R3is N(C3-6cycloalkyl).

28. The compound of any one of claims 1-23, wherein R3is NCF3.

29. The compound of any one of the preceding claims, wherein R4is H.

30. The compound of any one of claims 1-28, wherein R4is D.

31. The compound of any one of claims 1-28, wherein R4is -C(O)OH.

32. The compound of any one of claims 1-28, wherein R4is -C(O)OC1-6alkyl.

33. The compound of any one of claims 1-28, wherein R4is C1-6alkyl.

34. The compound of any one of the preceding claims, wherein R5is H.

35. The compound of any one of claims 1-33, wherein R5is D.

36. The compound of any one of claims 1-33, wherein R5is -C(O)OH.

37. The compound of any one of claims 1-33, wherein R5is -C(O)OC1-6alkyl.

38. The compound of any one of claims 1-33, wherein R5is C1-6alkyl.

39. The compound of any one of claims 1-33, wherein R4and R5combine to form a cycloalkyl or oxo, such as cycloalkyl, or such as oxo.

40. The compound of any one of the preceding claims, wherein R6is H.

41. The compound of any one of claims 1-39, wherein R6is OH.

42. The compound of any one of claims 1-39, wherein R6is D.

43. The compound of any one of claims 1-39, wherein R6is C1-6alkyl.

44. The compound of any one of claims 1-39, wherein R6is halo.

45. The compound of any one of the preceding claims, wherein R7is H.

46. The compound of any one of claims 1-44, wherein R7is OH.

47. The compound of any one of claims 1-44, wherein R7is D.

48. The compound of any one of claims 1-44, wherein R7is C1-6alkyl.

49. The compound of any one of claims 1-44, wherein R7is halo.

50. The compound of any one of claims 1-39, wherein R6and R7combine to form a cycloalkyl or oxo, such as cycloalkyl, or such as oxo.

51. The compound of any one of claims 1-28, 34-38, or 45-49, wherein R4and R6are joined, together with the atoms to which they are attached to form cyclopropyl.

