Compounds, pharmaceutical compositions and methods for treating inflammatory bowel disease

Abstract

The present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of Compound (A), Compound (B), Compound (C), Compound (D), Compound (E), Compound (F), Compound (G), Compound (H), Compound (J), Compound (K), Compound (L), Compound (M), Compound (N), Compound (O), Compound (P), or Compound (Q) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. Also provided are dosage units comprising one or more of Compound (A), Compound (B), Compound (C), Compound (D), Compound (E), Compound (F), Compound (G), Compound (H), Compound (J), Compound (K), Compound (L), Compound (M), Compound (N), Compound (O), Compound (P), or Compound (Q), or pharmaceutical compositions described herein, methods of treating inflammatory bowel disease in a subject in need thereof, or methods of modulating inflammatory bowel disease markers in a subject in need thereof. JPEG2025510284000518.jpg96160

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 63 / 324,741, filed March 29, 2022; 63 / 324,801, filed March 29, 2022; 63 / 324,897, filed March 29, 2022; and 63 / 324,934, filed March 29, 2022, the disclosures of which are incorporated herein by reference.

[0002] The present disclosure relates to compounds, pharmaceutical compositions and methods for treating inflammatory bowel disease. [Background technology]

[0003] Inflammatory bowel disease (IBD) typically refers to two conditions: Crohn's disease and ulcerative colitis. Crohn's disease is characterized by inflammation of the digestive tract lining, which can often extend deep into affected tissues. Ulcerative colitis is a condition that causes long-term inflammation and wounds (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 proper management, inflammatory bowel disease can progress, increasing the risk of colon cancer, primary sclerosing cholangitis, and blood clots in subjects. Complications of Crohn's disease include, for example, intestinal obstruction, malnutrition, ulcers, fistulas, and anal fissures. Complications of ulcerative colitis include, for example, toxic megacolon, colonic perforation, and severe dehydration. Various approaches have been developed for the management of inflammatory bowel disease, however these approaches are typically systemic and rely on suppressing inflammation rather than treating the underlying condition. Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need for small molecule-based therapeutic approaches for the treatment of inflammatory bowel disease. [Means for solving the problem]

[0005] In some aspects, the disclosure provides a compound that is Compound A, or Compound G, or a pharma- ceutically acceptable salt thereof. [ka]

[0006] In other aspects, the disclosure provides a compound that is Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharma- ceutically acceptable salt thereof. [ka]

[0007] In yet another aspect, the disclosure provides a compound that is Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or a pharma- ceutically acceptable salt thereof. [ka]

[0008] In a further aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein and a pharma- ceutically acceptable excipient.

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

[0010] In other embodiments, the present disclosure provides a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject one or more pharmaceutical compositions or dosage units described herein.

[0011] In a further embodiment, the present disclosure provides a method of modulating inflammatory bowel disease markers in a subject in need thereof comprising administering to the subject a therapeutically effective amount of one or more pharmaceutical compositions or dosage units described herein.

[0012] Other aspects and embodiments of the present invention will become readily apparent from the following detailed description of the invention. [Brief description of the drawings]

[0013] [Figure 1] 1 is a bar graph showing Dectin-1b activity of compound A-3, where Syk is Syk inhibitor IV (BAY 61-3606) and OD650nM values ​​were adjusted for cell number. [Diagram 2] FIG. 1 is a Luminex assay bar graph of compound A-3. [Diagram 3] 1 is a graph showing the dose response of the combination of compounds A-2 and A-3. [Figure 4] 1 is a bar graph showing the Dectin-1b activity of compounds A1, B1, and E1. [Diagram 5] 1 is a bar graph of a Luminex assay of compounds A1 and B1 at concentrations of 0.125, 0.25, 0.5, and 1 μM showing inhibition of zymosan-induced IL-12p40 expression in monocyte-derived dendritic cells. [Figure 6A] 1 is a bar graph of a Luminex assay for compounds A1, A2, and A3 at concentrations of 15.6 nM, 62.5 nM, 250 nM, and 1 μM for three donors showing inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells. [Figure 6B] 1 is a bar graph of a Luminex assay for compounds A1, A2, and A3 at concentrations of 15.6 nM, 62.5 nM, 250 nM, and 1 μM for three donors showing inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells. [Figure 6C] 1 is a bar graph of a Luminex assay for compounds A1, A2, and A3 at concentrations of 15.6 nM, 62.5 nM, 250 nM, and 1 μM for three donors showing inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells. [Figure 7A-7B] 4 is an IC50 curve for compounds A1, A2, and A3, respectively, showing inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells. [Figure 7C] 4 is an IC50 curve for compounds A1, A2, and A3, respectively, showing inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells. [Figure 8A] 1 is a bar graph of compounds I-100 and A6, respectively, showing inhibition of LPS-induced IRF reporter activity. [Figure 8B] 1 is a bar graph of compounds I-100 and A6, respectively, showing inhibition of LPS-induced IRF reporter activity. [Figure 9A-9B] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells. [Figure 9C] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells. [Fig. 9D-9E] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells. [Fig. 9F-9G] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells. [Figure 9H] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells. [Figure 10A-10B] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in R848-stimulated monocyte-derived dendritic cells. [Figure 10C] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in R848-stimulated monocyte-derived dendritic cells. [Fig. 10D-10E] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in R848-stimulated monocyte-derived dendritic cells. [Figure 10F] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in R848-stimulated monocyte-derived dendritic cells. [Fig. 10G-10H] FIG. 1 is a bar graph of compounds I-100 and A6 showing inhibition of pro-inflammatory cytokines in R848-stimulated monocyte-derived dendritic cells. [Figure 11A] 1 is a bar graph of the Luminex assay of compounds A3 and C3 at a concentration of 0.5 μM. [Figure 11B] 1 is a bar graph of the Luminex assay of compounds A3 and C3 at a concentration of 0.5 μM. [Figure 12] FIG. 1 is a bar graph of inhibition of BGP-induced Dectin-1b signaling in HEK cells for compounds A6, C2, and C3 at concentrations of 1, 10, and 30 μM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS In this disclosure, unless the context dictates otherwise, the singular forms "a," "an," and "the" include plural references, and a reference to a particular numerical value includes at least that particular value, for example, a reference to a "substance" is a reference to at least one of such substances and equivalents thereof known to those of skill in the art, etc.

[0015] When values ​​are expressed as approximations by use of the descriptor "about" or "approximately", it will be understood that the particular value forms another embodiment. In general, the use of the term "about" or "approximately" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and may be interpreted in the particular context in which it is used based on its function. Those 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 way of determining the range of the term "about" or "approximately". In other cases, the scale used for a series of values ​​may be used to determine the intended range that may be used for the term "about" or "approximately" for each value. When present, all ranges are inclusive and combinable. That is, reference to values ​​specified in a range includes all values ​​within that range.

[0016] When lists are presented, it is to be understood that each individual element and every combination is to be construed as a separate embodiment unless otherwise stated. For example, a list of embodiments presented as "A, B, or C" should be construed as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0017] For clarity, it should be understood that certain features of the invention that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless clearly incompatible or excluded, each separate embodiment is considered combinable with other embodiments, and such combinations are considered separate embodiments. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. Furthermore, it should be noted that the claims may be drafted to exclude optional elements. Thus, this statement is intended as a precondition for the use of exclusive language, such as "only," "only," or "negative" limitations in connection with the description of the claimed elements. Finally, while an embodiment may be described as part of a series of steps or as part of a more general structure, each step may be considered an independent embodiment in itself.

[0018] The compounds disclosed herein may exist in one or more specific chiral forms, such as R and S. In some embodiments, the compounds are enantiomers. In other embodiments, the compounds are diastereomers. In certain embodiments, one, two, three, or four carbon atoms are in the (R) configuration. In other embodiments, one, two, three, or four carbon atoms are in the (S) configuration. The compounds described herein may be enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S. In some embodiments, the compounds have an enantiomeric excess (ee%) of at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In other embodiments, the compound is racemic, i.e., has an ee of 0%. In further embodiments, the compound is a single enantiomer, i.e., has an ee of 100%.

[0019] The terms "subject" and "patient" are used interchangeably and include, but are not limited to, mammals. In some embodiments, a subject is a human. In other embodiments, a patient or subject is a veterinary or farm animal, a domestic animal or pet, or an animal used in clinical research.

[0020] "Treatment" or variations thereof refers to improving or alleviating the onset of a disease or disorder, i.e., delaying the onset of the disease. In certain embodiments, "treatment" refers to improving or reducing at least one physical parameter of the disease or disorder. In other embodiments, "treatment" is directed to improving the disease or disorder. In further embodiments, "treatment" is directed to the cause of the disease or disorder. In yet other embodiments, "treatment" is directed to alleviating the symptoms of the disease or disorder. In still further embodiments, "treatment" is directed to treating a disease or disorder as a complement to another therapy.

[0021] The term "halo" refers to chlorine, fluorine, bromine, or iodine.

[0022] As used herein, the term "alkyl" refers to a straight or branched chain alkyl group. In some embodiments, an alkyl group has 1 to 20 carbon atoms, i.e., C 1-20 In another embodiment, the alkyl group has 1 to 6 carbon atoms, i.e., C 1-6 Examples of alkyl include methyl (C 1 Alkyl)ethyl(C 2 Alkyl), n-propyl (C 3 Alkyl), isopropyl (C 3In some embodiments, the alkyl is methyl. In other embodiments, the alkyl is ethyl. In further embodiments, the alkyl is n-propyl or isopropyl. In yet 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 halo, OH, OC 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0023] As used herein, the term "alkoxy" refers to any of the groups represented by O-C. 1-6 "Alkoxy" refers to an alkoxy group, where alkyl is defined herein, and the point of attachment is through the oxygen atom of the alkoxy. In some embodiments, the alkoxy group has 1 to 20 carbon atoms, i.e., C 1-20 In another embodiment, the alkoxy has 1 to 6 carbon atoms, i.e., C 1-6 Examples of alkoxy include methoxy (C 1 Alkoxy), ethoxy (C 2 Alkoxy), n-propoxy (C 3 Alkoxy), isopropoxy (C 3 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 yet 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 halo, OH, OC 1-6 Alkyl, CN, NH 2, NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0024] The term "alkylene" or "-alk-" as used herein refers to a straight or branched chain alkyl group that connects two groups, i.e., an internal group. In some embodiments, the alkylene group has 1 to 6 carbon atoms, i.e., C 1-6 An example of an alkylene is C 1 Alkyl (-CH 2 -), C 2 Alkyl (-CH 2 CH 2 - or CH(CH 3 )-)、C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 Alkyl is an alkyl group. Alkylene is an alkyl group. 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0025] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms with at least one point of unsaturation that is a double bond. In other embodiments, the alkenyl group has 2 to 6 carbon atoms, i.e., C 2-6 Examples of alkenyl include, inter alia, ethenyl (C 2 alkenyl), propenyl (C 3 alkenyl). In some embodiments, alkenyl is -CH=CH 2In some embodiments, the alkenyl is a straight chain hydrocarbon. In other embodiments, the alkenyl is a branched chain hydrocarbon. In some embodiments, the alkenyl has one double bond. In other embodiments, the alkenyl has two or more double bonds. The alkenyl group may be substituted with one or more groups described herein. For example, the alkenyl may be substituted with halo, OH, OC ... 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0026] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms with at least one point of unsaturation that is a triple bond. In other embodiments, the alkynyl group has 2 to 6 carbon atoms, i.e., C 2-6 Examples of alkynyl include, among others, ethynyl (C 2 alkynyl), propynyl (C 3 In some embodiments, the alkynyl is -C≡C. In some embodiments, the alkynyl is a straight chain hydrocarbon. In other embodiments, the alkynyl is a branched chain hydrocarbon. 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 groups described herein. For example, the alkenyl may be substituted with halo, OH, OC ... 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0027] As used herein, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon group. In some embodiments, a cycloalkyl group is a group having 3 to 8 carbon atoms ("C 3-8 In some embodiments, the cycloalkyl has 3 to 6 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), 1-methylcyclopropyl (C 4 ), or 2-methylcyclopentyl (C 4 Cycloalkyl includes halo, OH, OC 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0028] The term "heterocyclyl" refers to a stable 3-14 membered non-aromatic ring radical containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl contains up to 14 ring atoms, such as 3 ring atoms, 4 ring atoms, and the like. A heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in a heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocyclyl radical is unsaturated, partially saturated, or fully saturated. A heterocyclyl may be attached to the remainder of the molecule through any atom of the ring. "Heterocyclyl" also includes bicyclic ring systems in which one non-aromatic ring contains at least two carbon atoms in addition to one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations containing at least one of the foregoing heteroatoms; and the other ring optionally contains one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic. In some embodiments, heterocyclyl is indolyl. Examples of heterocyclyls include 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, and pyrazolidinyl. aryl, 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, isothiocyanate, Midazolyl, 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,Heterocyclyl includes, but is not limited to, 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). Heterocyclyl is any of the following: halo, OH, OC, 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0029] The term "aryl" refers to groups with 6 to 10 carbon atoms (such as phenyl, naphthyl, etc. 6-10 "). Aryl refers to a carbocyclic aromatic group having a halo, OH, OC 1-6 Alkyl, CN, NH 2 , NH(C 1-6 alkyl), NH(C 1-6 Alkyl) 2 , C 3-8 It is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, heterocyclyl, or aryl.

[0030] compound The present disclosure provides compounds of formula I: [ka]

[0031] According to this disclosure, R 1 , R 2 , R 3 , and R 4 are independently H or optionally substituted C 1-6 In some embodiments, R 1 , R 2 , R 3 , and R 4is independently H. In other embodiments, R 1 , R 2 , R 3 , and R 4 are independently H or optionally substituted C 1-6 In a further embodiment, R 1 , R 2 , R 3 , and R 4 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1 , R 2 , R 3 , and R 4 is independently methyl. In still further embodiments, R 1 is methyl. In other embodiments, R 2 is methyl. In a further embodiment, R 3 is methyl. In yet other embodiments, R 4 is methyl. In yet a further embodiment, R 1 is H. In other embodiments, R 2 is H. In a further embodiment, R 3 is H. In yet another embodiment, R 4 is H.

[0032] According to this disclosure, R 5 is OH, optionally substituted C 1-6 Alkoxy, -N(R A )(Optionally replaced C 1-6 alkyl), or -X(R A )-R 13 -CH(X 6 )(X 7 )R 11 R 12 In some embodiments, R 5 is OH. In other embodiments, R 5 is optionally replaced by C 1-6 In a further embodiment, R 5 is optionally replaced by C 5 - 6In yet another embodiment, R 5 is optionally replaced by C 5 In yet a further embodiment, R 5 is optionally replaced by C 6 In another embodiment, R 5 is -N(R A )(Optionally replaced C 1-6 In a further embodiment, R 5 is -N(R A )(Optionally replaced C 5-6 In yet another embodiment, R 5 is -N(R A )(Optionally replaced C 5 In yet a further embodiment, R 5 is -N(R A )(Optionally replaced C 6 In another embodiment, R 5 is -X(R A )-R 13 -CH(X 6 )(X 7 )R 11 R 12 In a further embodiment, R 5 teeth, [ka] It is.

[0033] According to this disclosure, R 15 -C 1-6 In some embodiments, R 15 -C 1 In another embodiment, R 15 -C 2 In a further embodiment, R 15 -C 3 In yet another embodiment, R 15 -C 4 In yet a further embodiment, R 15 -C5 In another embodiment, R 15 -C 6 In a further embodiment, R 15 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 -It is.

[0034] According to this disclosure, R A is H or optionally substituted C 1-6 In some embodiments, R A is H. In other embodiments, R A is an optionally substituted C, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; 1-6 In a further embodiment, R A is methyl.

[0035] According to the present disclosure, X is O or NH. In some embodiments, X is O. In other embodiments, X is NH.

[0036] According to the present disclosure, X 1 CR 6 or N. In some embodiments, X 1 CR 6 In another embodiment, X 1 is N.

[0037] According to the present disclosure, X 2 CR 7 or N. In some embodiments, X 2 CR 7 In another embodiment, X 2 is N.

[0038] According to the present disclosure, X 3CR 8 or N. In some embodiments, X 3 CR 8 In another embodiment, X 3 is N.

[0039] According to the present disclosure, X 4 CR 9 or N. In some embodiments, X 4 CR 9 In another embodiment, X 4 is N.

[0040] According to the present disclosure, X 5 CR 10 or N. In some embodiments, X 5 CR 10 In another embodiment, X 5 is N.

[0041] In certain embodiments, X 1 ~X 5 Exactly one of them is N.

[0042] According to the present disclosure, X 6 and X 7 are independently H or optionally substituted C 1-6 alkyl or both are N and are linked to form a diazirinyl ring. 6 and X 7 is independently H. In other embodiments, X 6 is H. In a further embodiment, X 7 is H. In yet another embodiment, X 6 and X 7 independently represents an optionally substituted C 1-6 In yet a further embodiment, X is alkyl. 6 and X 7 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl, etc. In other embodiments, X 6 and X 7is independently methyl. In a further embodiment, X 6 and X 7 is N and is linked to form an optionally substituted diazirinyl ring.

[0043] According to this disclosure, R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, OH, halo, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or -(OC 1-6 alk) n -C 1-6 In some embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 is independently H. In other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 is independently OH. In a further embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 is independently halo, such as F, Cl, or Br. In yet other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 independently represents an optionally substituted C 1-6 In yet a further embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. 6 , R 7 , R 8 , R 9 , and R 10In a further embodiment, one of R 6 , R 7 , R 8 , R 9 , and R 10 independently represents an optionally substituted C 1-6 In yet another embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 is independently methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In yet a further embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 In another embodiment, one of R 6 , R 7 , R 8 , R 9 , and R 10 is independently -(OC 1-6 alk) n -C 1-6 In a further embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 One of them is independently OCH 2 CH 2 OCH 2 CH 2 OCH 3 It is.

[0044] According to this disclosure, R 11 and R 12 independently represents an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkoxy, OH, NH 2 , or N(R 13 )(R 14In some embodiments, R 11 and R 12 independently represents an optionally substituted C 1-6 In another embodiment, R 11 and R 12 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. In a further embodiment, R 11 and R 12 independently represents an optionally substituted C 2-6 In yet another embodiment, R 11 and R 12 is independently ethenyl, propenyl, butenyl, pentenyl, or hexenyl. In yet further embodiments, R 11 and R 12 independently represents an optionally substituted C 2-6 In another embodiment, R 11 and R 12 is independently ethynyl, propynyl, butynyl, pentynyl, or hexynyl. In a further embodiment, R 11 and R 12 independently represents an optionally substituted C 1-6 In yet another embodiment, R 11 and R 12 is independently methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In yet a further embodiment, R 11 and R 12 is independently OH. In other embodiments, R 11 and R 12 Independently, NH 2 In a further embodiment, R 11 and R 12 are independently N(R 13 )(R 14 In yet a further embodiment, R 11 and R 12 is an independent company, NHCH 3 In another embodiment, R 11 and R 12 are independently N(CH3 ) 2 It is.

[0045] According to this disclosure, R 13 and R 14 are independently H or C 1-6 In some embodiments, R 13 and R 14 is independently H. In other embodiments, R 13 and R 14 is independently 1-6 In some embodiments, R 13 and R 14 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0046] In accordance with the present disclosure, n is 2 to 8. In some embodiments, n is 2. In other embodiments, n is 3. In further embodiments, n is 4. In yet other embodiments, n is 5. In yet further embodiments, n is 6. In other embodiments, n is 7. In a further embodiment, n is 8.

[0047] The present disclosure also relates to a compound of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q: [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the present disclosure provides Compound A, or a pharma- ceutically acceptable salt thereof: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound A is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound A is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound A is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound A is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound A is [ka] or a pharma- ceutically acceptable salt thereof.