52. The compound of any one of the preceding claims, wherein R10is H.

53. The compound of any one of claims 1-51, wherein R10is C(O)OH.

54. The compound of any one of claims 1-51, wherein R10is OH.

55. The compound of any one of claims 1-51, wherein R10is C1-6alkoxy.

56. The compound of any one of claims 1-51, wherein R10is C1-6alkyl.

57. The compound of any one of claims 1-51, wherein R10is CN.

58. The compound of any one of claims 1-51, wherein R10is -C(O)H.

59. The compound of any one of claims 1-51, wherein R10is -C(O)C1-6alkyl.

60. The compound of any one of claims 1-51, wherein R10is halo.

61. The compound of any one of claims 1-51, wherein R10is -SO2NH2.

62. The compound of any one of claims 1-51, wherein R10is -SO2NHC1-6alkyl.

63. The compound of any one of claims 1-51, wherein R10is -SO2N(C1-6alkyl)2.

64. The compound of any one of claims 1-51, wherein R10is -SO2C1-6alkyl.

65. The compound of any one of claims 1-51, wherein R10is -CF3.

66. The compound of any one of claims 1-51, wherein R10is -CHF2.

67. The compound of any one of claims 1-51, wherein R10is -SF5.

68. The compound of any one of claims 1-51, wherein R10is oxo.

69. The compound of any one of claims 1-51, wherein R10is absent.

70. The compound of any one of the preceding claims, wherein R11is H.

71. The compound of any one of claims 1-69, wherein R11is C(O)OH.

72. The compound of any one of claims 1-69, wherein R11is OH.

73. The compound of any one of claims 1-69, wherein R11is C1-6alkoxy.

74. The compound of any one of claims 1-69, wherein R11is C1-6alkyl.

75. The compound of any one of claims 1-69, wherein R11is CN.

76. The compound of any one of claims 1-69, wherein R11is -C(O)H.

77. The compound of any one of claims 1-69, wherein R11is -C(O)C1-6alkyl.

78. The compound of any one of claims 1-69, wherein R11is halo.

79. The compound of any one of claims 1-69, wherein R11is -SO2NH2.

80. The compound of any one of claims 1-69, wherein R11is -SO2NHC1-6alkyl.

81. The compound of any one of claims 1-69, wherein R11is -SO2N(C1-6alkyl)2.

82. The compound of any one of claims 1-69, wherein R11is -SO2C1-6alkyl.

83. The compound of any one of claims 1-69, wherein R11is -CF3.

84. The compound of any one of claims 1-69, wherein R11is -CHF2.

85. The compound of any one of claims 1-69, wherein R11is -SF5.

86. The compound of any one of claims 1-69, wherein R11is oxo.

87. The compound of any one of claims 1-69, wherein R11is absent.

88. The compound of any one of the preceding claims, wherein R12is H.

89. The compound of any one of claims 1-87, wherein R12is C(O)OH.

90. The compound of any one of claims 1-87, wherein R12is OH.

91. The compound of any one of claims 1-87, wherein R12is C1-6alkoxy.

92. The compound of any one of claims 1-87, wherein R12is C1-6alkyl.

93. The compound of any one of claims 1-87, wherein R12is CN.

94. The compound of any one of claims 1-87, wherein R12is -C(O)H.

95. The compound of any one of claims 1-87, wherein R12is -C(O)C1-6alkyl.

96. The compound of any one of claims 1-87, wherein R12is halo.

97. The compound of any one of claims 1-87, wherein R12is -SO2NH2.

98. The compound of any one of claims 1-87, wherein R12is -SO2NHC1-6alkyl.

99. The compound of any one of claims 1-87, wherein R12is -SO2N(C1-6alkyl)2.

100. The compound of any one of clams 1-87, wherein R12is -SO2C1-6alkyl.

101. The compound of any one of claims 1-87, wherein R12is -CF3.

102. The compound of any one of claims 1-87, wherein R12is -CHF2.

103. The compound of any one of claims 1-87, wherein R12is -SF5.

104. The compound of any one of claims 1-87, wherein R12is oxo.

105. The compound of any one of claims 1-87, wherein R12is absent.

106. The compound of any one of the preceding claims, wherein R13is H.

107. The compound of any one of claims 1-105, wherein R13is C(O)OH.

108. The compound of any one of claims 1-105, wherein R13is OH.

109. The compound of any one of claims 1-105, wherein R13is C1-6alkoxy.

110. The compound of any one of claims 1-105, wherein R13is C1-6alkyl.

111. The compound of any one of claims 1-105, wherein R13is CN.

112. The compound of any one of claims 1-105, wherein R13is -C(O)H.

113. The compound of any one of claims 1-105, wherein R13is -C(O)C1-6alkyl.

114. The compound of any one of claims 1-105, wherein R13is halo.

115. The compound of any one of claims 1-105, wherein R13is -SO2NH2.

116. The compound of any one of claims 1-105, wherein R13is -SO2NHC1-6alkyl.

117. The compound of any one of claims 1-105, wherein R13is -SO2N(C1-6alkyl)2.

118. The compound of any one of claims 1-105, wherein R13is -SO2C1-6alkyl.

119. The compound of any one of claims 1-105, wherein R13is -CF3.

120. The compound of any one of claims 1-105, wherein R13is -CHF2.

121. The compound of any one of claims 1-105, wherein R13is -SF5.

122. The compound of any one of claims 1-105, wherein R13is oxo.

123. The compound of any one of claims 1-105, wherein R13is absent.