[0049] In other embodiments, the disclosure is compound B, or a pharma- ceutically acceptable salt thereof. [ka] In a particular embodiment, compound B is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound B is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound B is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound B is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound B is [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In a further embodiment, the present disclosure is compound C, or a pharma- ceutically acceptable salt thereof. [ka] In a particular embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound C is [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In yet other embodiments, the disclosure is compound D, or a pharma- ceutically acceptable salt thereof. [ka] In a particular embodiment, compound D is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound D is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound D is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound D is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound D is [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In other embodiments, the disclosure is compound E, or a pharma- ceutically acceptable salt thereof. [ka] In some embodiments, compound E is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound E is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound E is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound E is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound E is [ka] or a pharma- ceutically acceptable salt thereof.

[0053] In a further embodiment, the present disclosure is compound F, or a pharma- ceutically acceptable salt thereof. [ka] In a particular embodiment, compound F is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound F is [ka] In a further embodiment, compound F is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound F is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound F is [ka] or a pharma- ceutically acceptable salt thereof.

[0054] In yet other embodiments, the disclosure is compound G, or a pharma- ceutically acceptable salt thereof. [ka] In certain embodiments, compound G is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound G is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound G is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound G is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound G is [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In still further embodiments, the present disclosure provides: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof. [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0056] In a further embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound H is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound H is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound H is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound H is [ka] or a pharma- ceutically acceptable salt thereof.

[0057] In yet another embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound J is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound J is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound J is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound J is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound J is [ka] or a pharma- ceutically acceptable salt thereof.

[0058] In yet a further embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound K is [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound K is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound K is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound K is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound K is [ka] or a pharma- ceutically acceptable salt thereof.

[0059] In another embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound L is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound L is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound L is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound L is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound L is [ka] or a pharma- ceutically acceptable salt thereof.

[0060] In a further embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound M is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound M is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound M is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound M is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound M is [ka] or a pharma- ceutically acceptable salt thereof.

[0061] In yet another embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound N is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound N is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound N is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound N is [ka] In yet a further embodiment, compound N is [ka] or a pharma- ceutically acceptable salt thereof.

[0062] In yet a further embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound O is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound O is [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, compound O is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound O is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, compound O is [ka] or a pharma- ceutically acceptable salt thereof.

[0063] In another embodiment, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, compound P is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, compound P is [ka] or a pharma- ceutically acceptable salt thereof. In yet another embodiment, compound P is [ka] or a pharma- ceutically acceptable salt thereof. In yet a further embodiment, compound P is [ka] or a pharma- ceutically acceptable salt thereof.

[0064] The compounds described herein may be synthetically prepared, i.e., products not found in nature, or alternatively, such compounds are isolated.

[0065] The term " pharmaceutically acceptable salt " as used herein includes salts suitable for administration to subjects as defined herein. Pharmaceutically acceptable salts are known in the art. For example, see 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, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0066] Pharmaceutical Compositions The disclosure also provides pharmaceutical compositions comprising one or more compounds described herein, i.e., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q. The pharmaceutical composition may also include one or more stereoisomers of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q. In some embodiments, the pharmaceutical composition contains Compound A or a pharma- ceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0067] In other embodiments, the present disclosure provides a pharmaceutical composition comprising Compound B or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises: [ka] In a further aspect, the pharmaceutical composition comprises one or more of: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0068] In a further embodiment, the present disclosure provides a pharmaceutical composition comprising Compound C or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutical acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0069] In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising Compound D or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In a further aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0070] In further embodiments, the pharmaceutical composition comprises Compound E or a pharma- ceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0071] In yet other embodiments, the pharmaceutical composition comprises compound F. In certain aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0072] In yet further embodiments, the disclosure provides a pharmaceutical composition comprising compound G. In some aspects, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0073] In other embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] In some embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In other embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0078] In yet another embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0079] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0080] In other embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutical acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] In yet another aspect, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof. In yet a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof. In a further aspect, the pharmaceutical composition comprises [ka] or a pharma- ceutically acceptable salt thereof.

[0081] When a pharmaceutical composition contains two or more stereoisomers of Compound A, the stereoisomers may be present in equal or different ratios. In certain embodiments, the composition contains an excess of one of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q in an (S,S,S) ratio. In other embodiments, the composition contains an excess of one of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q in an (R,S,S) ratio.

[0082] In further embodiments, the composition contains an excess of an (S,R,S) ratio of one of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G. In yet other embodiments, the composition contains an excess of an (R,R,S) ratio of one of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q.

[0083] In certain embodiments, the pharmaceutical composition comprises a higher ratio of [ka] In another embodiment, the pharmaceutical composition comprises: [ka] in a ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In further embodiments, the molar ratio of A-2 to A-3 is about 25 to about 55:about 45 to about 75. In other embodiments, the molar ratio of A-2 to A-3 is about 40:about 60. In further embodiments, the molar ratio of A-2 to A-3 is about 25:about 75. In yet other embodiments, the molar ratio of A-2 to A-3 is about 30:about 70. In yet further embodiments, the molar ratio of A-2 to A-3 is about 35:about 65.

[0084] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of G-4 to G-5 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of G-4 to G-5 is about 40:about 60. In a further embodiment, the molar ratio of G-4 to G-5 is about 25:about 75. In yet another embodiment, the molar ratio of G-4 to G-5 is about 30:about 70. In yet a further embodiment, the molar ratio of G-4 to G-5 is about 35:about 65.

[0085] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of F-4 to F-5 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of F-4 to F-5 is about 40:about 60. In a further embodiment, the molar ratio of F-4 to F-5 is about 25:about 75. In yet another embodiment, the molar ratio of F-4 to F-5 is about 30:about 70. In yet a further embodiment, the molar ratio of F-4 to F-5 is about 35:about 65.

[0086] In yet another embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of G-9 to G-10 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of G-9 to G-10 is about 40:about 60. In a further embodiment, the molar ratio of G-9 to G-10 is about 25:about 75. In yet another embodiment, the molar ratio of G-9 to G-10 is about 30:about 70. In yet a further embodiment, the molar ratio of G-9 to G-10 is about 35:about 65.

[0087] In other embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of C-7 to C-8 is about 10: about 90, or about 50: about 50, or about 90: about 10. In further embodiments, the molar ratio of C-7 to C-8 is about 40: about 60. In further embodiments, the molar ratio is about 25: about 75. In yet other embodiments, the molar ratio of C-7 to C-8 is about 30: about 70. In yet further embodiments, the molar ratio of C-7 to C-8 is about 35: about 65.

[0088] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of H-2 to H-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of H-2 to H-3 is about 40:about 60. In a further embodiment, the molar ratio of H-2 to H-3 is about 25:about 75. In yet another embodiment, the molar ratio of H-2 to H-3 is about 30:about 70. In yet a further embodiment, the molar ratio of H-2 to H-3 is about 35:about 65.

[0089] In yet another embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of J-2 to J-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of J-2 to J-3 is about 40:about 60. In a further embodiment, the molar ratio of J-2 to J-3 is about 25:about 75. In yet another embodiment, the molar ratio of J-2 to J-3 is about 30:about 70. In yet a further embodiment, the molar ratio of J-2 to J-3 is about 35:about 65.

[0090] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of K-2 to K-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of K-2 to K-3 is about 40:about 60. In a further embodiment, the molar ratio of K-2 to K-3 is about 25:about 75. In yet another embodiment, the molar ratio of K-2 to K-3 is about 30:about 70. In yet a further embodiment, the molar ratio of K-2 to K-3 is about 35:about 65.

[0091] In other embodiments, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of L-2 to L-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of L-2 to L-3 is about 40:about 60. In a further embodiment, the molar ratio of L-2 to L-3 is about 25:about 75. In yet another embodiment, the molar ratio of L-2 to L-3 is about 30:about 70. In yet a further embodiment, the molar ratio of L-2 to L-3 is about 35:about 65.

[0092] In a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of O-2 to O-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of O-2 to O-3 is about 40:about 60. In a further embodiment, the molar ratio of O-2 to O-3 is about 25:about 75. In yet another embodiment, the molar ratio of O-2 to O-3 is about 30:about 70. In yet a further embodiment, the molar ratio of O-2 to O-3 is about 35:about 65.

[0093] In yet another embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of P-2 to P-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of P-2 to P-3 is about 40:about 60. In a further embodiment, the molar ratio of P-2 to P-3 is about 25:about 75. In yet another embodiment, the molar ratio of P-2 to P-3 is about 30:about 70. In yet a further embodiment, the molar ratio of P-2 to P-3 is about 35:about 65.

[0094] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of M-2 to M-3 is about 25 to about 55:about 45 to about 75. In another embodiment, the molar ratio of M-2 to M-3 is about 40:about 60. In a further embodiment, the molar ratio of M-2 to M-3 is about 25:about 75. In yet another embodiment, the molar ratio of M-2 to M-3 is about 30:about 70. In yet a further embodiment, the molar ratio of M-2 to M-3 is about 35:about 65.

[0095] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of M-5 to M-4 is about 50:about 50.

[0096] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In further embodiments, the molar ratio of N-2 to N-3 is about 25 to about 55:about 45 to about 75. In other embodiments, [ka] The molar ratio of N-2 to N-3 is about 40: about 60. In a further embodiment, the molar ratio of N-2 to N-3 is about 25: about 75. In yet another embodiment, the molar ratio of N-2 to N-3 is about 30: about 70. In yet a further embodiment, the molar ratio of N-2 to N-3 is about 35: about 65.

[0097] In yet a further embodiment, the pharmaceutical composition comprises: [ka] or a pharma- ceutically acceptable salt thereof in a molar ratio of about 10:about 90, or about 50:about 50, or about 90:about 10. In a further embodiment, the molar ratio of N-5 to N-4 is about 75:about 25.

[0098] In addition to the compounds described herein, the pharma- ceutically acceptable compositions contain one or more pharma- ceutically acceptable excipients. The pharma- ceutically acceptable excipients are selected based on the mode and route of administration. For suitable pharmaceutical carriers and pharmaceutical necessities for use in pharmaceutical preparations, see Remington: The Science and Practice of Pharmacy, 21 st Ed.,Gennaro,Ed.,Lippencott Williams&Wilkins(2005);Handbook of Pharmaceutical Excipients,6 th Edition, Rowe et al., Eds., Pharmaceutical Press (2009); and USP / NF (United States Pharmacopeia and the National Formulary).

[0099] In some embodiments, the pharma- ceutically acceptable excipient is one or more of an antioxidant, binder, buffer, colorant, diluent (e.g., solid or liquid), disintegrant, dispersant, dye, filler, emulsifier, flavoring agent, lubricant, pH adjuster, pigment, preservative, stabilizer, solubilizer, solvent, suspending agent, sweetener, or wetting agent, or combinations thereof.

[0100] Examples of suitable excipients include acacia, alginates, calcium phosphate, calcium carbonate, calcium silicate, carbopol gel, carboxymethylcellulose, carnauba wax, cellulose, crospovidone, dextrose, diacetylated monoglyceride, ethylcellulose, gelatin, glyceryl monostearate 40-50, gum acacia, gum arabic, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose phthalate, hypromellose, lactose, lecithin, magnesium stearate, kaolin, methacrylic acid copolymer type C, mannitol, methylcellulose, methylhydroxybenzoate, microcrystalline cellulose, povidone, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, propylhydroxybenzoate, sodium carboxymethylcellulose sodium hydroxide, sodium stearyl fumarate, sodium starch glycolate, starch, sorbitan monooleate. These include, but are not limited to, sorbitol, sorbic acid, sucrose, talc, tragacanth, talc, triethyl citrate, titanium dioxide, yellow iron oxide, talc, an oil vehicle (e.g., peanut oil, liquid paraffin, mineral oil, olive oil, almond oil, glycerin, propylene glycol), or water.

[0101] When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (e.g., saline solution) that acts as a vehicle, carrier, or medium for the active ingredient. As is known in the art, the type of diluent can vary depending on the intended route of administration.

[0102] The pharmaceutical compositions can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods for making formulations well known in the art are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21 stEd., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York.

[0103] Dosage Unit The present disclosure also provides a dosage unit containing one or more compounds or pharmaceutical compositions disclosed herein. Those skilled in the art will be able to select the dosage amount for use herein. In some embodiments, the dosage unit can be administered by any means known in the art. For example, the dosage unit can be a solid dosage form, a liquid dosage form, or a 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.

[0104] The dosage unit may be formulated for the most useful delivery to the subject. In some embodiments, the dosage unit is for enteral or parenteral administration. Examples of enteral administration include, but are not limited to, oral, rectal, sublingual, and buccal administration. In certain embodiments, the dosage unit is administered orally.

[0105] In other embodiments, the dosage unit is for parenteral administration, i.e., a parenteral dosage unit. As used herein, the term "parenteral" refers to other routes of administration than enteral administration. Examples of parenteral administration include, but are not limited to, buccal, epicutaneous, epidural, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intracerebral, intraventricular, intradermal, intralesional, intramuscular, intraocular, intraosseous, 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, or subcutaneously. In further embodiments, the dosage unit is administered orally, intravenously, intraperitoneally, intramuscularly, or subcutaneously. In further embodiments, the dosage unit is administered orally.

[0106] Parenteral dosage units are known in the art and include, but are not limited to, injections, inhalants, infusions, patches, and suppositories. In certain aspects, the parenteral dosage unit is an injection 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), candy, lozenge, paste, powder, sachet, or syrup. In further aspects, the oral dosage unit is a pill, tablet, capsule, syrup, 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 medium before use.

[0107] If the dosage form is a solid dosage form, an enteric coating may be applied or the solid dosage form may be scored. The enteric coating may be stable at low pH (e.g., in the stomach) and dissolve at high pH (e.g., in the small intestine).

[0108] The dosage form may be a controlled release dosage form. The term "controlled release" as used herein refers to a dosage form containing one or more excipients that modify the release. The controlled release dosage form may be an immediate release, delayed release, extended release, extended release, sustained release, pulsatile release, controlled release, extended release, accelerated release, fast release, targeted release, programmed release, or gastroretentive release dosage form. Suitable controlled release administration vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, dosage forms containing water-soluble separating layer coatings, dosage forms containing enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. These dosage forms can be prepared according to known methods and techniques. For example, see Remington: The Science and Practice of Pharmacy, 21 stEd., Gennaro, Ed., Lippencott Williams & Wilkins (2005); Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126, which are incorporated by reference in their entireties.

[0109] Regardless of the type of dosage unit, it may contain a therapeutically effective amount of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q, or a combination thereof.

[0110] One of skill in the art can determine the appropriate amount of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q to incorporate into a pharmaceutical composition or dosage unit of the present disclosure. In certain embodiments, the pharmaceutical composition or dosage unit contains from about 0.01 to about 1000 mg of one or more of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q. 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 Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q.In further embodiments, the pharmaceutical composition or dosage unit is from about 0.01 to about 750, from about 0.01 to about 500, from about 0.01 to about 250, from about 0.01 to about 100, from about 0.01 to about 50, from about 0.01 to about 25, from about 0.01 to about 10, from about 0.01 to about 5, from about 0.01 to about 0.1, from about 0.1 to about 1000, from about 0.1 to about 750, from about 0.1 to about 500, from about 0.1 to about 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 It contains 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 100 mg.

[0111] Treatment The compounds, pharmaceutical compositions, and dosage units described herein can be used in a method of modulating inflammatory bowel disease markers. In some embodiments, a method of modulating inflammatory bowel disease markers is provided, the method comprising administering one or more compounds disclosed herein to a subject in need thereof. In other embodiments, a method of modulating inflammatory bowel disease markers is provided, the method comprising administering one or more pharmaceutical compositions disclosed herein to a subject in need thereof. In further embodiments, a method of modulating inflammatory bowel disease markers is provided, the method comprising administering one or more dosage forms disclosed herein to a subject in need thereof.

[0112] The term "modulate" or variations thereof as used herein refers to an observable change in the level of an inflammatory bowel disease marker in a subject, as measured using techniques and methods known in the art for measuring inflammatory bowel disease. Modulation of an inflammatory bowel disease marker level in a subject can result in at least about 1% change compared to the marker level before administration of a compound, pharmaceutical composition, or dosage form. In some embodiments, modulation results in at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or at least about 98% or more change in the inflammatory bowel disease marker compared to before administration of a pharmaceutical composition. In other embodiments, modulation is increasing the level of an inflammatory bowel disease marker in a subject. In further embodiments, modulation includes decreasing the level of an inflammatory bowel disease marker in a subject.

[0113] As used herein, the term "inflammatory bowel disease marker" refers to a diagnostic marker that recognizes that a subject has inflammatory bowel disease. The marker can be a clinical marker (e.g., a symptom), a diagnostic marker (e.g., a test / scan), or a biochemical indicator (e.g., a biomarker). The methods provided herein reduce at least one inflammatory bowel disease marker. In some embodiments, the methods result in a beneficial change (e.g., a decrease or increase) in a clinical marker, a diagnostic marker, a biochemical indicator, or a combination thereof.

[0114] In certain embodiments, the inflammatory bowel disease marker is a diagnostic marker. Examples of diagnostic markers include results obtained from a clinical test (e.g., blood test, stool test), an endoscopy (e.g., colonoscopy, flexible sigmoidoscopy, upper endoscopy, capsule endoscopy, or balloon-assisted enteroscopy), or an imaging test (e.g., x-ray, computed tomography scan, or magnetic resonance imaging). In certain aspects, the method produces a positive change in a diagnostic marker. In certain embodiments, the method produces a positive change in a clinical test, such as a blood test (indicating anemia or infection) or a stool test (indicating blood or organisms). For example, the method may produce a reduction or absence of anemia, infection, blood in the stool, microorganisms in the stool, and the like. In other aspects, the method produces a positive change in an endoscopic procedure, such as a colonoscopy, flexible sigmoidoscopy, upper endoscopy, capsule endoscopy, or balloon-assisted enteroscopy. For example, the method reduces inflammation, tumors, lesions, polyps, fistulas, or colon perforations diagnosed by colonoscopy, flexible sigmoidoscopy, upper endoscopy, capsule endoscopy, or balloon-assisted enteroscopy.Also, for example, the method reduces inflammation, tumors, lesions, polyps, fistulas, or colon perforations diagnosed by X-ray, computed tomography scan, or magnetic resonance imaging.In certain embodiments, the method reduces inflammation or ulcers in the intestinal lining of a subject as observed by colonoscopy.

[0115] In other embodiments, the inflammatory bowel disease marker is a clinical marker. Examples of clinical markers of inflammatory bowel disease include, but are not limited to, ulcers (e.g., in the intestinal lining), inflammation (e.g., in the intestinal lining), diarrhea, fatigue, abdominal pain, cramps, bloody stools, loss of appetite, or unintentional weight loss, or a combination thereof.

[0116] The method may further result in a positive change in a biochemical indicator, such as a biomarker. Examples of biomarkers include tumor necrosis factor (TNF)-α (e.g., serum), interleukin (IL)-6 (e.g., serum), IL-1β (e.g., serum), nuclear factor kappa B (NF-κB, e.g., intestinal lining tissue), IL-8 (e.g., intestinal lining tissue), IL-23, IL-12 (e.g., intestinal lining tissue), IL-17A, M2-PK pyruvate kinase (e.g., feces), osteoprotegerin (e.g., intestinal lining tissue, serum, or feces), myeloperoxidase (MPO), High mobility group box-1 (HMGB1, e.g., feces), chitinase 3-like-1 (CHI3L1, e.g., serum or feces), human beta defensin 2 (HBD2), matrix metalloproteinases (e.g., MMP2 or MMP9, e.g., serum or urine), calprotectin (e.g., feces), lactoferrin, peripheral antineutrophil cytoplasmic antibodies (pANCA, e.g., serum of subjects suffering from ulcerative colitis), anti-Saccharomyces cerevisiae antibodies (ASCA, e.g., creatinine, erythrocyte sequestration), and / or anti-inflammatory and anti-inflammatory drugs. serum of patients with Rohn's disease, etc.), eotaxin-1, monocyte chemoattractant protein-1 (MCP-1, e.g., intestinal lining tissue), macrophage inflammatory proteins (such as MIP-1 and MIP-2, e.g., intestinal lining tissue), regulated upon activation, expressed and possibly secreted by normal T cells (RANTES, e.g., intestinal lining tissue), chemokine (CXC motif) ligand (CXCL-1, e.g., intestinal lining tissue), cysteine-cysteine ​​motif chemokine ligand 20 (CCL20, e.g., intestinal lining tissue), granulocyte colony-stimulating factor (GCSF, e.g., intestinal lining tissue), granulocyte-macrophage colony-stimulating factor (GM-CSF, e.g., intestinal lining tissue), C-reactive protein (CRP), fibrinogen, cluster of differentiation (CD3, CD69, CD80, CD86, etc.), C4, sialic acid, C1-activating enzyme, C3a, C5, bradykinin, plasminogen activator, serum amyloid A protein (SAA), prostaglandin E 2(PGE2), D2, F2 / Leukotriene A4 (LTA4), B4, C4, D4, cationic proteins, oxygen-derived free radicals, nitrogen-derived free radicals, vasoactive amines (such as histamine or serotonin), integrins / adhesion molecules (such as a / β integrins, Ig superfamily, selectins, cadherins, etc.), erythrocyte sedimentation rate, procalcitonin, white blood cell count, immunoglobulins (such as IgA, IgG, or IgM), MHC, interferon (IFN)-γ (e.g., gut lining tissue), or combinations thereof. In some embodiments, the biomarker is TNF-α, IL-1β, IL-6, IL-8, IL-23, IL-12, or IL-17A. In further embodiments, the biomarker is NF-κB, MCP-1, CCL20, or IFN-γ levels, or combinations thereof. In other aspects, the biomarker is M2-PK, osteoprotegerin, MPO, HMGB1, CHI3L1, HBD2, MMP, p-ANCA, or ASCA, or a combination thereof. In yet further aspects, the biomarker is SAA or eotaxin-1. In further aspects, the methods described herein can be used to reduce TNF-α serum levels, IL-6 serum levels, or IL-1β serum levels, or a combination thereof. In still other aspects, the methods can be used to reduce NF-κB levels, IL-8 levels, MCP-1 levels, CCL20 levels, or IFNγ levels in a subject. In still further aspects, the methods are useful for reducing NF-κB levels in gut lining tissue, IL-8 levels in gut lining tissue, MCP-1 levels in gut lining tissue, CCL20 levels in gut lining tissue, or IFNγ levels in gut lining tissue of a subject. In other aspects, the methods described herein can be used to reduce inflammation of the intestinal lining and / or ulcers of the intestinal lining as observed by colonoscopy. In further aspects, the methods described herein are useful for reducing levels of NF-κB, MCP-1, CCL20, or IFN-γ in a subject.In yet other aspects, the methods described herein are useful for reducing the levels of TNF-α, IL-1β, IL-6, IL-8, IL-23, IL-12, or IL-17A in a subject. In yet further aspects, the methods described herein can be used to reduce the levels of M2-PK pyruvate kinase, osteoprotegerin, MPO, HMGB1, CHI3L1, HBD2, MMP, calprotectin, lactoferrin, pANCA, or ASCA in a subject. In other aspects, the methods reduce the activity or level of TNF-α, IL-1β, IL-6, IL-8, IL-23, IL-12, or IL-17A, or a combination thereof, in a subject. In further aspects, the methods reduce the activity or level of NF-κB, MCP-1, CCL20, or IFN-γ, or a combination thereof, in a subject. In yet other aspects, the methods reduce the activity or levels of M2-PK, osteoprotegerin, MPO, HMGB1, CHI3L1, HBD2, MMP, calprotectin, lactoferrin, p-ANCA, or ASCA, or a combination thereof, in the subject. In yet further aspects, the methods reduce the activity or levels of one or both of SAA or eotaxin-1 in the subject.

[0117] Thus, the compounds disclosed herein can be used to treat inflammatory bowel disease. As used herein, the term "inflammatory bowel disease" or "IBD" refers to disorders involving 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 in the intestinal lining. The subject may have inflammatory bowel disease or may be at risk of developing inflammatory bowel disease. In some embodiments, the patient has inflammatory bowel disease or has been diagnosed with inflammatory bowel disease. In other embodiments, the patient is at risk of developing inflammatory bowel disease.

[0118] As used herein, the term "at risk of developing inflammatory bowel disease" refers to a subject that has a genetic predisposition to developing inflammatory bowel disease.In some embodiments, the subject has a genetic mutation that causes inflammatory bowel disease.In other embodiments, the subject may have one or more genetic mutations that may lead to the diagnosis of inflammatory bowel disease.

[0119] Thus, the present disclosure provides a method of treating inflammatory bowel disease in a subject in need thereof by administering one or more compounds, pharmaceutical compositions, or dosage units to the subject in need thereof. In some embodiments, the method comprises administering one or more compounds disclosed herein to the subject in need thereof. In other embodiments, the method comprises administering one or more pharmaceutical compositions disclosed herein to the subject in need thereof. In further embodiments, the method comprises administering one or more dosage units to the subject in need thereof.

[0120] The method includes administering a therapeutically effective amount of one or more of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q. In some embodiments, the therapeutically effective amount is about 0.01 to about 1000 mg / day. In other embodiments, the therapeutically effective amount is 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 1 about 1,000, about 50 to about 750, about 50 to about 500, about 50 to about 250, about 50 to about 100, about 100 to about 1,000, about 100 to about 750, about 100 to about 500, about 100 to about 250, about 250 to about 1,000, about 250 to about 750, about 250 to about 500, about 500 to about 1,000, about 500 to about 750, or about 750 to about 100 mg / day.

[0121] The methods described herein include administering Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q (optionally in a pharmaceutical composition) together 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 an anti-inflammatory drug, an immune system suppressant, a biologic, an antibiotic, an antidiarrheal drug, an analgesic, or a supplement. Examples of anti-inflammatory drugs include, but are not limited to, corticosteroids and / or aminosalicylates (e.g., mesalamine, balsalazide, or olsalazine). Examples of immune system suppressants include, but are not limited to, azathioprine, mercaptopurine, and methotrexate. Examples of biologics include, but are not limited to, infliximab, adalimumab, golimumab, certolizumab, vedolizumab, and ustekinumab. Examples of antibiotics include, but are not limited to, ciprofloxacin and metronidazole. Examples of antidiarrheal drugs include dietary fiber supplements (e.g., psyllium powder or methylcellulose) or loperamide. An example of an analgesic includes acetaminophen.

[0122] The method may also include administering a therapeutically effective amount of one or more of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q. In some embodiments, the therapeutically effective amount is about 0.01 to about 1000 mg / day. In other embodiments, the therapeutically effective amount is 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 1 about 1,000, about 50 to about 750, about 50 to about 500, about 50 to about 250, about 50 to about 100, about 100 to about 1,000, about 100 to about 750, about 100 to about 500, about 100 to about 250, about 250 to about 1,000, about 250 to about 750, about 250 to about 500, about 500 to about 1,000, about 500 to about 750, or about 750 to about 100 mg / day.

[0123] The methods described herein may further include administering Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or Compound Q (optionally in a pharmaceutical composition) together 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 an anti-inflammatory drug, an immune system suppressant, a biologic, an antibiotic, an antidiarrheal drug, an analgesic, or a supplement. Examples of anti-inflammatory drugs include, but are not limited to, corticosteroids and / or aminosalicylates (e.g., mesalamine, balsalazide, or olsalazine). Examples of immune system suppressants include, but are not limited to, azathioprine, mercaptopurine, and methotrexate. Examples of biologics include, but are not limited to, infliximab, adalimumab, golimumab, certolizumab, vedolizumab, and ustekinumab. Examples of antibiotics include, but are not limited to, ciprofloxacin and metronidazole. Examples of antidiarrheal drugs include dietary fiber supplements (e.g., psyllium powder or methylcellulose) or loperamide. An example of an analgesic includes acetaminophen.

[0124] In certain embodiments, the additional agent may be therapeutic, i.e., non-pharmacological. For example, the subject may require nutritional support, i.e., a special diet, or may be fed enterally (e.g., via a feeding tube) or parenterally (e.g., injection of nutrients).

[0125] Aspect A Aspect A1. Compound A or Compound G: [ka] or a pharma- ceutically acceptable salt thereof. Aspect A2. A compound according to aspect A1, which is compound A, or a pharma- ceutically acceptable salt thereof. Aspect A3. A compound according to aspect A1 or A2, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A4. A compound according to any one of aspects A1 to A3, [ka] or a pharma- ceutically acceptable salt thereof. A5. A compound according to any one of A1 to A3, [ka] or a pharma- ceutically acceptable salt thereof. A6. A compound according to any one of A1 to A3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A7. A compound according to any one of aspects A1 to A3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A8. A compound according to aspect A1 which is compound G, or a pharma- ceutically acceptable salt thereof. Aspect A9. A compound according to aspect A1 or A38, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A10. A compound according to any one of aspects A1, A8 or A9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A11. A compound according to any one of aspects A1, A8 or A9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A12. A compound according to any one of aspects A1, A8, or A9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A13. A compound according to any one of aspects A1, A8 or A9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect A14. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any one of aspects A1-A13 and a pharma- ceutically acceptable excipient. A pharmaceutical composition according to A14, comprising [ka] 13. A pharmaceutical composition comprising: A pharmaceutical composition according to A15, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. A pharmaceutical composition according to embodiment A44, comprising [ka] 13. A pharmaceutical composition comprising: A pharmaceutical composition according to A48, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. Aspect A19. A dosage unit comprising a compound according to any one of aspects A1 to A13, or a pharmaceutical composition according to any one of aspects A14 to A18. Aspect A20. The dosage unit according to aspect A19, which is an oral dosage unit such as a pill, tablet, capsule, syrup, solution, powder, paste, or film, or a parenteral dosage unit such as an injectable solution. Aspect A21. The dosage unit according to aspect A19 or A20, comprising from about 0.01 to about 1000 mg of the compound. Aspect A22. The dosage unit according to any one of aspects A19-A21, which is a solid dosage form. Aspect A23. The dosage unit according to any one of aspects A19-A21, which is a liquid dosage form. Aspect A24. The method of any one of Aspects A24-A26, wherein the composition is administered orally, intravenously, intraperitoneally, intramuscularly, or subcutaneously. Aspect A25. The method of aspect A27, wherein the composition is administered orally. Aspect A26. The method of any one of aspects A24-A28, wherein bradykinesia frequency, bradykinesia intensity, resting tremor, muscular rigidity, or a combination thereof is reduced in the subject. Aspect A27. The method of any one of aspects A24-A29, wherein the subject's score on the MDS-UPDRS scale improves following administration of the pharmaceutical composition or dosage unit.

[0126] Aspect B Aspect B1. Compound A or Compound G: [ka] or a pharma- ceutically acceptable salt thereof. Aspect B2. A compound according to Aspect B1, which is Compound A, or a pharma- ceutically acceptable salt thereof. Aspect B3. The compound according to aspect B1 or B2, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B4. A compound according to any one of aspects B1 to B3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B5. A compound according to any one of aspects B1 to B3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B6. A compound according to any one of aspects B1 to B3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B7. A compound according to any one of aspects B1 to B3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B8. The compound according to aspect B1, which is compound G, or a pharma- ceutically acceptable salt thereof. Aspect B9. The compound according to aspect B1 or B8, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B10. A compound according to any one of aspects B1, B8, or B9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B11. A compound according to any one of Aspects B1, B8, or B9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B12. A compound according to any one of aspects B1, B8, or B9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B13. A compound according to any one of aspects B1, B8, or B9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect B14. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to any one of aspects B1-B13 and a pharma- ceutically acceptable excipient. Aspect B15. A pharmaceutical composition according to aspect B14, comprising [ka] 13. A pharmaceutical composition comprising: Aspect B16. A pharmaceutical composition according to aspect B15, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. Aspect B17. A pharmaceutical composition according to aspect B14, comprising [ka] 13. A pharmaceutical composition comprising: Aspect B18. A pharmaceutical composition according to aspect B14, comprising [ka] 13. A pharmaceutical composition comprising: Aspect B19. A pharmaceutical composition according to aspect B18, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. Aspect B20. A dosage unit comprising a compound according to any one of aspects B1 to B13, or a pharmaceutical composition according to any one of aspects B14 to B19. Aspect B21. A dosage unit according to aspect B20 which is an oral dosage unit such as a pill, tablet, capsule, syrup, solution, powder, paste, or film, or a parenteral dosage unit such as an injectable solution. Aspect B22. The dosage unit according to aspect B20 or B21, comprising from about 0.01 to about 1000 mg of the compound. Aspect B23. The dosage unit according to any one of aspects B20-B22, which is a solid dosage form. Aspect B24. The dosage unit according to any one of aspects B20-B22, which is a liquid dosage form. Aspect B25. A method of modulating an Inflammatory Bowel Disease (IBD) marker in a subject in need thereof, comprising administering to a subject in need thereof a compound according to any one of aspects B1-B13, a pharmaceutical composition according to any one of aspects B14-B19, or a dosage form according to any one of aspects B20-B24. Aspect B26. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a compound according to any one of aspects B1-B13, a pharmaceutical composition according to any one of aspects B14-B19, or a dosage form according to any one of aspects B20-B24. Aspect B27. The method according to aspect B25 or B26, wherein the subject has or is at risk of developing IBD. Aspect B28. The method of any one of aspects B25-B27, wherein the pharmaceutical composition or dosage unit is administered orally, intravenously, intraperitoneally, intramuscularly, or subcutaneously. Aspect B29. The method according to aspect B28, wherein the pharmaceutical composition or dosage form is administered orally. Aspect B30. The method according to any one of aspects B25-B29, wherein the IBD is ulcerative colitis. Aspect B31. The method according to any one of aspects B25-B29, wherein the IBD is Crohn's disease. Aspect B32. The method of any one of aspects B25-B31, wherein inflammation or ulcers in the intestinal lining of the subject as observed by colonoscopy are reduced. Aspect B33. The method of any one of aspects B25 to B32, wherein the level of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-23 (IL-23), interleukin-12 (IL-12), or interleukin-17A (IL-17A), or a combination thereof, is reduced in the subject. Aspect B34. The method of any one of aspects B25 to B33, wherein the level of nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), cysteine-cysteine ​​motif chemokine ligand 20 (CCL20), or interferon-γ (IFN-γ), or a combination thereof, is reduced in the subject. Aspect B35. The method of any one of aspects B25 to B34, wherein the level of M2 pyruvate kinase (M2-PK), osteoprotegerin, myeloperoxidase (MPO), high mobility group box protein 1 (HMGB1), chitinase 3-like 1 (CHI3L1), human beta defensin 2 (HBD2), metalloproteinase (MMP), calprotectin, lactoferrin, peripheral antineutrophil cytoplasmic antibody (p-ANCA), or anti-Saccharomyces cerevisiae antibody (ASCA), or a combination thereof, is reduced in the subject. Aspect B36. The method according to any one of aspects B25-B35, wherein the level of one or both of serum amyloid A protein (SAA) or eotaxin-1 is reduced in the subject.

[0127] Aspect C Aspect C1. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G: [ka] or a pharma- ceutically acceptable salt thereof. Aspect C2. A compound according to aspect C1, which is compound A, or a pharma- ceutically acceptable salt thereof. Aspect C3. The compound according to aspect C1 or C2, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C4. A compound according to any one of aspects C1 to C3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C5. A compound according to any one of aspects C1 to C3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C6. A compound according to any one of aspects C1 to C3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C7. A compound according to any one of aspects C1 to C3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C8. A compound according to aspect C1, which is compound B, or a pharma- ceutically acceptable salt thereof. Aspect C9. The compound according to aspect C8, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C10. A compound according to any one of aspects C1, C8 or C9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C11. A compound according to any one of aspects C1, C8 or C9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C12. A compound according to any one of aspects C1, C8 or C9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C13. A compound according to any one of aspects C1, C8 or C9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C14. A compound according to aspect C1, which is compound C, or a pharma- ceutically acceptable salt thereof. Aspect C15. A compound according to aspect C1 or C14, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C16. A compound according to any one of aspects C1, C14 or 1C5, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C17. A compound according to any one of aspects C1, C14 or C15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C18. A compound according to any one of aspects C1, C14 or C15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C19. A compound according to any one of aspects C1, C14, or C15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C20. A compound according to aspect C1, which is compound D, or a pharma- ceutically acceptable salt thereof. Aspect C21. A compound according to aspect C1 or C20, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C22. A compound according to any one of aspects C1, C20, or C21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C23. A compound according to any one of aspects C1, 20 or 21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C24. A compound according to any one of aspects C1, C20, or C21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C25. A compound according to any one of aspects C1, C20, or C21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C26. A compound according to aspect C1, which is compound E, or a pharma- ceutically acceptable salt thereof. Aspect C27. A compound according to aspect C1 or C26, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C28. A compound according to any one of aspects C1, C26, or C27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C29. A compound according to any one of aspects C1, C26, or C27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C30. A compound according to any one of aspects C1, C26 or C27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C31. A compound according to any one of aspects C1, C26 or C27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C32. A compound according to aspect C1, which is compound F, or a pharma- ceutically acceptable salt thereof. Aspect C33. A compound according to aspect C1 or C32, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C34. A compound according to any one of aspects C1, C32, or C33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C35. A compound according to any one of aspects C1, C32, or C33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C36. A compound according to any one of aspects C1, C32, or C33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C37. A compound according to any one of aspects C1, C32 or C33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C38. A compound according to aspect C1, which is compound G, or a pharma- ceutically acceptable salt thereof. Aspect C39. A compound according to aspect C1 or C38, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C40. A compound according to any one of aspects C1, C38 or C39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C41. A compound according to any one of aspects C1, C38, or C39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C42. A compound according to any one of aspects C1, C38, or C39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C43. A compound according to any one of aspects C1, C38, or C39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect C44. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any one of aspects C1-C43 and a pharma- ceutically acceptable excipient. Aspect C45. A pharmaceutical composition according to aspect C44, comprising [ka] 13. A pharmaceutical composition comprising: A pharmaceutical composition according to embodiment C45, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. A pharmaceutical composition according to embodiment C44, comprising [ka] 13. A pharmaceutical composition comprising: Aspect C48. A pharmaceutical composition according to aspect C44, comprising [ka] 13. A pharmaceutical composition comprising: Aspect C49. A pharmaceutical composition according to aspect C48, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. Aspect C50. A dosage unit comprising a compound according to any one of aspects C1 to C43, or a pharmaceutical composition according to any one of aspects C44 to C49. Aspect C51. The dosage unit according to aspect C50, which is an oral dosage unit such as a pill, tablet, capsule, syrup, solution, powder, paste, or film, or a parenteral dosage unit such as an injectable solution. Aspect C52. The dosage unit of aspect C50 or C51, comprising from about 0.01 to about 1000 mg of the compound. Aspect C53. The dosage unit of any one of aspects C50-C52, which is a solid dosage form. Aspect C54. The dosage unit of any one of aspects C50-C52, which is a liquid dosage form. Aspect C55. The method of any one of aspects C55-C57, wherein the composition is administered orally, intravenously, intraperitoneally, intramuscularly, or subcutaneously. Aspect C56. The method according to aspect C58, wherein the composition is administered orally. Aspect C57. The method of any one of aspects C55-C59, wherein the frequency of bradykinesia, the intensity of bradykinesia, resting tremor, muscle rigidity, or a combination thereof is reduced in the subject. Aspect C58. The method of any one of aspects C55-C60, wherein the subject's score on the MDS-UPDRS scale improves following administration of the pharmaceutical composition or dosage unit.