124. The compound of any one of the preceding claims, wherein R14is H.

125. The compound of any one of claims 1-123, wherein R14is C(O)OH.

126. The compound of any one of claims 1-123, wherein R14is OH.

127. The compound of any one of claims 1-123, wherein R14is C1-6alkoxy.

128. The compound of any one of claims 1-123, wherein R14is C1-6alkyl.

129. The compound of any one of claims 1-123, wherein R14is CN.

130. The compound of any one of claims 1-123, wherein R14is -C(O)H.

131. The compound of any one of claims 1-123, wherein R14is -C(O)C1-6alkyl.

132. The compound of any one of claims 1-123, wherein R14is halo.

133. The compound of any one of claims 1-123, wherein R14is -SO2NH2.

134. The compound of any one of claims 1-123, wherein R14is -SO2NHC1-6alkyl.

135. The compound of any one of claims 1-123, wherein R14is -SO2N(C1-6alkyl)2.

136. The compound of any one of claims 1-123, wherein R14is -SO2C1-6alkyl.

137. The compound of any one of claims 1-123, wherein R14is -CF3.

138. The compound of any one of claims 1-123, wherein R14is -CHF2.

139. The compound of any one of claims 1-123, wherein R14is -SF5.

140. The compound of any one of claims 1-123, wherein R14is oxo.

141. The compound of any one of claims 1-123, wherein R14is absent.

142. The compound of any one of the preceding claims, wherein R15is H.

143. The compound of any one of claims 1-141, wherein R15is C(O)OH.

144. The compound of any one of claims 1-141, wherein R15is OH.

145. The compound of any one of claims 1-141, wherein R15is C1-6alkoxy.

146. The compound of any one of claims 1-141, wherein R15is C1-6alkyl.

147. The compound of any one of claims 1-141, wherein R15is CN.

148. The compound of any one of claims 1-141, wherein R15is -C(O)H.

149. The compound of any one of claims 1-141, wherein R15is -C(O)C1-6alkyl.

150. The compound of any one of claims 1-141, wherein R15is halo.

151. The compound of any one of claims 1-141, wherein R15is -SO2NH2.

152. The compound of any one of claims 1-141, wherein R15is -SO2NHC1-6alkyl.

153. The compound of any one of claims 1-141, wherein R15is -SO2N(C1-6alkyl)2.

154. The compound of any one of claims 1-141, wherein R15is -SO2C1-6alkyl.

155. The compound of any one of claims 1-141, wherein R15is -CF3.

156. The compound of any one of claims 1-141, wherein R15is -CHF2.

157. The compound of any one of claims 1-141, wherein R15is -SF5.

158. The compound of any one of claims 1-141, wherein R15is oxo.

159. The compound of any one of claims 1-141, wherein R15is absent.

160. The compound of any one of the preceding claims, wherein R16is H.

161. The compound of any one of claims 1-159, wherein R16is C(O)OH.

162. The compound of any one of claims 1-159, wherein R16is OH.

163. The compound of any one of claims 1-159, wherein R16is C1-6alkoxy.

164. The compound of any one of claims 1-159, wherein R16is C1-6alkyl.

165. The compound of any one of claims 1-159, wherein R16is CN.

166. The compound of any one of claims 1-159, wherein R16is -C(O)H.

167. The compound of any one of claims 1-159, wherein R16is -C(O)C1-6alkyl.

168. The compound of any one of claims 1-159, wherein R16is halo.

169. The compound of any one of claims 1-159, wherein R16is -SO2NH2.

170. The compound of any one of claims 1-159, wherein R16is -SO2NHC1-6alkyl.

171. The compound of any one of claims 1-159, wherein R16is -SO2N(C1-6alkyl)2.

172. The compound of any one of claims 1-159, wherein R16is -SO2C1-6alkyl.

173. The compound of any one of claims 1-159, wherein R16is -CF3.

174. The compound of any one of claims 1-159, wherein R16is -CHF2.

175. The compound of any one of claims 1-159, wherein R16is -SF5.

176. The compound of any one of claims 1-159, wherein R16is oxo.

177. The compound of any one of claims 1-159, wherein R16is absent.

178. The compound of any one of the preceding claims, wherein R17is H.

179. The compound of any one of claims 1-177, wherein R17is C(O)OH.

180. The compound of any one of claims 1-177, wherein R17is OH.

181. The compound of any one of claims 1-177, wherein R17is C1-6alkoxy.

182. The compound of any one of claims 1-177, wherein R17is C1-6alkyl.

183. The compound of any one of claims 1-177, wherein R17is CN.

184. The compound of any one of claims 1-177, wherein R17is -C(O)H.

185. The compound of any one of claims 1-177, wherein R17is -C(O)C1-6alkyl.

186. The compound of any one of claims 1-177, wherein R17is halo.

187. The compound of any one of claims 1-177, wherein R17is -SO2NH2.

188. The compound of any one of claims 1-177, wherein R17is -SO2NHC1-6alkyl.

189. The compound of any one of claims 1-177, wherein R17is -SO2N(C1-6alkyl)2.

190. The compound of any one of claims 1-177, wherein R17is -SO2C1-6alkyl.

191. The compound of any one of claims 1-177, wherein R17is -CF3.

192. The compound of any one of claims 1-177, wherein R17is -CHF2.

193. The compound of any one of claims 1-177, wherein R17is -SF5.

194. The compound of any one of claims 1-177, wherein R17is oxo.