[0128] Aspect D Aspect D1. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G: [ka] or a pharma- ceutically acceptable salt thereof. Aspect D2. A compound according to aspect D1, which is compound A, or a pharma- ceutically acceptable salt thereof. Aspect D3. The compound according to aspect D1 or D2, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D4. A compound according to any one of aspects D1 to D3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D5. A compound according to any one of aspects D1 to D3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D6. A compound according to any one of aspects D1 to D3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D7. A compound according to any one of aspects D1 to D3, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D8. A compound according to aspect D1 which is compound B, or a pharma- ceutically acceptable salt thereof. A compound according to embodiment D8, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D10. A compound according to any one of aspects D1, D8, or D9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D11. A compound according to any one of aspects D1, D8, or D9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D12. A compound according to any one of aspects D1, D8, or D9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D13. A compound according to any one of aspects D1, D8, or D9, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D14. A compound according to aspect 1, which is compound C, or a pharma- ceutically acceptable salt thereof. Aspect D15. A compound according to aspect D1 or D14, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D16. A compound according to any one of aspects D1, D14, or D15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D17. A compound according to any one of aspects D1, D14, or D15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D18. A compound according to any one of aspects D1, D14, or D15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D19. A compound according to any one of aspects D1, D14, or D15, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D20. A compound according to aspect D1 which is compound D, or a pharma- ceutically acceptable salt thereof. Aspect D21. A compound according to aspect D1 or D20, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D22. A compound according to any one of aspects D1, D20, or D21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D23. A compound according to any one of aspects D1, D20, or D21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D24. A compound according to any one of aspects D1, D20, or D21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D25. A compound according to any one of aspects D1, D20, or D21, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D26. A compound according to aspect D1 which is compound E, or a pharma- ceutically acceptable salt thereof. Aspect D27. A compound according to aspect D1 or D26, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D28. A compound according to any one of aspects D1, D26, or D27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D29. A compound according to any one of aspects D1, D26, or D27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D30. A compound according to any one of aspects D1, D26 or D27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D31. A compound according to any one of aspects D1, D26, or D27, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D32. The compound according to aspect D1, which is compound F, or a pharma- ceutically acceptable salt thereof. Aspect D33. A compound according to aspect D1 or D32, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D34. A compound according to any one of aspects D1, D32, or D33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D35. A compound according to any one of aspects D1, D32, or D33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D36. A compound according to any one of aspects D1, D32, or D33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D37. A compound according to any one of aspects D1, D32, or D33, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D38. A compound according to aspect D1 which is compound G, or a pharma- ceutically acceptable salt thereof. Aspect D39. A compound according to aspect D1 or D38, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D40. A compound according to any one of aspects D1, D38, or D39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D41. A compound according to any one of aspects D1, D38, or D39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D42. A compound according to any one of aspects D1, D38, or D39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D43. A compound according to any one of aspects D1, D38, or D39, [ka] or a pharma- ceutically acceptable salt thereof. Aspect D44. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any one of aspects D1-D43 and a pharma- ceutically acceptable excipient. Aspect D45. A pharmaceutical composition according to aspect D44, comprising [ka] 13. A pharmaceutical composition comprising: A pharmaceutical composition according to embodiment D45, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. A pharmaceutical composition according to embodiment D44, comprising [ka] 13. A pharmaceutical composition comprising: A pharmaceutical composition according to embodiment D44, comprising [ka] 13. A pharmaceutical composition comprising: Aspect D49. A pharmaceutical composition according to aspect D48, comprising [ka] The molar ratio of said pharmaceutical composition is about 40: about 60. Aspect D50. A dosage unit comprising a compound according to any one of aspects D1 to D43 or a pharmaceutical composition according to any one of aspects D44 to D49. Aspect D51. The dosage unit according to aspect D50 which is an oral dosage unit such as a pill, tablet, capsule, syrup, solution, powder, paste, or film, or a parenteral dosage unit such as an injectable solution. Aspect D52. The dosage unit according to aspect D50 or D51, comprising from about 0.01 to about 1000 mg of the compound. Aspect D53. The dosage unit according to any one of aspects D50-D52, which is a solid dosage form. Aspect D54. The dosage unit according to any one of aspects D50-D52, which is a liquid dosage form. Aspect D55. A method of modulating an inflammatory bowel disease (IBD) marker in a subject in need thereof, comprising administering to a subject in need thereof a compound according to any one of aspects D1-D43, a pharmaceutical composition according to any one of aspects D44-4D9, or a dosage form according to any one of aspects D50-D54. Aspect D56. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a compound according to any one of aspects D1 to D43, a pharmaceutical composition according to any one of aspects D44 to D49, or a dosage form according to any one of aspects D50 to D54. Aspect D57. The method according to aspect D55 or D56, wherein the subject has or is at risk of developing IBD. Aspect D58. The method of any one of aspects D55-D57, wherein the pharmaceutical composition or dosage unit is administered orally, intravenously, intraperitoneally, intramuscularly, or subcutaneously. Aspect D59. The method according to aspect D58, wherein the pharmaceutical composition or dosage form is administered orally. Embodiment D60. The method according to any one of embodiments D55-D59, wherein the IBD is ulcerative colitis. Embodiment D61. The method according to any one of embodiments D55-D59, wherein the IBD is Crohn's disease. Aspect D62. The method of any one of aspects D55-D61, wherein inflammation or ulcers in the intestinal lining of the subject as observed by colonoscopy are reduced. Embodiment D63. The method of any one of embodiments D55-D62, wherein the level of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-23 (IL-23), interleukin-12 (IL-12), or interleukin-17A (IL-17A), or a combination thereof, is reduced in the subject. Embodiment D64. The method of any one of embodiments D55 to D63, wherein the level of nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), cysteine-cysteine ​​motif chemokine ligand 20 (CCL20), or interferon-γ (IFN-γ), or a combination thereof, is reduced in the subject. Aspect D65. The method according to any one of aspects D55 to D64, wherein the level of M2 pyruvate kinase (M2-PK), osteoprotegerin, myeloperoxidase (MPO), high mobility group box protein 1 (HMGB1), chitinase 3-like 1 (CHI3L1), human beta defensin 2 (HBD2), metalloproteinase (MMP), calprotectin, lactoferrin, peripheral antineutrophil cytoplasmic antibody (p-ANCA), or anti-Saccharomyces cerevisiae antibody (ASCA), or a combination thereof, is reduced in the subject. Aspect D66. The method of any one of aspects D55-D65, wherein the level of one or both of serum amyloid A protein (SAA) or eotaxin-1 is reduced in the subject.

[0129] The following examples are provided to illustrate some of the concepts described within this disclosure. Each example is believed to provide a particular, individual embodiment of the compositions, methods of preparation, and uses, but no example should be construed as limiting the more general embodiments described herein. EXAMPLES

[0130] Example 1: Preparation of Compounds A-2 to A-5 - (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0131] Synthesis of 2.2: A mixture of methyl (2S)-2-amino-3-sulfanylpropanoate (2.1, 30 g, 174.78 mmol, 1 equiv., HCl) in acetone (600 mL) was degassed and cooled with N 2 After purging three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 12 hours. The reaction mixture was concentrated under reduced pressure to remove acetone. The residue was diluted with ethyl acetate (200 mL) and washed successively with water, 5% aqueous sodium bicarbonate solution (3×200 mL), and brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 0 / 1 to 3 / 1) to give 22.3 g of 2.2 (72%) as a colorless oil. (ES, m / z): [M+1] + 176.1.

[0132] Synthesis of 2.3: Methyl (4S)-2,2-dimethylthiazolidine-4-carboxylate (2.2, 11 g, 62.8 mmol, 1 equiv.) and K 2 CO 3 (13 g, 94.2 mmol, 1.5 equiv.) in DMF (50 mL) 2 SO 4(11.9 g, 94.2 mmol, 8.93 mL, 1.5 equiv) was added dropwise with stirring at 0 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL) at 0 °C. The residue was diluted with water (45 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, 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 0-5% ethyl acetate / petroleum ether, gradient @ 60 mL / min) to give 6 g of 2.3 (50%) as a colorless oil. (ES, m / z): [M+1] + 190.1.

[0133] Synthesis of 2.4: A mixture of methyl (4S)-2,2,3-trimethylthiazolidine-4-carboxylate (2.3, 4 g, 21.13 mmol, 1 equiv.) in HCl (6 M, 80 mL, 22.71 equiv.) was degassed and purged with Ar three times, after which the mixture was stirred under Ar atmosphere at 100° C. for 8 h. The reaction mixture was concentrated under reduced pressure to give 3.8 g of 2.4 (crude, HCl) as a yellow solid. The crude product was used directly in the next step without further purification. (ES, m / z): [M+1] + 136.0.

[0134] Synthesis of 2.6: To a solution of 2-hydroxybenzonitrile (2.5, 10 g, 83.95 mmol, 1 equiv.) in MeOH (150 mL) and phosphate buffer (150 mL) was added (2R)-2-amino-3-sulfanylpropanoic acid (26.46 g, 167.90 mmol, 2 equiv., HCl) at room temperature. 2 CO 3The solution was adjusted to pH=6.4 by careful addition, and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure, and the crude yellow residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (30 mL×3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.6 (17 g, 84% yield) as a yellow solid. (ES, m / z): [M+1] + 224.0.

[0135] Synthesis of 2.7: To a solution of (4R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (2.6, 17 g, 72.34 mmol, 1 equiv.), N-methoxymethanamine (7.76 g, 79.58 mmol, 1.1 equiv., HCl) and DECP (12.98 g, 79.58 mmol, 1.57 mL, 12.02 equiv.) in DMF (170 mL) was added N 2 DIPEA (14.02 g, 108.52 mmol, 18.9 mL, 1.5 equiv) was added at 0° C. under reduced pressure. The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with NaHCO 3 (30mL×3), and washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 19:1) to give 2.7 (12.95 g, 96.48% yield) as a pale yellow solid. (ES, m / z): [M+1] + 267.1.

[0136] Synthesis of 2.8: To a solution of (R)-2-(2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (2.7, 12.00 g, 45.06 mmol, 1 equiv.) in THF (240 mL), LAH (2.57 g, 67.59 mmol, 1.5 equiv.) was added to the N 2The mixture was added at −40° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (200 mL) and KHSO 4 (200 mL) of 1M solution of was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After extraction with dichloromethane (100 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 2.8 (9.34 g, crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 208.0.

[0137] Synthesis of A-2 to A-5: (R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (2.8, 9.34 g, 45.07 mmol, 1 equiv.) in EtOH (300 mL) and H 2 To the mixture solution of 2.4, 9.28 g, 54.08 mmol, 1.2 equiv., HCl) and KOAc (30.96 g, 315.47 mmol, 7 equiv.) were added at 20° C. The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 5%-35%, 20 min) to give A-2 to A-5 (6.15 g, 42.06% yield), a mixture of four stereoisomers, as pale yellow solids. (ES, m / z): [M+1] + 325.1.

[0138] Example 2: Purification of Compounds A-2 to A-5 - (2R, 4S)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-2); (2R, 4S)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-5); (2S, 4S)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-4); and (2S, 4S)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-3) [ka]

[0139] 2 grams of the compounds of Example 1 (A-2 to A-5) (a mixture of four peaks) were purified twice by SFC separation to obtain 290 mg of A-2 (yield 14.5%, de value 87.56%, peak 1), 80 mg of A-5 (yield 4%, de value 94.2%, peak 2), 120 mg of A-4 (yield 6%, de value 96.22%, peak 3) and 480 mg of A-3 (yield 24%, de value 98.38%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 325.1.

[0140] Method 1: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); gradient: B%=30% isocratic elution mode; flow rate: 57 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0141] Method 2: Apparatus: Waters SFC80Q fractionation SFC; cartridge: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A is CO 2 ,BはMeOH(0.1%NH 3 H 2 O); グラジエント: B%=46% アイソクラティック DISSOLUTION モード; flow rate: 75 g / min; wavelength: 220nm; カラム temperature: 40℃; システム back pressure: 100バール.

[0142] A-2: 1 HNMR(400MHz,アセトン-d 6 )δ=7.46-7.37(m,2H),6.99-6.90(m,2H),5.00(q,J=8.3Hz,1H),4.54(d,J=8.5Hz,1H),4.20(t, J=6.6Hz,1H),3.67(dd,J=8.7,11.3Hz,1H),3.57-3.39(m,1H),3.29-3.16(m,2H),2.49(s,3H).

[0143] A-3: 1 HNMR(400MHz,アセトン-d 6 )δ=7.46-7.38(m,2H),6.97-6.91(m,2H),5.22(dt,J=5.4,8.9Hz,1H),4.63(d,J=5.4Hz,1H),3.71(br t,J=7.4Hz,1H),3.50(d,J=8.9Hz,2H),3.26-3.17(m,2H),2.65(s,3H).

[0144] A-5: 1 HNMR(400MHz,アセトン-d6)δ=7.47-7.36(m,2H),7.00-6.87(m,2H),4.85(br d,J=8.2Hz,1H),4.34(d,J=8.2Hz,1H),3.99(br s,1H),3.68-3.58(m,1H),3.57-3.40(m,2H),3.29(br dd,J=7.0,10.8Hz,1H),2.63(s,3H).

[0145] A-4: 1HNMR(400MHz, acetone-d6)δ=7.46-7.37(m,2H),6.98-6.89(m,2H),5.29(dt,J=4.7,9.0Hz,1H),5.07(d,J=4.8Hz,1H),4.25(br d,J=4.9Hz,1H),3.53-3.36(m,2H),3.22(dd,J=6.5,10.4Hz,1H),3.07(br d,J=9.1Hz,1H),2.71(s,3H).

[0146] Example 3: Preparation of compounds G-2 to G-5: (2R,4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-4); (2S,4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-5); (2R,4S)-2-((R)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-3); (2S,4S)-2-((R)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-2) [ka]

[0147] Synthesis of 11.2. To a solution of 2-hydroxy-4-methylbenzonitrile (11.1, 3 g, 22.53 mmol, 1 equiv.) in MeOH (30 mL) and phosphate buffer (150 mL) was added (2R)-2-amino-3-sulfanylpropanoic acid (5.46 g, 45.06 mmol, 2 equiv.) and phosphate buffer (30 mL). Solid K 2 CO 3The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (3×20 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.35 g of 11.2 (98%, % purity, ee value 100.0%) as a yellow solid. (ES, m / z): [M+1] + 238.0.

[0148] Synthesis of 11.3. To a solution of (R)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazole-4-carboxylic acid (11.2, 3 g, 12.64 mmol, 1 equiv.), N-methoxymethanamine (849.54 mg, 13.91 mmol, 1.1 equiv., HCl) and DECP (2.39 g, 13.91 mmol, 2.21 mL, 95% purity, 1.1 equiv.) in DMF (5 mL) was added DIEA (2.45 g, 18.97 mmol, 3.30 mL, 1.5 equiv.) to obtain a 3-chloroformamide (11.4, 1.0 g, 1.2 mmol, 1.0 equiv., HCl) solution. 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The reaction mixture was stirred at H 2 The mixture was diluted with O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with NaHCO 3 Wash with aqueous solution and brine (10 mL) and add Na 2 SO 4 The organic phase was washed with NaHCO 3 The residue and the filter cake were purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 1:1) to give 2.05 g of 11.3 (57.84%, %ee value 84.94%) as a pale yellow solid. (ES, m / z): [M+1] + 281.1.

[0149] Synthesis of 11.4. To a solution of (R)-2-(2-hydroxy-4-methylphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (11.3, 1.8 g, 6.42 mmol, 1 equiv.) in THF (15 mL) was added LAH (365.54 mg, 9.63 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (30 mL) and KHSO 4 (30 mL) of 1M solution of 11.4 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (2×20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 210 mg of 11.4 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 222.2

[0150] Synthesis of 11.5. (R)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazole-4-carbaldehyde (11.4, 1.4 g, 6.33 mmol, 1 equiv.) in EtOH (21 mL) and H 2 To the mixture solution of 2H2O (7 mL), (2S)-2-(methylamino)-3-sulfanylpropanoic acid (1.30 g, 7.59 mmol, 1.2 equiv., HCl) and KOAc (4.35 g, 44.29 mmol, 7 equiv.) were added at 20° C. The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified using a preparative HPLC column: Welch Xtimate C18 250*70 mm#10 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 10% to 40%, 20 min) to give 150 mg of 11.5 (25.69%) (mixture of G-2, G-3, G-4, and G-5) as a pale yellow solid. (ES, m / z): [M+1] + 339.0.

[0151] Separation of G-2 to G-5. 300 mg of 11.5 (a mixture of four peaks) was purified by two SFC separations to give 70.91 mg of G-5 (23%, de value 93%, peak 1), 33.9 mg of G-4 (11%, de value 99%, peak 2), 28.91 mg of G-2 (9.6%, de value 63%, peak 3), and 67.94 mg of G-3 (22.6%, de value 89%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 339.0

[0152] Method 1: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase: A is CO 2 B is IPA (0.1% NH 3 H 2 O); Gradient: B38%-38% in 7 min

[0153] Method 2: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); Mobile phase: A is CO 2 B is IPA (0.1% NH 3 H 2 O); Gradient: B30%-30% in 15 min

[0154] G-4: 1H NMR(400MHz,アセトン-d6)δ=7.29(d,J=7.9Hz,1H),6.81-6.70(m,2H),4.98(d,J=8.2Hz,1H),4.53(d,J=8.3Hz,1H),4.25(t,J=6.4Hz,1H),3.64(dd,J=8.6,11.3Hz,1H),3.44(dd,J=7.9,11.3Hz,1H),3.23(d,J=6.4Hz,2H),2.50(s,3H),2.31(s,3H)

[0155] G-5: 1 H NMR(400MHz,アセトン-d6)δ=7.30(d,J=7.9Hz,1H),6.85-6.64(m,2H),5.25-5.11(m,1H),4.61(d,1H),3.76-3.65(m,1H),3.47(d,J=8.9Hz,1H),3.20(br d,J=7.0Hz,2H),2.64(s,3H),2.31(s,3H)

[0156] G-3: 1 H NMR(400MHz,アセトン-d6)δ=7.29(d,J=7.9Hz,1H),6.82-6.68(m,2H),5.33-5.18(m,1H),5.04(d,J=4.8Hz,1H),4.26(dd,J=2.1,6.5Hz,1H),3.68-3.56(m,2H),3.38-3.28(m,1H),3.25-3.19(m,1H),3.07(s,1H),2.73-2.63(m,3H),2.31(s,3H)

[0157] G-2: 1 H NMR(400MHz,アセトン-d6)δ=7.29(d,J=8.0Hz,1H),6.82-6.64(m,2H),4.81(d,J=8.2Hz,1H),4.33(d,J=8.3Hz,1H),4.03(dd,J=5.4,6.7Hz,1H),3.67-3.58(m,1H),3.55-3.40(m,2H),3.30(dd,J=6.9,11.0Hz,2H),2.63(s,3H),2.31(s,3H)

[0158] Example 4: Preparation of (4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0159] Synthesis of G-6. A solution of (2R,4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-4, 7.9 mg) and (2S,4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (G-5, 15.2 mg) was dissolved in ACN (3 mL) and H 2 HO (1 mL) and the mixture was lyophilized to give 15.74 mg of G-6 (100%) as a pale yellow solid. (ES, m / z): [M+1] + 339.0.

[0160] G-6:1H NMR (400MHz, acetone) δ=7.30(d,J=7.7Hz,1.74H),6.81-6.71(m,3.48H),5.25-5.12(m, 1.02H),5.07-4.92(m,0.78H),4.61(d,J=5.4Hz,0.98H),4.54(d,J=8.3Hz,0.74H),4. 25(s,0.80H),3.72(t,J=7.3Hz,1.18H),3.64(dd,J=8.8,11.0Hz,0.93H),3.52-3.42 (m,3.14H),3.26-3.18(m,3.92H),2.65(s,3H),2.52-2.47(m,2.72H),2.31(s,5.85H)

[0161] Example 5: Preparation of Compounds C-2 to C-5 - (4S)-N-(2-(3-but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methyl-thiazolidine-4-carboxamide [ka]

[0162] To a mixture of (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-2 to A-5, 40 mg, 123.30 μmol, 1 equiv.), 2-(3-but-3-ynyldiazirin-3-yl)ethanamine (4.1, 16.91 mg, 123.30 μmol, 1 equiv.) in DMF (2 mL) was added HATU (93.76 mg, 246.60 μmol, 2 equiv.) and DIEA (31.87 mg, 246.60 μmol, 42.95 μL, 2 equiv.) at 25° C. The mixture was degassed and purged with Ar three times, then stirred under Ar atmosphere at 25° C. for 12 h. The reaction mixture was filtered to obtain a solution. The solution was purified by preparative HPLC (neutral conditions; column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 40%-70%, 8 min) to give 15 mg of C-2 to C-5 (27% yield), a mixture of four stereoisomers, as a black gum. (ES, m / z): [M+1] + 444.1.