195. The compound of any one of claims 1-177 wherein R17is absent.

196. The compound of any one of the preceding claims, wherein R18is H.

197. The compound of any one of claims 1-195, wherein R18is C(O)OH.

198. The compound of any one of claims 1-195, wherein R18is OH.

199. The compound of any one of claims 1-195, wherein R18is C1-6alkoxy.

200. The compound of any one of claims 1-195, wherein R18is C1-6alkyl.

201. The compound of any one of claims 1-195, wherein R18is CN.

202. The compound of any one of claims 1-195, wherein R18is -C(O)H.

203. The compound of any one of claims 1-195, wherein R18is -C(O)C1-6alkyl.

204. The compound of any one of claims 1-195, wherein R18is halo.

205. The compound of any one of claims 1-195, wherein R18is -SO2NH2.

206. The compound of any one of claims 1-195, wherein R18is -SO2NHC1-6alkyl.

207. The compound of any one of claims 1-195, wherein R18is -SO2N(C1-6alkyl)2.

208. The compound of any one of claims 1-195, wherein R18is -SO2C1-6alkyl.

209. The compound of any one of claims 1-195, wherein R18is -CF3.

210. The compound of any one of claims 1-195, wherein R18is -CHF2.

211. The compound of any one of claims 1-195, wherein R18is -SF5.

212. The compound of any one of claims 1-195, wherein R18is oxo.

213. The compound of any one of claims 1-195, wherein R18is absent.

214. The compound of any one of the preceding claims, wherein R19is H.

215. The compound of any one of claims 1-213, wherein R19is C(O)OH.

216. The compound of any one of claims 213, wherein R19is OH.

217. The compound of any one of claims 1-213, wherein R19is C1-6alkoxy.

218. The compound of any one of claims 1-213, wherein R19is C1-6alkyl.

219. The compound of any one of claims 1-213, wherein R19is CN.

220. The compound of any one of claims 1-213, wherein R19is -C(O)H.

221. The compound of any one of claims 1-213, wherein R19is -C(O)C1-6alkyl.

222. The compound of any one of claims 1-213, wherein R19is halo.

223. The compound of any one of claims 1-213, wherein R19is -SO2NH2.

224. The compound of any one of claims 1-213, wherein R19is -SO2NHC1-6alkyl.

225. The compound of any one of claims 1-213, wherein R19is -SO2N(C1-6alkyl)2.

226. The compound of any one of claims 1-213, wherein R19is -SO2C1-6alkyl.

227. The compound of any one of claims 1-213, wherein R19is -CF3.

228. The compound of any one of claims 1-213, wherein R19is -CHF2.

229. The compound of any one of claims 1-213, wherein R19is -SF5.

230. The compound of any one of claims 1-213, wherein R19is oxo.

231. The compound of any one of claims 1-213, wherein R19is absent.

232. The compound of any one of the preceding claims, wherein R20is H.

233. The compound of any one of claims 1-231, wherein R20is C(O)OH.

234. The compound of any one of claims 1-231, wherein R20is OH.

235. The compound of any one of claims 1-231, wherein R20is C1-6alkoxy.

236. The compound of any one of claims 1-231, wherein R20is C1-6alkyl.

237. The compound of any one of claims 1-231, wherein R20is CN.

238. The compound of any one of claims 1-231, wherein R20is -C(O)H.

239. The compound of any one of claims 1-231, wherein R20is -C(O)C1-6alkyl.

240. The compound of any one of claims 1-231, wherein R20is halo.

241. The compound of any one of claims 1-231, wherein R20is -SO2NH2.

242. The compound of any one of claims 1-231, wherein R20is -SO2NHC1-6alkyl.

243. The compound of any one of claims 1-231, wherein R20is -SO2N(C1-6alkyl)2.

244. The compound of any one of claims 1-231, wherein R20is H, -SO2C1-6alkyl.

245. The compound of any one of claims 1-231, wherein R20is -CF3.

246. The compound of any one of claims 1-231, wherein R20is -CHF2.

247. The compound of any one of claims 1-231, wherein R20is -SF5.

248. The compound of any one of claims 1-231, wherein R20is oxo.

249. The compound of any one of claims 1-231, wherein R20is absent.

250. The compound of any one of the preceding claims, wherein R21is H.

251. The compound of any one of claims 1-249, wherein R21is C(O)OH.

252. The compound of any one of claims 1-249, wherein R21is OH.

253. The compound of any one of claims 1-249, wherein R21is C1-6alkoxy.

254. The compound of any one of claims 1-249, wherein R21is C1-6alkyl.

255. The compound of any one of claims 1-249, wherein R21is CN.

256. The compound of any one of claims 1-249, wherein R21is -C(O)H.

257. The compound of any one of claims 1-249, wherein R21is -C(O)C1-6alkyl.

258. The compound of any one of claims 1-249, wherein R21is halo.

259. The compound of any one of claims 1-249, wherein R21is -SO2NH2.

260. The compound of any one of claims 1-249, wherein R21is -SO2NHC1-6alkyl.

261. The compound of any one of claims 1-249, wherein R21is -SO2N(C1-6alkyl)2.

262. The compound of any one of claims 1-249, wherein R21is -SO2C1-6alkyl.

263. The compound of any one of claims 1-249, wherein R21is -CF3.

264. The compound of any one of claims 1-249, wherein R21is -CHF2.

265. The compound of any one of claims 1-249, wherein R21is -SF5.

266. The compound of any one of claims 1-249, wherein R21is oxo.

267. The compound of any one of claims 1-249, wherein R21is absent.

268. The compound of any one of the preceding claims, wherein R22is H.

269. The compound of any one of claims 1-267, wherein R22is C(O)OH.

270. The compound of any one of claims 1-267, wherein R22is OH.

271. The compound of any one of claims 1-267, wherein R22is C1-6alkoxy.

272. The compound of any one of claims 1-267, wherein R22is C1-6alkyl.

273. The compound of any one of claims 1-267, wherein R22is CN.

274. The compound of any one of claims 1-267, wherein R22is -C(O)H.

275. The compound of any one of claims 1-267, wherein R22is -C(O)C1-6alkyl.

276. The compound of any one of claims 1-267, wherein R22is halo.

277. The compound of any one of claims 1-267, wherein R22is -SO2NH2.

278. The compound of any one of claims 1-267, wherein R22is -SO2NHC1-6alkyl.

279. The compound of any one of claims 1-267, wherein R22is -SO2N(C1-6alkyl)2.

280. The compound of any one of claims 1-267, wherein R22is -SO2C1-6alkyl.

281. The compound of any one of claims 1-267, wherein R22is -CF3.

282. The compound of any one of claims 1-267, wherein R22is -CHF2.

283. The compound of any one of claims 1-267, wherein R22is -SF5.

284. The compound of any one of claims 1-267, wherein R22is oxo.

285. The compound of any one of claims 1-267, wherein R22is absent.

286. The compound of any one of claims 1-51, wherein R10and R11are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

287. The compound of any one of claims 1-51, wherein R11and R12are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

288. The compound of any one of claims 1-51, wherein R12and R13are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

289. The compound of any one of claims 1-51, wherein R13and R14are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

290. The compound of any one of claims 1-51, wherein R15and R16are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

291. The compound of any one of claims 1-51, wherein R16and R17are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

292. The compound of any one of claims 1-51, wherein R17and R18are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

293. The compound of any one of claims 1-51, wherein R19and R20are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

294. The compound of any one of claims 1-51, wherein R21and R22are joined, together with the atoms to which they are attached, to form an optionally substituted phenyl.

295. The compound of any one of the preceding claims, wherein m is 0.

296. The compound of any one of claims 1-294, wherein m is 1.

297. The compound of any one of claims 1-294, wherein m is 2.

298. The compound of any one of the preceding claims, wherein n are is 0.

299. The compound of any one of claims 1-297, wherein n is 1.

300. The compound of any one of claims 1-297, wherein n is 2.

301. The compound of claim 1, that is of Formula X-1 to X-6, XX-1 to XX-4, XXX-1 to XXX-3, I-A, I-B, I-C, I-D, I-E, I-F, I-G, II-A, III-A, IV-A, IV-B, or V-A:)I303. The compound of claim 1, that is:or a pharmaceutically acceptable salt thereof.

304. The compound of claim 1, that is:

305. The compound of claim 1, that is:

306. The compound of claim 1, that is:

308. The compound of claim 1, that is of formula IMID-II:wherein, R5is C6-19alkyl optionally substituted by C2-6alkynyl.

309. The compound of claim 1, that is formula PROP-IA, PROP-IB, PROP-IC, PROP-ID, or PROP-IE:para position of the phenyl ring; 310. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

311. A dosage form comprising the compound of any one of claims 1-309 or the pharmaceutical composition of claim 303.

312. The dosage form of claim 311 that is formulated for oral, intravenous, intraperitoneal, intramuscular, intradermal or subcutaneous administration.

313. The dosage form of claim 311 that is formulated for intradermal, intramuscular, or subcutaneous administration.

314. A compound of any one of claims 1-309, pharmaceutical composition of claim 310, or dosage form of any one of claims 311-313 for treating inflammation in a subject in need thereof.

315. A compound of any one of claims 1-309, pharmaceutical composition of claim 310, or dosage form of any one of claims 311-313 for decreasing inflammation in a subject in need thereof.

316. A compound of any one of claims 1-309, pharmaceutical composition of claim 310, or dosage form of any one of claims 311-313 for decreasing an inflammatory marker in a subject in need thereof.

317. A compound of any one of claims 1-309, pharmaceutical composition of claim 310, or dosage form of any one of claims 311-313 for treating inflammatory bowel disease in a subject in need thereof.

318. A compound of any one of claims 1-309, pharmaceutical composition of claim 3010, or dosage form of any one of claims 311-313 for treating colorectal cancer in a subject in need thereof.