[0163] Example 6: Preparation of Compound C-3 - (2S,4S)-N-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxamide [ka]

[0164] To a mixture of (4S)-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methylthiazolidine-4-carboxylic acid (A-3, 25 mg, 0.077 mmol, 1 equiv.), 2-(3-but-3-ynyldiazirin-3-yl)ethanamine (4.1, 10.57 mg, 0.077 mmol, 1 equiv.) in DMF (1 mL) was added HATU (58.60 mg, 0.154 mmol, 2 equiv.) and DIEA (19.92 mg, 0.154 mmol, 26.84 μL, 2 equiv.). The mixture was degassed and purged with Ar three times, then stirred under Ar atmosphere at 25° C. for 12 h. The reaction mixture was filtered to obtain a solution. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 35% to 70%, 10 min) to give 19 mg of C-3 (52.8%) as a yellow oil. (ES, m / z): [M+1] + 444.6. 1 H NMR (400MHz, acetone) δ=12.49(s,1H),7.57-7.48(m,1H),7.47-7.35(m,2H),7 .03-6.86(m,2H),5.13(dt,J=6.1,8.8Hz,1H),4.62(d,J=5.9Hz,1H),3.68- 3.55(m,2H),3.53-3.43(m,1H),3.22(s,2H),3.12(dq,J=3.7,6.7Hz,2H),2 .65(s,3H),2.39(t,J=2.6Hz,1H),2.03-1.99(m,2H),1.63(q,J=7.1Hz,4H)

[0165] Example 7: Preparation of compound C-2-(4S)-N-[2-(3-but-3-ynyldiazirin-3-yl)ethyl]-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methylthiazolidine-4-carboxamide [ka]

[0166] To a mixture of (4S)-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methylthiazolidine-4-carboxylic acid (A-2, 15 mg, 0.046 mmol, 1 equiv.), 2-(3-but-3-ynyldiazirin-3-yl)ethanamine (4.1, 6.34 mg, 0.046 mmol, 1 equiv.) in DMF (1 mL) was added HATU (35.16 mg, 0.092 mmol, 2 equiv.) and DIEA (11.95 mg, 0.092 μmol, 16.11 μL, 2 equiv.). The mixture was degassed and purged with Ar three times, then stirred under Ar atmosphere at 25° C. for 12 h. The reaction mixture was filtered to obtain a solution. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 45% to 75%, 8 min) to give 13 mg of C-2 (62.7%) as a yellow oil. (ES, m / z): [M+1] + 444.1. 1 H NMR (400MHz, acetone-d 6 )δ=7.65-7.53(m,1H),7.52-7.31(m,2H),6.96(quin,J=7.5Hz,2H),5.25-4.92(m,1H),4.70-4.45(m,1H),4.11(dd,J=4.3,7 .2Hz,1H),3.91-3.71(m,1H),3.69-3.43(m,2H),3.38-3.06(m,3H),2.60-2.31(m,3H),2.05-2.02(m,2H),1.75-1.56(m,4H).

[0167] Example 8: Preparation of Compounds E-2 to E-5 - (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-4-methyl-thiazolidine-4-carboxylic acid [ka]

[0168] Synthesis of 7.3. To a solution of methyl (2S)-2-amino-3-sulfanylpropanoate (7.1, 20 g, 116.52 mmol, 1 equiv, HCl) in toluene (300 mL), 2,2-dimethylpropanal (7.2, 12.04 g, 139.82 mmol, 15.46 mL, 1.2 equiv) was added in one portion, followed by TEA (17.69 g, 174.78 mmol, 24.33 mL, 1.5 equiv), and the mixture was heated to reflux (oil bath temperature: 110 °C) and dewatered in a Dean-Stark oven for 18 h. The mixture was cooled to room temperature, then filtered, the filter cake was washed with ethyl acetate (2 × 50 mL), and the filtrate was concentrated under vacuum to give a residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether, gradient @ 150 mL / min) to give 20 g of 7.3 (84%) as a colorless oil. (ES, m / z): [M+1] + 204.1.

[0169] Synthesis of 7.4. A solution of methyl (4S)-2-tert-butylthiazolidine-4-carboxylate (7.4, 10 g, 49.19 mmol, 1 equiv.) in HCOOH (150 mL) was added with AcOEt at 0-5 °C with stirring. 2 2H2O (15.06 g, 147.56 mmol, 13.82 mL, 3 equiv) and HCOONa (4.01 g, 59.03 mmol, 3.19 mL, 1.2 equiv) were added. The reaction mixture was warmed to 15 °C and stirred for 18 h. The solvent was removed under reduced pressure and the resulting oil was concentrated to NaHCO 3 (100 mL) and ethyl acetate (100 mL) was added. The organic phase was washed with saturated NaHCO 3The residue, combined with another batch, was purified by flash silica gel chromatography (ISCO®; 330 g Sepa Flash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether, gradient @ 150 mL / min) to give 22 g of 7.4 as a white solid. (ES, m / z): [M+1] + 232.1.

[0170] Synthesis of 7.5. i-PrNH 2 To a stirred solution of (6.52 g, 110.24 mmol, 9.47 mL, 1.5 equiv) in THF (150 mL) was added dropwise under nitrogen at -65°C. DMPU (37.68 g, 293.98 mmol, 35.55 mL, 4 equiv) was added dropwise at this temperature. After addition, the reaction mixture was stirred at -65°C for 1 h and a solution of methyl (4S)-2-tert-butyl-3-formyl-thiazolidine-4-carboxylate (7.4, 17 g, 73.49 mmol, 1 equiv) in THF (100 mL) was added dropwise at -65°C. The reaction mixture was stirred for 1 h and then MeI (12.52 g, 88.19 mmol, 5.49 mL, 1.2 equiv) was added dropwise. The reaction mixture was stirred at this temperature for another hour. After completion of the reaction, the reaction mixture was diluted with saturated NH 4 Quenched with Cl solution (20 mL) and extracted with ethyl acetate (3 x 100 mL), the organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluent of 0-25% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to give 12 g of 7.5 (65%) as a yellow solid. (ES, m / z): [M+1] + 246.1.

[0171] Synthesis of 7.6. A solution of methyl (4S)-2-tert-butyl-3-formyl-4-methylthiazolidine-4-carboxylate (7.5, 1 g, 4.08 mmol, 1 equiv) in HCl (10.04 g, 101.90 mmol, 9.84 mL, 37% purity, 25 equiv) was degassed and purged with Ar three times, then heated to 100° C. and stirred for 5 days. The reaction mixture was dried in vacuum to give 700 mg of 7.6 (crude) as a yellow solid. The crude product was used directly in the next step without further purification.

[0172] Synthesis of E-2 to E-5. (R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (2.8, 200 mg, 965.02 μmol, 1 equiv.) in EtOH (24 mL) and H 2 To the mixture solution of 2H2O (8 mL) was added (2S)-2-amino-2-methyl-3-sulfanylpropanoic acid (7.6, 364.41 mg, 2.12 mmol, 2.2 equiv., HCl) and KOAc (662.95 mg, 6.76 mmol, 7 equiv.) at 20° C. The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid and then extracted with ethyl acetate (2×30 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (neutral condition; column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 10%-30%, 8 min) to give 150 mg of E-2, E-3, E-4, and E-5 (43% yield) as a mixture of four stereoisomers as pale yellow solids. (ES, m / z): [M+1] + 325.1.

[0173] 1 HNMR (400MHz, acetone-d 6)δ=1.38(s,3H),1.40(s,4H),1.50(s,1H),1.53(s,3H),2.76-2.87(m,2H),2.88-2.95(m,2H),3. 04(d,J=10.13Hz,1H),3.11(d,J=10.25Hz,1H),3.36-3.47(m,4H),3.56(s,2H),3.57-3.67(m,2H ),3.73(dd,J=11.27,8.76Hz,1H),4.73(d,J=7.27Hz,1H),4.82(d,J=7.63Hz,1H),4.91(q,J=7.9 1Hz,1H),5.03-5.13(m,2H),5.18(td,J=9.03,4.59Hz,1H),6.89-6.99(m,7H),7.37-7.47(m,7H).

[0174] Example 9: Preparation of Compounds B-2 to B-5 - (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3,4-dimethylthiazolidine-4-carboxylic acid [ka]

[0175] A solution of (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-4-methylthiazolidine-4-carboxylic acid (E-2 to E-5, 40 mg, 123.30 μmol, 1 equiv.) and formaldehyde (I10, 40.02 mg, 493.19 μmol, 36.72 μL, 37% purity, 4 equiv.) in MeOH (5 mL) was added with NaBH 3 CN (30.99 mg, 493.19 μmol, 4 equiv.) was added. The mixture was stirred at 15° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 15%-45%, 8 min) to give 36 mg of B-2 to B-5 (83%), a mixture of four stereoisomers, as white solids. (ES, m / z): [M+1] +339.1.

[0176] 1 HNMR (400MHz, chloroform-d) δ = 1.46-1.62 (m, 3H), 2.52 (s, 1H), 2.58 (s, 1H), 2.61 (s, 1H), 2.65 (s, 1H), 2.76-2.95 (m, 1H), 3.14-3.66 (m, 3H), 4.38 (d, J = 3.73Hz, 1H), 4.45-4.54 (m, 1H), 4.69-4.80 (m, 1H), 4.99-5.14 (m, 1H), 5.16-5.29 (m, 1H), 6.85-6.94 (m, 1H), 6.96-7.04 (m, 1H), 7.32-7.45 (m, 2H).

[0177] Example 10: Preparation of Compounds D2 to D5 - 2-(3-but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylate [ka]

[0178] A solution of (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-2 to A-5, 45 mg, 138.71 μmol, 1 equiv.) in DMF (5 mL) was added with 3-but-3-ynyl-3-(2-iodoethyl)diazirine (41.29 mg, 166.45 μmol, 1.2 equiv.), K 2 CO 3 (23 mg, 166.45 μmol, 1.2 equiv) was added under Ar. The mixture was stirred under Ar at 15° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions, column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH 4 HCO 3)-ACN]; B%: 50%-80%, 8 min) to give 18 mg of D-2 to D-5 (29%), a mixture of four stereoisomers, as a yellow gum. (ES, m / z): [M+1] + 445.1. 1 HNMR(400MHz,chloroform-d)δ=1.70(br t,J=7.19Hz,2H),1.77-1.88(m,2H),1.97-2.09(m,3H),2.54(s,1H),2.62(d,J=2.00Hz,2H),2.71(s,1 H),3.07-3.13(m,1H),3.15-3.34(m,2H),3.38-3.59(m,2H),3.68(dd,J=9.07,6.44Hz,1H),3.84(t,J= 6.88Hz,1H),4.00-4.14(m,2H),4.17(dd,J=6.13,1.88Hz,1H),4.27(d,J=7.38Hz,1H),4.54(d,J=5.13 Hz,1H),4.61(d,J=6.75Hz,1H),4.85(q,J=8.00Hz,1H),4.90-5.01(m,1H),5.04-5.19(m,1H),6.88(br t,J=7.50Hz,1H),7.00(br d,J=8.25Hz,1H),7.31-7.45(m,2H),12.13-12.78(m,1H).

[0179] Example 11: Preparation of compounds F-2 to F-5 - (2R, 4S)-3-methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl) thiazolidine-4-carboxylic acid (F-4); (2R, 4S)-3-methyl-2-((R)-2-phenyl-4,5-dihydrothiazol-4-yl) thiazolidine-4-carboxylic acid (F-3); (2S, 4S)-3-methyl-2-((R)-2-phenyl-4,5-dihydrothiazol-4-yl) thiazolidine-4-carboxylic acid (F-2); (2S, 4S)-3-methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl) thiazolidine-4-carboxylic acid (F-5) [ka]

[0180] Synthesis of I-1. [ka] Benzonitrile (1.1, 1.0 g, 9.70 mmol, 990 μL, 1 equiv.) and (R)-2-amino-3-mercaptopropanoic acid hydrochloride (1.2, 2.29 g, 14.6 mmol, 1.5 equiv.) in MeOH (45.0 mL) and H 2 NaHCO in O (17.5 mL) solution 3 (2.04 g, 24.2 mmol, 943 μL, 2.5 equiv) and NaOH (2 mg, 48.5 μmol, 0.005 equiv) were added in one portion at 25° C. The mixture was stirred at 40° C. for 12 h. The mixture was then concentrated in vacuo to remove most of the MeOH. The residue was extracted with ethyl acetate (2×20 mL), the aqueous phase was adjusted to pH 3 with 2M HCl (aq), then extracted with ethyl acetate (3×30 mL), and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 1.5 g of I-1 (74%, %ee value 100.0%) as a white solid. (ES, m / z): [M+1] + 208.0.

[0181] Synthesis of 10.1. To a solution of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (900.00 mg, 4.34 mmol, 1 equiv.), N-methoxymethanamine (465.95 mg, 4.78 mmol, 1.1 equiv., HCl salt) and DECP (820.17 mg, 4.78 mmol, 759.42 μL, 95% pure, 1.1 equiv.) in DMF (10 mL) was added DIPEA (1.12 g, 8.69 mmol, 1.51 mL, 2 equiv.) and N-methoxymethanamine (465.95 mg, 4.78 mmol, 1.1 equiv., HCl salt) to obtain a 10 mL solution of N-methoxymethanamine (465.95 mg, 4.78 mmol, 1.1 equiv., HCl salt). 2 The mixture was stirred at 0° C. for 30 min, and then the reaction mixture was stirred at 25° C. for 11.5 h. After the reaction was completed, 3% aqueous citric acid solution (40 mL) was added dropwise at room temperature to precipitate a white solid, and then the slurry was filtered. The filter cake was saved, and the filtrate was extracted twice with a mixture of toluene and ethyl acetate (1:1, v / v, 50 mL). The organic phase was washed with NaHCO 3The residue and the filter cake were purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 1:1) to give 900 mg of 10.1 (82%, ee value 100.0%) as a pale yellow solid. (ES, m / z): [M+1] + 251.1.

[0182] Synthesis of 10.2. To a solution of (R)-N-methoxy-N-methyl-2-phenyl-4,5-dihydrothiazole-4-carboxamide (10.1, 700 mg, 2.80 mmol, 1 equiv.) in THF (20 mL), LAH (159.19 mg, 4.19 mmol, 1.5 equiv.) was added to the N 2 The mixture was added at −40° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl (aq) (20 mL), then KHSO 4 (10 mL) of 1M solution of 10.2 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with dichloromethane (2×20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 534 mg of 10.2 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 192.0.

[0183] Synthesis of F-1. (R)-2-phenyl-4,5-dihydrothiazole-4-carbaldehyde (10.2, 534 mg, 2.79 mmol, 1 equiv.) in EtOH (60 mL) and H 2To a mixture solution of 2O (20 mL), (2S)-2-(methylamino)-3-sulfanylpropanoic acid (575.12 mg, 3.35 mmol, 1.2 equiv., HCl salt) and KOAc (1.92 g, 19.55 mmol, 7 equiv.) were added under Ar at 20° C. The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; neutral conditions; column: Welch Xtimate C18 250*70 mm#10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 15%-45%, 20 min) to give 300 mg of F-1 mixture (34%, 4 desired isomers and 2 aromatized isomers) as a pale yellow solid. (ES, m / z): [M+1] + 309.1.

[0184] Separation of F-2 to F-5. 500 mg of F-1 was purified twice by SFC separation to obtain 22.09 mg of F-4 (4%, de value 99%, peak 1), 57.16 mg of F-5 (11%, de value 100%, peak 2), 48.3 mg of F-3 (9%, de value 95%, peak 3) and 10.98 mg of F-2 (2%, de value 100%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 339.0.

[0185] SFC separation method: Method 1: Equipment: Waters SFC 80 Q preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); Gradient: B40%-40% in 10 min

[0186] Method 2: Apparatus: Waters SFC 80 Q fractionation SFC; cartridge: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: A is CO 2 ,BはMeOH(0.1%NH 3 H 2 O);グラジエント:16 pointsでB%35%-35%

[0187] F-4: 1 H NMR(400MHz,アセトン-d6)δ=7.85-7.79(m,2H),7.55-7.43(m,3H),4.92(d,J=8.0Hz,1H),4.57(d,J=7.7Hz,1H),4. 30(t,J=6.3Hz,1H),3.66(dd,J=8.7,11.2Hz,1H),3.46(dd,J=8.6,11.1Hz,1H),3.25-3.18(m,3H),2.48(s,3H)

[0188] F-5: 1 H NMR(400MHz,アセトン-d6)δ=7.81(d,J=7.1Hz,2H),7.58-7.38(m,3H),5.01(dt,J=5.8,8.8Hz,1H),4.56(br d,J=5.5Hz,1H),3.70(t,J=7.5Hz,1H),3.48(br d,J=8.9Hz,2H),3.26-3.17(m,2H),2.63(s,3H)

[0189] F-3: 1 H NMR(400MHz,アセトン-d6)δ=7.95-7.69(m,2H),7.65-7.33(m,3H),5.01(dt,J=5.4,9.2Hz,1H),4.49(d,J=5.2Hz,1H),3.89(br t,J=6.4Hz,1H),3.62(dd,J=8.7,11.1Hz,1H),3.42-3.16(m,3H),2.68(s,3H)

[0190] F-2: 1H NMR (400MHz, acetone-d6)δ=7.83-7.77(m,2H),7.54-7.41(m,3H),5.22-5.07(m,1H),4 .25(dd,J=1.6,6.5Hz,1H),3.50-3.37(m,2H),3.19(dd,J=6.6,10.4Hz,1H),3.01(br d,J=10.6Hz,2H),2.72(s,3H)

[0191] Example 12: (2R,4S)-2-((S)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0192] Synthesis of 95.2. To a mixture of p-cresol (95.1, 3 g, 27.74 mmol, 2.91 mL, 1 equiv) in dry THF (70 mL) in a 100 mL sealed tube was added anhydrous magnesium chloride (5.28 g, 55.48 mmol, 2.28 mL, 2 equiv), TEA (8.42 g, 83.23 mmol, 11.58 mL, 3 equiv), and paraformaldehyde (2.5 g, 83.23 mmol, 3 equiv). The mixture was stirred at 80° C. for 16 h. The reaction was used in the next step without further purification. NH 3 .H 2 O (254.83 g, 1.82 mol, 280.03 mL, 25% purity, 65.47 equiv.) and I 2 (8.46 g, 33.32 mmol, 6.71 mL, 1.2 equiv) was added to the above mixture at 0° C., and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with saturated Na 2 SO 3 The resulting mixture was extracted with ethyl acetate (3×40 mL), and the organic layers were then combined and washed with Na 2 SO 4The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether, gradient @ 36 mL / min) to give 1.6 g of 95.2 (43%) as a yellow solid.

[0193] Synthesis of 95.3. To a solution of 2-hydroxy-5-methylbenzonitrile (95.2, 0.7 g, 5.26 mmol, 1 equiv.) in MeOH (10 mL) was added L-cysteine ​​(1.66 g, 10.51 mmol, 2 equiv., HCl salt) and phosphate buffer (10 mL) at 25 °C. Solid K 2 CO 3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (3×20 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.05 g of 95.3 (73%, ee value: 95.3%) as a yellow solid. (ES, m / z): [M+1] + 238.1.

[0194] Synthesis of 95.4. To a solution of (R)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazole-4-carboxylic acid (95.3, 1.05 g, 4.43 mmol, 1 equiv.), N,O-dimethylhydroxylamine (2A, 474.82 mg, 4.87 mmol, 1.1 equiv., HCl) and DECP (793.99 mg, 4.87 mmol, 735.18 uL, 1.1 equiv.) in DMF (11 mL) was added DIPEA (857.90 mg, 6.64 mmol, 1.16 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The residue was poured into water (10 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phase was diluted with NaHCO 3 Wash with aqueous solution, then with brine, and anhydrous Na2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to give 1.14 g of 95.4 (58%, ee value: 97.1%) as a yellow solid. (ES, m / z): [M+1] + 281.1.

[0195] Synthesis of 95.5. A solution of (R)-2-(2-hydroxy-5-methylphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (95.4, 1.2 g, 4.28 mmol, 1 equiv.) in THF (14.5 mL) was added to N 2 LAH (243.69 mg, 6.42 mmol, 1.5 equiv) was added at −30° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (20 mL) and KHSO 4 (100 mL) of 1M solution of 95.5 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (3×50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 947 mg of 95.5 (crude) as a yellow oil. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 240.2.

[0196] Synthesis of 95.6. (R)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazole-4-carbaldehyde (95.5, 947 mg, 4.28 mmol, 1 equiv.) in EtOH (30 mL) and H 2To the mixture solution of 2H2O (10 mL), (2S)-2-(methylamino)-3-sulfanylpropanoic acid (A-3S, 881.52 mg, 5.14 mmol, 1.2 equiv., HCl) and KOAc (2.94 g, 29.96 mmol, 7 equiv.) were added at 25° C. The suspension was gently stirred in the dark at 25° C. for 2.5 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 5% to 40%, 20 min) to give 320 mg of 95.6 (22%) as a yellow solid. (ES, m / z): [M+1] + 339.2.

[0197] Synthesis of I-95, I-96, I-95a, and I-96a. 320 mg of 95.6 (mixture of four peaks) was purified by SFC separation to give 57.12 mg of I-95 (18%, de value: 84.9%, peak 1), 55.04 mg of I-95a (17%, ee value: 91.6%, peak 2), 18.52 mg of I-96a (6.0%, de value: 92.2%, peak 3), and 78.97 mg of I-96 (24%, de value: 90.6%, peak 4) as pale yellow solids. (ES, m / z): [M+1]+339.1.

[0198] Method 1: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); Gradient: B%=50% Isocratic elution mode; Flow rate: 80 g / min; Wavelength: 220 nm; Column temperature: 40° C.; System back pressure: 100 bar

[0199] I-95: 1H NMR(400MHz,アセトン-d6)δ=7.26-7.20(m,2H),6.85(d,J=8.9Hz,1H),5.00(q,J=8.3Hz,1H),4.54(d,J=8.3Hz,1H),4.25(t,J=6.4Hz,1H),3.66(dd,J=8.6,11.3Hz,1H),3.45(dd,J=7.9,11.3Hz,1H),3.23(d,J=6.6Hz,2H),2.50(s,3H),2.28(s,3H).

[0200] I-96: 1 H NMR(400MHz,アセトン-d6)δ=7.28-7.18(m,2H),6.85(d,J=8.9Hz,1H),5.24-5.16(m,1H),4.59(br d,J=5.1Hz,1H),3.70-3.60(m,1H),3.48(br d,J=9.0Hz,2H),3.19(br d,J=7.3Hz,2H),2.63(s,3H),2.28(s,3H).

[0201] I-95a: 1 H NMR(400MHz,アセトン-d6)δ=7.29-7.17(m,2H),6.84(d,J=9.0Hz,1H),4.83(br d,J=8.1Hz,1H),4.33(d,J=8.3Hz,1H),4.01(br t,J=5.8Hz,1H),3.68-3.57(m,1H),3.56-3.39(m,2H),3.30(dd,J=6.9,11.0Hz,1H),2.63(s,3H),2.28(s,3H).

[0202] I-96a: 1 H NMR(400MHz,アセトン-d6)δ=7.28-7.14(m,2H),6.92-6.76(m,1H),5.26(dt,J=4.6,9.1Hz,1H),5.05(d,J=4.6Hz,1H),4.25(dd,J=1.7,6.3Hz,1H),3.48-3.33(m,2H),3.21(dd,J=6.5,10.4Hz,1H),3.12-2.96(m,1H),2.70(s,3H),2.27(s,3H).

[0203] Example 13: (4S)-2-((S)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0204] Synthesis of I-97. CH of 50 mg of I-95 and 75 mg of I-96 3 CN / H 2 The 0 (3 / 1, 2.5 mL) solution was shaken for 2 min to give a clear solution. The mixture was then lyophilized for 24 h to give 85.52 mg of I-97 (68%). (ES, m / z): [M+1] + 339.1. 1 H NMR (400MHz, acetone) δ=7.23(br s,2.93H),6.85(dd,J=2.7,8.8Hz,1.52H),5.24-5.14(m,0.86H),5.04-4.96(m,0.61H),4.62(d,J=5.4Hz,0.87H),4.55(d,J=8.4Hz,0.68H), 4.25(t,J=6.5Hz,0.71H),3.75-3.60(m,1.99H),3.55-3.40(m,3.27H) ,3.27-3.18(m,4.05H),2.65(s,3H),2.50(s,2.12H),2.28(s,5.16H).

[0205] Example 14: (2R,4S)-2-((S)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0206] Synthesis of 89.2. To a solution of 2-hydroxy-3-methylbenzonitrile (89.1, 3 g, 22.53 mmol, 1 equiv.) in MeOH (30 mL) was added L-cysteine ​​(7.10 g, 45.06 mmol, 2 equiv., HCl salt) and phosphate buffer (30 mL) at room temperature. Solid K 2 CO 3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (500 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with ethyl acetate (3×500 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.06 g of 89.2 (94%, ee value: 93.4%) as a yellow solid. (ES, m / z): [M+1] + 238.1.

[0207] Synthesis of 89.3. To a solution of (R)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazole-4-carboxylic acid (89.2, 3 g, 12.64 mmol, 1 equiv.), N,O-dimethylhydroxylamine (2A, 1.36 g, 13.91 mmol, 1.1 equiv., HCl) and DECP (2.27 g, 13.91 mmol, 2.10 mL, 1.1 equiv.) in DMF (30 mL) was added DIPEA (2.45 g, 18.97 mmol, 3.30 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was diluted with NaHCO 3 The residue and the filter cake were purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 1:1) to give 2.5 g of 89.3 (67%, ee value: 91.0%) as a pale yellow solid. (ES, m / z): [M+1] + 281.1.

[0208] Synthesis of 89.4. To a solution of (R)-2-(2-hydroxy-3-methylphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (89.3, 2.2 g, 7.85 mmol, 1 equiv.) in THF (22 mL) was added LAH (446.72 mg, 11.77 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. The temperature was raised to −30° C. and stirred for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (25 mL) and KHSO 4 (25 mL) of 1M solution of 89.4 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (2×200 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.74 g of 89.4 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 222.1.

[0209] Synthesis of 89.5. Dissolve 2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazole-4-carbaldehyde (89.4, 1.74 g, 7.86 mmol, 1 equiv.) in EtOH (51 mL) and H 2 To the mixture solution of 2,4-dimethylaminopropanoic acid (A-3S, 1.62 g, 9.44 mmol, 1.2 equiv., HCl) and KOAc (5.40 g, 55.04 mmol, 7 equiv.) were added under Ar at 25° C. The suspension was gently stirred in the dark at 25° C. for 16 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15% to 40%, 20 min) to give 89.5% (37%) of 1g as a pale yellow solid. (ES, m / z): [M+1]+ 339.2.

[0210] Synthesis of I-89, I-90, I-89a, and I-90a. 500 mg of 89.5 (mixture of four peaks) was purified by two SFC separations (method 1 followed by method 2) and one preparative HPLC purification to give 2 mg of I-89a (0.4%, de value: 41.8%, peak 1), 10 mg of I-90a (2.0%, de value: 94.1%, peak 2), 38 mg of I-90 (7.6%, de value: 94.4%, peak 3), and 14 mg of I-89 (2.8%, de value: 97.4%, peak 4) as pale yellow solids.

[0211] SFC separation method: Method 1 (first SFC separation): Instrument: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK ID (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); gradient: B%=56% isocratic elution mode; flow rate: 72 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0212] Method 2 (second SFC separation): Instrument: Waters SFC80Q preparative SFC; Column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10um); Mobile phase: A is CO 2 , B is MeOH (0.1% IPAm); gradient: B%=35% isocratic elution mode; flow rate: 62 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0213] Preparative HPLC purification: Column: Phenomenex C18 80*40mm*3um; Mobile phase: [Water (NH 4 HCO 3 )-ACN]; B%: 10%~40%, 8 min.

[0214] I-90: 1H NMR(400MHz,アセトン-d6)δ=7.28(d,J=7.5Hz,2H),6.83(t,J=7.6Hz,1H),5.22(dt,J=5.6,8.9Hz,1H),4.63(d,J=5.5Hz,1H),3.69(t,J=7.5Hz,1H),3.49(d,J=8.8Hz,2H),3.23-3.18(m,2H),2.65(s,3H),2.22(s,3H).

[0215] I-89: 1 H NMR(400MHz,アセトン-d6)δ=7.30-7.26(m,2H),6.82(t,J=7.6Hz,1H),5.01(q,J=8.5Hz,1H),4.55(d,J=8.6Hz,1H),4.23(t,J=6.5Hz,1H),3.66(dd,J=8.7,11.3Hz,1H),3.51-3.43(m,1H),3.28-3.19(m,2H),2.50(s,3H),2.23(s,3H).

[0216] I-89a: 1 H NMR(400MHz,アセトン-d6)δ=7.28(d,J=7.6Hz,2H),6.82(t,J=7.4Hz,1H),5.29(dt,J=4.8,9.3Hz,1H),5.07(d,J=4.6Hz,1H),4.27(dd,J=2.3,6.6Hz,1H),3.50-3.40(m,2H),3.27-3.20(m,1H),3.10-3.05(m,1H),2.72(s,3H),2.22(s,3H).

[0217] I-90a: 1 H NMR(400MHz,アセトン-d6)δ=7.28(d,J=7.6Hz,2H),6.82(t,J=7.6Hz,1H),4.84(q,J=8.3Hz,1H),4.35(d,J=8.5Hz,1H),4.02(t,J=5.9Hz,1H),3.68-3.61(m,1H),3.57-3.43(m,2H),3.31(dd,J=6.9,10.9Hz,1H),2.64(s,3H),2.22(s,3H).

[0218] Example 15: (4S)-2-((S)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0219] Synthesis of I-91. (2R,4S)-2-((S)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-89, 13.25 mg) and (2S,4S)-2-((S)-2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-90, 19.87 mg) were dissolved in ACN / H 2 The 0 (3 / 1, 2 mL) solution was shaken for 2 min to give a clear solution. The clear solution was then lyophilized for 48 h to give 27.10 mg of I-91 (82%) as a pale yellow solid. (ES, m / z): [M+1] + 339.1.

[0220] 1 H NMR (400MHz, acetone-d6) δ=7.28(d,J=7.7Hz,3.12H),6.83(t,J=7.6Hz,1.60H),5.21(d t,J=5.5,8.9Hz,0.95H),5.02(q,J=8.3Hz,0.64H),4.64(d,J=5.5Hz,0.93H),4.56(d, J=8.4Hz,0.64H),4.26(t,J=6.5Hz,0.66H),3.78-3.60(m,2.01H),3.52-3.41(m,3.40 H),3.29-3.17(m,4.07H),2.66(s,3.00H),2.51(s,2.00H),2.23(d,J=2.3Hz,4.93H).

[0221] Example 16: (2R,4S)-2-((S)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0222] Synthesis of 112.2. To a mixture of 5-fluoro-2-hydroxybenzonitrile (112.1, 4.5 g, 32.82 mmol, 1 equiv.) in MeOH (45 mL) was added L-cysteine ​​(10.35 g, 65.64 mmol, 2 equiv., HCl salt) and phosphate buffer (45 mL) at room temperature. Solid K 2 CO 3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (40 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with ethyl acetate (3×60 mL), the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which gave 7.47 g of 112.2 (94%, ee value: 89.0%) as a yellow solid. (ES, m / z): [M+1] + 242.0.

[0223] Synthesis of 112.3. To a solution of (R)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (112.2, 3 g, 11.81 mmol, 95% purity, 1 equiv.), N-methoxymethanamine (1.27 g, 13.00 mmol, 1.1 equiv., HCl) and DECP (2.12 g, 13.00 mmol, 1.96 mL, 1.1 equiv.) in DMF (30 mL) was added DIEA (2.29 g, 17.72 mmol, 3.09 mL, 1.5 equiv.) and N-methoxymethanamine (1.27 g, 13.00 mmol, 1.1 equiv., HCl) and DECP (2.12 g, 13.00 mmol, 1.96 mL, 1.1 equiv.) in DMF (30 mL). 2The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The reaction mixture was diluted with water (45 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with NaHCO 3 (30mL×3), and washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which gave 1.74 g of 112.3 (49%, ee value: 79.0%) as a pale yellow solid. (ES, m / z): [M+1] + 285.1.

[0224] Synthesis of 112.4. To a solution of (R)-2-(5-fluoro-2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (112.3, 2 g, 7.03 mmol, 1 equiv.) in THF (20 mL) was added LAH (400.45 mg, 10.55 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (42 mL) and KHSO 4 (42 mL) of a 1M solution of 1,2-dichlorophenyl ether (1M) was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (3×30 mL), the organic layer was collected and washed with Na 2 SO 4 After drying at 40° C., filtration and evaporation under reduced pressure gave 1.58 g of 112.4 (crude) as a yellow oil. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 226.1.

[0225] Synthesis of I-112.5. Dissolve (R)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (112.4, 1.58 g, 7.01 mmol, 1 equiv.) in EtOH (45 mL) and H 2To a mixture solution of 2H2O (15 mL) was added (2S)-2-(methylamino)-3-sulfanylpropanoic acid (A-3S, 1.14 g, 8.42 mmol, 1.2 equiv., HCl) and KOAc (4.82 g, 49.10 mmol, 7 equiv.). The suspension was gently stirred in the dark at 25° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and the solution was then extracted with ethyl acetate (3×80 mL). The organic layer was collected and diluted with Na 2 SO 4 The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10%-40%, 20 min) to give 690 mg of I-112.5 (29%) as a pale yellow solid. I-110 and I-111 were not recovered by preparative HPLC purification. (ES, m / z): [M+1] + 343.1.

[0226] Synthesis of I-110 and I-111. 600 mg of I-112.5 (mixture of two peaks) was purified by two SFC separations (same separation method) to give 160 mg of I-110 (27%, de value: 98.4%, peak 1) and 224 mg of I-111 (37%, de value: 99.4%, peak 2) as pale yellow solids. (ES, m / z): [M+1]+343.1.

[0227] Method 1: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is EtOH (0.1% NH 3 H 2 O); gradient: B%=50% isocratic elution mode; flow rate: 80 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0228] I-110: 1H NMR (400MHz, acetone-d6)δ=7.29-7.12(m,2H),6.98(dd,J=4.6,9.0Hz,1H),5.05(q,J=8.2Hz,1H),4.56(d,J=8.2Hz,1H ),4.25(t,J=6.4Hz,1H),3.71(dd,J=8.7,11.2Hz,1H),3.51(dd,J=8.0,11.3Hz,1H),3.28-3.19(m,2H),2.51(s,3H).

[0229] I-111: 1 H NMR (400MHz, acetone-d6)δ=7.26-7.12(m,2H),6.97(dd,J=4.6,9.0Hz,1H),5.26(dt,J=5.2, 9.0Hz,1H),4.61(d,J=5.1Hz,1H),3.67-3.50(m,3H),3.19(d,J=7.6Hz,2H),2.63(s,3H).

[0230] Example 17: (4S)-2-((S)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0231] Synthesis of I-112. 148.88 mg of I-110 and 223.32 mg of I-111 in ACN / H 2 The 0 (3 / 1, 4 mL) solution was shaken for 2 min to give a clear solution. The solution was then lyophilized for 24 h to give 337.12 mg of I-112 (91%). (ES, m / z): [M+1] = 343.1.

[0232] 1H NMR (400MHz, acetone-d6) δ =7.26-7.13(m,3.10H),6.98(ddd,J=3.1,4.6,9.0Hz,1.55H),5.24(dt,J=5 .5,8.9Hz,0.99H),5.05(q,J=8.3Hz,0.57H),4.64(d,J=5.4Hz,0.98H),4.5 7(d,J=8.3Hz,0.55H),4.26(t,J=6.5Hz,0.56H),3.77-3.66(m,1.68H),3.5 8-3.48(m,2.68H),3.28-3.18(m,3.26H),2.65(s,3.00H),2.51(s,1.67H).

[0233] Example 18: (2R,4S)-2-((S)-2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0234] Synthesis of 101.2. To a solution of 2-fluoro-6-hydroxybenzonitrile (101.1, 3.3 g, 24.07 mmol, 1 equiv.) in MeOH (33 mL) was added L-cysteine ​​(37.94 g, 240.68 mmol, 10 equiv., HCl salt) and phosphate buffer (33 mL) at room temperature. Solid K 2 CO 3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (500 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with ethyl acetate (3×500 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4.10 g of 101.2 (70%, ee value: 80.0%) as a yellow solid. (ES, m / z): [M+1] + 242.3.

[0235] Synthesis of 101.3. To a solution of (R)-2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (101.2, 4.10 g, 17.00 mmol, 1 equiv.), N,O-dimethylhydroxylamine (2A, 1.82 g, 18.70 mmol, 1.1 equiv., HCl) and DECP (3.05 g, 18.70 mmol, 2.82 mL, 1.1 equiv.) in DMF (30 mL) was added DIPEA (3.29 g, 25.49 mmol, 4.44 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was diluted with NaHCO 3 The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether:ethyl acetate 1:0 to 1:1) to give 4.58 g of 101.3 (94%, ee value: 56.0%) as a pale yellow solid. (ES, m / z): [M+1] + 285.3.

[0236] Synthesis of 101.4. To a solution of (R)-2-(2-fluoro-6-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (101.3, 4 g, 14.07 mmol, 1 equiv.) in THF (40 mL), LAH (800.90 mg, 21.10 mmol, 1.5 equiv.) was added to the N 2 The mixture was added at −40° C. The temperature was raised to −30° C. and stirred for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (50 mL) and KHSO 4 (50 mL) of 1M solution of 101.4 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (2×200 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.5 g of 101.4 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] +226.2.

[0237] Synthesis of 101.5. Dissolve 2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (101.4, 2.5 g, 11.10 mmol, 1 equiv.) in EtOH (75 mL) and H 2 To the mixture solution of 2H2O (25 mL), (S)-3-mercapto-2-(methylamino)propanoic acid (A-3S, 1.80 g, 13.32 mmol, 1.2 equiv, HCl) and KOAc (7.63 g, 77.70 mmol, 7 equiv) were added at 25° C. The suspension was gently stirred in the dark at 25° C. for 16 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm / 10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15% to 50%, 20 min) to give 695 mg of 101.5 (18%) as a pale yellow solid. (ES, m / z): [M+1] + 343.3.

[0238] Synthesis of I-101, I-102, I-101a, I-102a. 500 mg of 101.5 (mixture of four peaks) was purified by three SFC separations (method 1 followed by methods 2 and 3) to give 80 mg of I-101a (16%, de value: 85.0%, peak 1), 47 mg of I-102a (9.4%, de value: 98.0%, peak 2), 79 mg of I-102 (16%, de value: 95.6%, peak 3) and 50 mg of I-101 (10%, de value: 99.3%, peak 4) as pale yellow solids.

[0239] Method 1: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2O); gradient: B%=60% isocratic elution mode; flow rate: 80 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0240] Method 2: Apparatus: Waters SFC80Q preparative SFC; Column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); gradient: B%=42% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0241] Method 3: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is IPA (0.1% NH 3 H 2 O); gradient: B%=44% isocratic elution mode; flow rate: 72 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0242] I-101a: 1 H NMR (400MHz, acetone-d6)δ=7.44-7.35(m,1H),6.79(br d,J=8.4Hz,1H),6.73-6.64(m,1H),4.74(q,J=8.4Hz,1H),4.33(br d,J=8.1Hz,1H),4.03(br t,J=5.5Hz,1H),3.64-3.53(m,1H),3.52-3.41(m,2H),3.32(br dd,J=7.0,10.6Hz,1H),2.64(s,3H).

[0243] I-102a: 1H NMR(400MHz,アセトン-d6)δ=7.40(q,J=7.4Hz,1H),6.79(br d,J=8.1Hz,1H),6.70(br t,J=9.8Hz,1H),5.23-5.13(m,1H),5.05(br d,J=3.5Hz,1H),4.25(br d,J=5.5Hz,1H),3.39(quin,J=9.9Hz,2H),3.27-3.18(m,1H),3.07(br d,J=10.4Hz,1H),2.70(s,3H).

[0244] I-102: 1 H NMR(400MHz,アセトン-d6)δ=7.45-7.35(m,1H),6.79(br d,J=8.3Hz,1H),6.70(br dd,J=8.7,11.1Hz,1H),5.15-5.05(m,1H),4.61(d,J=5.5Hz,1H),3.77-3.67(m,1H),3.44(br d,J=9.2Hz,2H),3.22(br d,J=7.3Hz,2H),2.64(s,3H).

[0245] I-101: 1 H NMR(400MHz,アセトン-d6)δ=7.45-7.36(m,1H),6.80(br d,J=8.3Hz,1H),6.69(br dd,J=8.6,11.1Hz,1H),4.98-4.88(m,1H),4.54(br d,J=8.2Hz,1H),4.23(br t,J=5.9Hz,1H),3.62(br t,J=10.1Hz,1H),3.40(br s,1H),3.22(br d,J=5.1Hz,2H),2.51(s,3H).

[0246] Example 19: (4S)-2-((S)-2-(2-フルオロ-6-ヒドロキシフェニル) -4,5-ジヒドロチアゾール-4-イル)-3-メチルチアゾリジン-4-カルボン acid.

change

[0247] Synthesis of I-103. CH of (2R,4S)-2-((S)-2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-101, 49.03 mg) and (2S,4S)-2-((S)-2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-102, 73.55 mg) 3 CN / H 2 The 0 (3 / 1, 5 mL) solution was shaken for 2 min to give a clear solution. The mixture was then lyophilized for 48 h to give 101.05 mg of I-103 (82%) as a pale yellow solid. (ES, m / z): [M+1] + 343.1.

[0248] 1 H NMR (400MHz, acetone-d6)δ=7.44-7.36(m,1.64H),6.80(td,J=1.2,8.4Hz,1.62H),6.70(dd,J=8.3 ,11.7Hz,1.65H),5.16-5.05(m,0.98H),4.93(q,J=8.6Hz,0.66H),4.61(d,J=5.5Hz,0.96H),4. 54(d,J=8.2Hz,0.66H),4.25(t,J=6.5Hz,0.68H),3.73(t,J=7.3Hz,0.99H),3.62(dd,J=9.4,11 .1Hz,0.72H),3.48-3.36(m,2.81H),3.23(d,J=7.5Hz,3.33H),2.65(s,3.00H),2.52(s,1.90H).

[0249] Example 20: (2R,4S)-2-((S)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0250] Synthesis of 104.2. To a solution of 3-fluoro-2-hydroxybenzonitrile (104.1, (4.7 g, 34.13 mmol, 1 equiv.) in MeOH (47 mL) was added L-cysteine ​​(10.76 g, 68.27 mmol, 2 equiv., HCl salt) and phosphate buffer (47 mL). Solid K 2 CO 3 (5.19 g, 37.55 mmol, 1.1 equiv) was carefully added to adjust the solution to pH=6.4 and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (50 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (3×50 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.18 g of 104.2 (75%, ee value: 100.0%) as a yellow solid. (ES, m / z): [M+1] + 242.0.

[0251] Synthesis of 104.3. To a solution of (R)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (104.2, 5 g, 20.73 mmol, 1 equiv.), N,O-dimethylhydroxylamine hydrochloride (2A, 2.22 g, 22.80 mmol, 1.1 equiv., HCl) and diethoxyphosphorylformonitrile (3.91 g, 22.80 mmol, 3.62 mL, 95% purity, 1.1 equiv.) in DMF (50 mL) was added DIEA (4.02 g, 31.09 mmol, 5.42 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 20° C. for an additional 2 h. The reaction mixture was stirred at H 2 The mixture was diluted with 200 mL of O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with NaHCO 3 Wash with aqueous solution and brine (50 mL) and add Na 2 SO 4 The residue was purified by silica gel column chromatography (SiO 2, petroleum ether:ethyl acetate 1:0 to 1:1) to give 4.68 g of 104.3 (79%, ee value: 91.0%) as a pale yellow solid. (ES, m / z): [M+1] + 285.3.

[0252] Synthesis of 104.4. To a solution of (R)-2-(3-fluoro-2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (104.3, 3 g, 10.55 mmol, 1 equiv.) in THF (50 mL) was added LAH (600.67 mg, 15.83 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. The temperature was raised to −30° C. and stirred for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (30 mL) and KHSO 4 (30 mL) of 1M solution of 104.4. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (2×50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.25 g of 104.4 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 226.3

[0253] Synthesis of 104.5. To a solution of 2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (104.4, 2.25 g, 9.99 mmol, 1 equiv.) in a mixture of EtOH (66 mL) and HO (22 mL), (S)-3-mercapto-2-(methylamino)propanoic acid (A-3S, 2.06 g, 11.99 mmol, 1.2 equiv., HCl) and KOAc (6.86 g, 69.93 mmol, 7 equiv.) were added sequentially at 20° C. The suspension was gently stirred in the dark at 20° C. for 16 h. The ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by the addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified using a preparative HPLC column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15% to 45%, 20 min) to give 485 mg of 104.5 (14%) as a pale yellow solid. (ES, m / z): [M+1] + 343.1.

[0254] Synthesis of I-104, I-105, I-104a, I-105a. 523 mg of 104.5 (mixture of 4 peaks) was purified by two SFC separations (method 1 followed by method 2) to give 55.4 mg of I-104a (11%, de value: 96.0%, peak 1), 73.7 mg of I-105 (14%, de value: 96.0%, peak 2), 27.1 mg of I-105a (5%, de value: 86.0%, peak 3) and 105.11 mg of I-104 (20%, de value: 97.0%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 343.1

[0255] Method 1: Apparatus: Waters SFC 80 Preparative SFC; Column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.2%NH 3 H 2O); gradient: B%=45% isocratic elution mode; flow rate: 60 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0256] Method 2: Equipment: Waters SFC 80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is IPA (0.1% NH 3 H 2 O); gradient: B%=35% isocratic elution mode; flow rate: 65 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0257] I-104a: 1 H NMR (400MHz, acetone-d6)δ=7.34-7.18(m,2H),6.90(dt,J=4.8,8.1Hz,1H),4.87(q,J=8.4Hz,1H),4.36(d,J=8.4Hz,1H),4.02(dd, J=5.4,6.9Hz,1H),3.73-3.61(m,1H),3.58-3.51(m,1H),3.44(dd,J=5.4,11.1Hz,1H),3.31(dd,J=6.9,11.1Hz,1H),2.63(s,3H)

[0258] I-105: 1 H NMR (400MHz, acetone-d6)δ=7.36-7.23(m,2H),6.97-6.86(m,1H),5.24(d,J=5.5Hz,1H),4.64( d,J=5.5Hz,1H),3.74(t,J=7.4Hz,1H),3.54(d,J=8.9Hz,2H),3.27-3.19(m,2H),2.65(s,3H)

[0259] I-105a: 1H NMR (400MHz, acetone-d6)δ=7.36-7.23(m,2H),6.92(br d,J=4.6Hz,1H),5.33(br d,J=4.6Hz,1H),5.07(d,J=4.8Hz,1H),4.27(dd,J=2.3,6.5Hz,1H),3.48(dd,J=7.6 ,9.1Hz,2H),3.24(dd,J=6.6,10.4Hz,1H),3.07(dd,J=2.2,10.4Hz,1H),2.72(s,3H)

[0260] I-104: 1 H NMR (400MHz, acetone-d6)δ=7.34-7.23(m,2H),6.97-6.88(m,1H),5.06(q,J=8.3Hz,1H),4.57(d,J=8.1Hz,1H),4.26(t,J=6. 4Hz,1H),3.71(dd,J=8.8,11.3Hz,1H),3.51(dt,J=8.5,11.3Hz,1H),3.24(d,J=6.4Hz,2H),2.66-2.65(m,1H),2.52(s,3H)

[0261] Example 21: (4S)-2-((S)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0262] Synthesis of I-106. CH of (2R,4S)-2-((S)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-104, 48.57 mg) and (2S,4S)-2-((S)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-105, 72.85 mg) 3 CN / H 2The 0 (3 / 1, 4 mL) solution was shaken for 2 min to give a clear solution. The mixture was then lyophilized for 24 h to give 94.65 mg of I-106 (78%) as a pale yellow solid. (ES, m / z): [M+1] + 343.1.

[0263] I-106: 1 H NMR (400MHz, acetone-d6)δ=7.37-7.21(m,3H),6.92(dt,J=4.6,8.0Hz,1.59H),5.24(dt,J=5.5,8. 9Hz,0.95H),5.06(d,J=8.5Hz,0.54H),4.64(d,J=5.6Hz,0.95H),4.57(d,J=8.1Hz,0.54H),4.27 (t,J=6.4Hz,0.58H),3.78-3.73(m,0.92H),3.72-3.68(m,0.61H),3.54(d,J=8.9Hz,1.98H),3.5 2-3.45(m,0.79H),3.26-3.23(m,1.56H),3.23-3.21(m,1.43H),2.65(s,3.09H),2.52(s,1.81H)

[0264] Example 22: (4S)-2-((R)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0265] Synthesis of I-118. CH of (2R,4S)-2-((R)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-104a, 51.88 mg) and (2S,4S)-2-((R)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (105a, 27.89 mg) 3 CN / H 2The 0 (3 / 1, 3 mL) solution was shaken for 2 min to give a clear solution. The mixture was then lyophilized for 48 h to give 40.88 mg of I-118 (51%) as a pale yellow solid. (ES, m / z): [M+1] + 343.1.

[0266] I-118: 1 H NMR (400MHz, acetone-d6)δ=7.51-7.23(m,2.69H),6.94-6.87(m,1.28H),5.33(dt,J=4.8,9.1Hz,0 .44H),5.06(d,J=4.6Hz,0.39H),4.87(q,J=8.3Hz,0.90H),4.37(d,J=8.3Hz,0.84H),4.27(dd,J =2.4,6.5Hz,0.41H),4.02(dd,J=5.4,6.9Hz,0.89H),3.70-3.64(m,1H),3.60-3.52(m,1.19H),3 .51-3.42(m,1.90H),3.32(dd,J=6.9,11.1Hz,1.06H),3.23(dd,J=6.5,10.5Hz,0.71H),3.07(br dd,J=2.3,10.5Hz,0.92H),2.71(s,1.76H),2.64(s,3.00H)

[0267] Example 23: (2R,4S)-2-((S)-2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0268] Synthesis of 107.2. To a mixture of 4-fluoro-2-hydroxybenzonitrile (107.1, 5 g, 36.47 mmol, 1 equiv.) in phosphate buffer (50 mL) and MeOH (50 mL) was added L-cysteine ​​(11.50 g, 72.93 mmol, 2 equiv., HCl salt) at 25 °C. Solid K 2 CO3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (3×20 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7.4 g of 107.2 (84%, ee value: 100.0%) as a yellow solid. (ES, m / z): [M+1] + 242.1.

[0269] Synthesis of 107.3. To a solution of (R)-2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (107.2, 5.5 g, 22.80 mmol, 1 equiv.), N,O-dimethylhydroxylamine (2A, 5.5 g, 22.80 mmol, 1 equiv., HCl) and DECP (4.09 g, 25.08 mmol, 3.79 mL, 1.1 equiv.) in DMF (60 mL) was added DIPEA (4.42 g, 34.20 mmol, 5.96 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The mixture was poured into water (60 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic phase was diluted with NaHCO 3 Wash with aqueous solution, then with brine, and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 4 g of 107.3 (63%, ee value: 79.8%) as a white solid. (ES, m / z): [M+1] + 285.1.

[0270] Synthesis of 107.4. A solution of (R)-2-(4-fluoro-2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (107.3, 2 g, 7.03 mmol, 1 equiv.) in THF (20 mL) was 2LAH (2 g, 7.03 mmol, 1 equiv.) was added at −30° C. under reduced pressure. The mixture was stirred at −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (40 mL) and KHSO 4 (40 mL) of 1M solution of 107.4 was added successively to hydrolyze. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (2×200 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 1.63 g of 107.4 (crude) as a yellow solid. The crude product was used in the next step without further purification.

[0271] Synthesis of 107.5. Dissolve 2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (107.4, 1.58 g, 7.01 mmol, 1 equiv.) in EtOH (45 mL) and H 2 To the mixture solution of A-3S, 1.14 g, 8.42 mmol, 1.2 eq, HCl) and KOAc (4.82 g, 49.10 mmol, 7 eq) were added at 25° C. The suspension was gently stirred in the dark at 25° C. for 16 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid and then the solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 5% to 30%, 8 min) to give 730 mg of 107.5 (30%) as a yellow solid. (ES, m / z): [M+1] + 343.1.

[0272] Synthesis of I-107, I-108, I-107a, I-108a. 0.5 mg of 107.5 (mixture of 4 peaks) was purified by two SFC separations (method 1 followed by method 2) to give 10.06 mg of I-107 (2.0%, de value: 100.0%, peak 1), 57.79 mg of I-107a (not pure, mixture of I-107 and I-107a), 12.07 mg of I-108a (not pure, mixture of I-108 and I-108a), and 163.15 mg of I-108 (32%, de value: 93.2%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 343.1.

[0273] SFC separation method: Method 1: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: A is CO 2 B is MeOH (0.1%NH 3 H 2 O); gradient: B%=38% isocratic elution mode; flow rate: 65 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0274] Method 2: Apparatus: Waters SFC80Q preparative SFC; Column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10um); Mobile phase: A is CO 2 B is EtOH (0.1% NH 3 H 2 O); gradient: B%=38% isocratic elution mode; flow rate: 65 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0275] I-107: 1H NMR (400MHz, acetone-d6)δ=7.56-7.43(m,1H),6.80-6.62(m,2H),5.00(q,J=8.1Hz,1H),4.54(d,J=8.3Hz,1H),4.23(br t,J=6.4Hz,1H),3.68(dd,J=8.9,11.0Hz,1H),3.47(br dd,J=7.9,11.2Hz,1H),3.31-3.10(m,2H),2.50(s,3H).

[0276] I-108: 1 H NMR (400MHz, acetone-d6)δ=7.49(dd,J=6.5,8.6Hz,1H),6.79-6.65(m,2H),5.26-5.12(m,1H),4.62(d ,J=5.5Hz,1H),3.72(dd,J=6.8,7.9Hz,1H),3.51(d,J=8.9Hz,2H),3.29-3.15(m,2H),2.64(s,3H).

[0277] Example 24: (4S)-2-((S)-2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0278] Synthesis of I-109. 10.06 mg of I-107 and 15.15 mg of I-108 in ACN / H 2 The 0 (3 / 1, 1 mL) solution was shaken for 2 min to give a clear solution. The solution was then lyophilized for 48 h to give 18.68 mg of I-109 (74%). (ES, m / z): [M+1] + 343.1.

[0279] I-109: 1H NMR (400MHz, acetone-d6)δ=7.49(dd,J=6.4,8.6Hz,1.47H),6.78-6.67(m,2.99H) ,5.21(dt,J=5.6,8.8Hz,0.86H),5.01(q,J=8.3Hz,0.64H),4.62(d,J=5.5Hz,0. 83H),4.55(d,J=8.3Hz,0.65H),4.26(t,J=6.5Hz,0.66H),3.78-3.63(m,1.66H) ,3.58-3.44(m,2.61H),3.26-3.20(m,3.13H),2.65(s,3.00H),2.51(s,2.07H).

[0280] Example 25: (2R,4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0281] Synthesis of 126.2. To a mixture of 3-hydroxypicolinonitrile (126.1, 4.5 g, 37.47 mmol, 1 equiv.) in MeOH (45 mL) was added L-cysteine ​​(11.81 g, 74.93 mmol, 2 equiv., HCl salt) and phosphate buffer (45 mL). Solid K 2 CO 3 The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (200 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with ethyl acetate (3×200 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7.46 g of 126.2 (85%, ee value: 85.6%) as a yellow solid. (ES, m / z): [M+1] + 225.0.

[0282] Synthesis of 126.3. To a solution of (R)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazole-4-carboxylic acid (126.2, 7.46 g, 33.26 mmol, 1 equiv.), N,O-dimethylhydroxylamine hydrochloride (2A, 3.56 g, 33.6 mmol, 1.1 equiv., HCl) and DECP (5.96 g, 33.6 mmol, 5.52 mL, 1.1 equiv.) in DMF (75 mL) was added DIEA (6.44 g, 49.9 mmol, 99.89 mL, 1.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and then at 20° C. for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was diluted with NaHCO 3 Wash with aqueous solution and brine, and add anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give 6.7 g of 126.3 (73%, ee value: 84.2%) as a yellow solid. (ES, m / z): [M+1]+ 268.1.

[0283] Synthesis of 126.4. To a solution of (R)-2-(3-hydroxypyridin-2-yl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (126.3, 5 g, 18.71 mmol, 1 equiv.) in THF (50 mL) was added LAH (1.06 g, 28.06 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. The temperature was raised to −30° C. and stirred for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (50 mL) and KHSO 4 (50 mL) of a 1 M solution of ethyl acetate. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with ethyl acetate (3×200 mL), the organic phase was collected and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 2.99 g of 126.4 (76.6%, ee value: 84.2%). (ES, m / z): [M-1] - 207.0.

[0284] Synthesis of 126.5. (R)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazole-4-carbaldehyde (126.4, 2.78 g, 13.34 mmol, 1 equiv.) in EtOH (30 mL) and H 2 To the mixture solution of 2,4-dimethylformamide (A-3S, 2.75 g, 16.01 mmol, 1.2 equiv., HCl) and KOAc (9.16 g, 93.38 mmol, 7 equiv.) were added sequentially at 25° C. The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 1% to 30%, 8 min) to give 1.21 g of 126.5 (27%) as a pale yellow solid. (ES, m / z): [M+1] + 326.1.

[0285] Synthesis of I-126, I-127, I-126a, I-127a. 1 g of 126.5 (mixture of 4 peaks) was purified by three SFC separations (method 1 followed by methods 2 and 3) to give 100 mg of I-127 (0.1%, de value: 100.0%, peak 2), 75 mg of I-126 (0.075%, de value: 96%, peak 1), 9 mg of I-127a (mixture of I-127 and 127a), and 12 mg of I-126a (0.012%, de value: 100%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 326.0.

[0286] Method 1: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase: A is CO 2 B is EtOH (0.1% NH 3 H 2O); gradient: B%=50% isocratic elution mode; flow rate: 80 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0287] Method 2: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Mobile phase: A is CO 2 B is EtOH (0.1% NH 3 H 2 O); gradient: B%=28% isocratic elution mode; flow rate: 56 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0288] Method 3: Equipment: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IH (250mm*30mm, 10um); Mobile phase: A is CO 2 B is IPA (0.1% NH 3 H 2 O); gradient: B%=40% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0289] I-126: 1 H NMR (400MHz, acetone) δ=8.17(dd,J=1.6,4.4Hz,1H),7.44-7.35(m,2H),4.94(q,J=8.4Hz,1H),4.38(d,J=8.0Hz,1H),4. 03(dd,J=5.2,6.8Hz,1H),3.56(dd,J=1.2,11.6Hz,1H),3.49-3.41(m,2H),3.32(dd,J=6.8,10.8Hz,1H),2.66(s,3H).

[0290] I-127: 1H NMR (400MHz, acetone) δ=8.17(dd,J=2.1,4.4Hz,1H),7.46-7.31(m,2H),5.31-5.22(m,1H),4.64( d,J=6Hz,1H),3.73(t,J=7.6Hz,1H),3.42(d,J=9.2Hz,2H),3.23(d,J=7.6Hz,2H),2.65(s,3H).

[0291] I-126a: 1 H NMR (400 MHz, acetone) δ = 8.21-8.14 (m, 1.19H), 7.46-7.34 (m, 2.49H), 5.31-5.25 (m, 1H), 5.32 (s, 0.22H), 5.14-5.05 (m, 1.02H), 4.64 (d, J = 5.6 Hz, 0.22H), 4.58 (d, J = 8.4 Hz, 0. 98H),4.27(t,J=6.4Hz,1.02H),3.93-3.85(m,0.90H),3.76-3.71(m,0.23H),3.62-3. 55(m,1H),3.45-3.35(m,1.93H),3.26-3.21(m,2.45H),2.65(s,0.87H),2.52(s,3H).

[0292] I-127a: 1 H NMR (400 MHz, acetone) δ = 8.20-8.15 (m, 1H), 7.45-7.39 (m, 1H), 7.39-7.35 (m, 1H), 5.44-5.32 (m, 1H), 5.08 (d, J = 4.4 Hz, 1H), 4.32-4.24 (m, 1H), 3.46-3.30 (m, 2H), 3.28-3.19 (m, 1H), 3.12-3.02 (m, 1H), 2.72 (s, 3H).

[0293] Example 26: (4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0294] Synthesis of I-128. A solution of (2R,4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-126, 60.28 mg) and (2S,4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-127, 90.42 mg) was dissolved in ACN (3 mL) and H 2 0 (1 mL) and the mixture was lyophilized to give 125.32 mg of I-128 (83%) as a pale yellow solid. (ES, m / z): [M+1] + 326.1. 1 H NMR (400MHz, acetone) δ=8.17(br s,2H),7.47-7.34(m,4.07H),5.37-5.25(m,1.20H),4.99-4.89(m,0.81H),4.64(br d,J=5.2Hz,1.22H),4.38(br d,J=8.4Hz,0.81H),4.06-3.98(m,0.81H),3.72(br t,J=7.2Hz,1.25H),3.61-3.52(m,1.16H),3.48-3.39(m,4.03H),3.31(br dd,J=7.2,10.8Hz,1.09H),3.22(br d,J=7.2Hz,2.30H),2.65(s,6H)

[0295] Example 27: (2R,4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2S,4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid Synthesis of 123.2. To a solution of 2,4-dihydroxybenzoic acid (123.1, 50 g, 324.42 mmol, 1 equiv.), acetone (28.26 g, 486.63 mmol, 35.78 mL, 1.5 equiv.), and DMAP (2.38 g, 19.47 mmol, 0.06 equiv.) in dimethoxyethane (200 mL) was added thionyl chloride (77.19 g, 648.85 mmol, 47.07 mL, 2 equiv.) dropwise at 0° C. for 1 h, then stirred at 25° C. for 7 h. The reaction mixture was cooled to 10° C. with NaHCO 3 (400 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated aqueous NaCl (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was dried at 40° C. and concentrated to give a residue which was triturated with dichloromethane to give the product as a yellowish solid. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:1 to 0:1) to give 12.45 g of 123.2 (crude) as a yellow solid. (ES, m / z): [M+1] + 195.1.

[0296] Synthesis of 123.3. A solution of 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (123.2, 11.45 g, 58.96 mmol, 1 equiv.) and 1-bromo-2-(2-methoxyethoxy)ethane (11.87 g, 64.86 mmol, 1.1 equiv.) in ACN (110 mL) was added with K 2 CO 3 (24.45 g, 176.89 mmol, 3 equiv.) was added. The mixture was stirred at 90° C. for 5 h. The suspension was filtered through a pad of Celite and the filter cake was washed with ethyl acetate (3×50 mL). The combined filtrate was concentrated to dryness to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 99:1 to 10:1) to give 14.05 g of 123.3 (80%) as a pale yellow oil. (ES, m / z): [M+1] + 297.1.

[0297] Synthesis of 123.4. The NH reaction of 7-(2-(2-methoxyethoxy)ethoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (123.3, 5.75 g, 19.24 mmol, 1 equiv.) 3 The solution of 10M / i-PrOH (60 mL) was stirred at 15° C. for 0.5 h. The mixture was then heated to 80° C. and stirred for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=3:1 to 1:1) to give 4.22 g of 123.4 (86%) as a pale yellow oil. (ES, m / z): [M+1] + 256.1.

[0298] Synthesis of 123.5. To a solution of 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzamide (123.4, 4.22 g, 15.20 mmol, 1 equiv) in THF (40 mL) was added Burgess reagent (5.91 g, 22.80 mmol, 1.5 equiv). The mixture was stirred at 60° C. for 12 h. The reaction mixture was diluted with H 2 The mixture was diluted with 2,4-dichloromethane (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , DCM:MeOH=30:1 to 10:1) to give 1.1 g of 123.5 (28%) as a yellow solid. (ES, m / z): [M-1] - 236.1.

[0299] Synthesis of 123.6. To a solution of 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzonitrile (123.5, 980 mg, 4.13 mmol, 1 equiv.) in MeOH (10 mL) was added L-cysteine ​​(1.30 g, 8.26 mmol, 2 equiv., HCl salt) and phosphate buffer (10 mL) at room temperature. Solid K 2 CO 3The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (100 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with dichloromethane (3×100 mL), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.35 g of 123.6 (96%, ee value: 100%) as a yellow solid. (ES, m / z): [M+1] + 342.0.

[0300] Synthesis of 123.7. To a solution of (R)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazole-4-carboxylic acid (123.6, 1.85 g, 5.42 mmol, 1 equiv.), N,O-dimethylhydroxylamine hydrochloride (2A, 1.11 g, 11.38 mmol, 2.1 equiv., HCl) and DECP (1.95 g, 11.38 mmol, 1.81 mL, 2.1 equiv.) in DMF (30 mL) was added DIEA (1.75 g, 13.55 mmol, 2.36 mL, 2.5 equiv.) and N 2 The mixture was stirred at 0° C. for 30 min and at 20° C. for an additional 2 h. The reaction mixture was stirred at H 2 The mixture was diluted with 200 mL of O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with NaHCO 3 Wash with aqueous solution and brine, and add Na 2 SO 4 The residue was purified by silica gel column chromatography (SiO 2 The mixture was purified with petroleum ether:ethyl acetate (1:0 to 1:1) to give 1.27 g of 123.7 (61%, ee value: 86.0%) as a pale yellow solid. (ES, m / z): [M+1] + 385.2.

[0301] Synthesis of 123.8. To a solution of (R)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (123.7, 1.27 g, 2.73 mmol, 1 equiv.) in THF (20 mL) was added LAH (155.47 mg, 4.10 mmol, 1.5 equiv.) 2 The mixture was added at −40° C. The temperature was raised to −30° C. and stirred for 0.5 h. The reaction mixture was then diluted with saturated NH 4 Cl aqueous solution (30 mL) and KHSO 4 (30 mL) of 1M solution of 123.8. The mixture was stirred vigorously and allowed to warm to room temperature until two phases formed. After partitioning and extraction with ethyl acetate (2x50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 690 mg of 123.8 (crude) as a yellow solid. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 326.1.

[0302] Synthesis of 123.9 (R)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazole-4-carbaldehyde (123.8, 690 mg, 2.12 mmol, 1 equiv.) in EtOH (21 mL) and H 2 To the mixture solution of 2,4-dimethylaminopropanoic acid (A-3S, 436.79 mg, 2.54 mmol, 1.2 equiv., HCl) and KOAc (1.46 g, 14.84 mmol, 7 equiv.) were added at 25° C. The suspension was gently stirred in the dark at 25° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and then the solution was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10um; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 10% to 35%, 20 min) to give 360 ​​mg of 123.9 (38%) as a pale yellow solid. (ES, m / z): [M+1] + 443.1.

[0303] Synthesis of I-123, I-124, I-123a, I-124a 360 mg of 123.9 (mixture of 4 peaks) was purified by two SFC separations (method 1 followed by method 2) to give 23.19 mg of I-123 (6%, de value: 100%, peak 2), 46.82 mg of I-124 (13%, de value: 97%, peak 1), 20.11 mg of I-123a (6%, de value: 97%, peak 3) and 28.19 mg of I-124a (8%, de value: 98%, peak 4) as pale yellow solids. (ES, m / z): [M+1] + 443.1

[0304] Method 1 (first SFC separation): Instrument: Waters SFC 80 Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: A is CO 2 B is EtOH (0.1% NH 3 H 2 O); gradient: B%=44% isocratic elution mode; flow rate: 72 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar.

[0305] Method 2 (second SFC separation): Instrument: Waters SFC 150 AP preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um) Mobile phase: A is CO 2 B is MEOH (0.1%NH 3 H 2 O); gradient: B%=50% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 35° C.; system back pressure: 120 bar.

[0306] I-123: 1H NMR(400MHz,アセトン)δ=7.32(d,J=8.4Hz,1H),6.56-6.42(m,2H),4.95(q,J=8Hz,1H),4.53(d,J=9.6Hz,1H),4.25(br t,J=6.4Hz,1H),4.18(br t,J=4.8Hz,2H),3.85-3.79(t,J=4.8Hz,2H),3.67-3.58(m,3H),3.5(t,J=4.8Hz 2H),3.47-3.41(m,1H),3.29(s,3H),3.23(d,J=6Hz,2H),2.50(s,3H)

[0307] I-124: 1 H NMR(400MHz,アセトン)δ=7.33(d,J=8.4Hz,1H),6.55-6.46(m,2H),5.13(dt,J=5.6,8.8Hz,1H),4.58(d,J=5.6Hz,1H),4.20-4.15(br t,J=7.8Hz,2H),3.82(br dd,J=4.0,5.6Hz,2H),3.71(br t,J=7.2Hz,1H),3.64(dd,J=4.8,5.6Hz,2H),3.50(dd,J=4.0,5.6Hz,2H),3.45(d,J=8.4Hz,2H),3.29(s,3H),3.26-3.17(m,2H),2.64(s,3H)

[0308] I-123a: 1 H NMR(400MHz,アセトン)δ=7.32(d,J=8.8Hz,1H),6.56-6.46(m,2H),4.78(q,J=8.4Hz,1H),4.32(d,J=8.0Hz,1H),4.17(t,J=4.4Hz,2H),4.02(br t,J=6Hz,1H),3.85-3.79(m,2H),3.66-3.62(m,2H),3.61-3.56(m,1H),3.53-3.40(m,4H),3.34-3.26(m,4H),2.63(s,3H)

[0309] I-124a: 1H NMR (400MHz, acetone) δ=7.32(d,J=8.4Hz,1H),6.52(dd,J=2.4,8.8Hz,1H),6.48(d,J=2.4Hz,1H),5.21(m,1H),5.03(br d,J=4.4Hz,1H),4.26-4.23(m,1H),4.17(br t,J=4.4Hz,2H),3.81(br t,J=4.8Hz,2H),3.64(dd,J=4.8,6.4Hz,2H),3.50(dd,J=3.6,5.6Hz,2H),3.40(br t,J=7.2Hz,2H),3.29(s,3H),3.21(dd,J=6.4,10Hz,1H),3.07(br d,J=8.8Hz,1H),2.69(s,3H)

[0310] Example 28: (4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid [ka]

[0311] Synthesis of I-125. CH of (2R,4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-123, 23.17 mg) and (2S,4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-124, 34.76 mg) 3 CN / H 2 The 0 (3 / 1, 4 mL) solution was shaken for 2 min to give a clear solution. The mixture was then lyophilized for 24 h to give 50.89 mg of I-125 (87%) as a pale yellow solid. (ES, m / z): [M+1] + 443.1

[0312] I-125: 1H NMR (400MHz, acetone) δ=7.32(dd,J=2.4,8.4Hz,1.51H),6.54-6.47(m,3.19H),5.18-5.07(m,1.15H),4.94(q,J=8.0Hz,0.73H),4.58(br d,J=5.6Hz,0.98H),4.51(br d,J=8.4Hz,0.64H),4.23(br t,J=6.4Hz,0.86H),4.17(br t,J=4.4Hz,3.66H),3.81(t,J=4.8Hz,3.82H),3.71(br t,J=7.6Hz,1.34H),3.66-3.62(m,3.82H),3.52-3.47(m,3.58H),3.45(br d,J=9.2Hz,2.31H),3.29(br s,4.99H),3.24-3.19(m,3.09H),2.63(s,3H),2.48(s,1.80H)

[0313] Example 29: (4S)-3-Methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl)thiazolidine-4-carboxylic acid. [ka]

[0314] Synthesis of F-6. (2R,4S)-3-methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl)thiazolidine-4-carboxylic acid (F-4, 7.01 mg) and (2S,4S)-3-methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl)thiazolidine-4-carboxylic acid (F-5, 10.55 mg) were dissolved in ACN (3 mL) and H 2 HO (1 mL) and the mixture was lyophilized to give 10.37 mg of F-6 (100%) as a pale yellow solid. (ES, m / z): [M+1] + 339.0.

[0315] F-6: 1H NMR (400MHz, acetone-d6) δ=7.82(d,J=8.1Hz,3H),7.59-7.40(m,5H),5.03(br d,J=5.6Hz,1H),4.93(d,J=8.1Hz,0.71H),4.66-4.51(m,1.72H),4.36-4.22(m,0.72H),3.73-3.68(m,1H),3. 66-3.60(m,0.60H),3.50(d,J=9.0Hz,2H),3.47-3.41(m,0.63H),3.25-3.18(m,3H),2.65(s,3H),2.49(s,2H)

[0316] Example 30: (2S,4R)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid and (2R,4R)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0317] Synthesis of 100.2. Acetone-d 6 A mixture of (R)-methyl 2-amino-3-mercaptopropanoate (5 g, 29.13 mmol, 1 equiv., HCl) in (100 mL) was degassed and cooled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 16 hours. The reaction mixture was concentrated under reduced pressure to remove acetone-d6. The residue was diluted with ethyl acetate (50 mL) and washed successively with water, 5% aqueous sodium bicarbonate solution (3×50 mL), and brine (25 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 0 / 1 to 15.6 / 1) to give 4.6 g of 100.2 (90.11%) as a colorless oil. (ES, m / z): [M+1] + 176.0.

[0318] Synthesis of 100.3. (R)-methyl 2,2-dimethylthiazolidine-4-carboxylate (100.2, 3.08 g, 17.58 mmol, 1 equiv.) and K 2 CO 3 (3.64 g, 26.36 mmol, 1.5 equiv.) in DMF (30 mL) 2 SO 4 (6.65 g, 52.73 mmol, 5.00 mL, 3 equiv) was added dropwise with stirring at 0° C. The mixture was stirred at 15° C. for 5 h. The reaction mixture was quenched by the addition of water (20 mL) at 0° C. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 60 / 1) to give 1.5 g of 103.3 (46%) as a colorless oil. (ES, m / z): [M+1] + 190.8.

[0319] Synthesis of A-2S. A mixture of (R)-methyl 2,2,3-trimethylthiazolidine-4-carboxylate (103.3, 1.5 g, 21.13 mmol, 1 equiv.) in HCl (6M, 20 mL, 15.14 equiv.) was degassed and purged with Ar three times, then the mixture was stirred at 100° C. under Ar atmosphere for 8 h. The reaction mixture was concentrated under reduced pressure to give 1.36 g of A-2S (crude, HCl) as a brown solid. The crude product was used directly in the next step without further purification. (ES, m / z): [M+1] + 136.1.

[0320] Synthesis of 100.5. To a mixture of 2-hydroxybenzonitrile (100.4, 2 g, 16.79 mmol, 1 equiv.) in methanol (20 mL) and phosphate buffer (20 mL) was added (2S)-2-amino-3-sulfanylpropanoic acid (5.29 g, 33.58 mmol, 2 equiv., HCl) at room temperature. Solid K 2 CO 3The solution was adjusted to pH=6.4 by careful addition and the reaction mixture was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and the crude yellow residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by addition of solid citric acid. After extraction with EA (3×30 mL), the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which gave 3.7 g of 100.5 (96.24%, %ee value 93.12%) as a yellow solid. (ES, m / z): [M+1] + 223.9.

[0321] Synthesis of 100.6. To a solution of (S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid (100.5, 2.1 g, 8.94 mmol, 1 equiv.), N-methoxymethanamine (2A, 958.84 mg, 9.83 mmol, 1.1 equiv., HCl) and DECP (1.60 g, 9.83 mmol, 1.48 mL, 1.1 equiv.) in DMF (20 mL) was added DIEA (1.73 g, 13.40 mmol, 2.33 mL, 1.5 equiv.) and N-methoxymethanamine (2A, 958.84 mg, 9.83 mmol, 1.1 equiv., HCl). 2 The mixture was stirred at 0° C. for 30 min and then at 25° C. for an additional 2 h. The reaction mixture was diluted with water (45 mL) and extracted with 180 mL of EA (60 mL×3). The combined organic layers were washed with NaHCO 3 Wash with 90mL (30mL x 3) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which gave 2 g of 100.6 (81%, ee value 83.62%) as a pale yellow solid. (ES, m / z): [M+1] + 267.0.

[0322] Synthesis of 100.7. To a solution of (S)-2-(2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (100.6, 2.1 g, 7.89 mmol, 1 equiv.) in THF (42 mL), LAH (448.93 mg, 11.83 mmol, 1.5 equiv.) was added to the N 2 The mixture was added at −40° C. under reduced pressure. The temperature was allowed to rise to −30° C. for 0.5 h. The reaction mixture was then diluted with saturated NH4 Cl aqueous solution (42 mL) and KHSO 4 (42 mL) of a 1 M solution of 100.7 was added successively. The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After partitioning and extraction with EA (3×30 mL), the organic layer was collected, dried over Na2SO4, filtered and evaporated under reduced pressure to give 1.27 g of 100.7 (crude) as a yellow oil. The crude product was used in the next step without further purification. (ES, m / z): [M+1] + 208.1.

[0323] Synthesis of I-100.8. (S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (100.7, 1.3 g, 6.27 mmol, 1 equiv.) in EtOH (60 mL) and H 2 To a mixture solution of 200 (20 mL) was added (R)-3-mercapto-2-(methylamino)propanoic acid (A-2S, 1.29 g, 7.53 mmol, 1.2 equiv., HCl) and KOAc (4.31 g, 43.91 mmol, 7 equiv.). The suspension was gently stirred in the dark at 20° C. for 12 h. Ethanol was removed under reduced pressure and the crude was diluted with water. The aqueous layer was acidified to pH=5 by addition of solid citric acid, and the solution was then extracted with ethyl acetate (3×100 mL). The organic layer was collected and diluted with Na 2 SO 4 The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10% to 40%, 20 min) to give 540 mg of I-100.8 (26.54%) as a pale yellow solid. (ES, m / z): [M+1] + 325.1.

[0324] Synthesis of I-98, I-99, I-98a, and I-99a. 200 mg of I-100.8 (mixture of four peaks) was purified by two SFC separations to give 40 mg of I-98 (20%, ee 77.21%, peak 4), 50 mg of I-99 (25%, ee 84.92%, peak 1), 23.67 mg of I-98a (11.83%, ee 86.04%, peak 3), and 9.73 mg of I-99a (4.86%, ee 56.66%, peak 2) as pale yellow solids. (ES, m / z): [M+1] + 325.1.

[0325] SFC separation method: Method 1: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: [0.1%NH 3 H 2 O EtOH];B%:33%~33%, 9 min.

[0326] Method 2: Equipment: Waters SFC80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: [0.1%NH 3 H 2 O IPA]; B%: 35%-35%, 9 min.

[0327] I-98: 1 H NMR (400MHz, acetone-d6)δ=7.49-7.35(m,2H),7.01-6.87(m,2H),5.02(d,J=8.3Hz,1H),4.56(d,J=8.3Hz,1H),4. 26(t,J=6.5Hz,1H),3.67(dd,J=8.6,11.3Hz,1H),3.47(dd,J=7.9,11.4Hz,1H),3.28-3.18(m,2H),2.51(s,3H).

[0328] I-99: 1H NMR (400MHz, acetone-d6) δ=7.48-7.37(m,2H),6.98-6.89(m,2H),5.22(d,J=5.5Hz,1H),4.63(d,J=5.4 Hz,1H),3.72(dd,J=6.8,8.0Hz,1H),3.50(d,J=8.9Hz,2H),3.22(dd,J=1.8,7.4Hz,2H),2.65(s,3H).

[0329] I-98a: 1 H NMR (400MHz, acetone-d6)δ=7.48-7.35(m,2H),6.99-6.87(m,2H),4.85(q,J=8.4Hz,1H),4.35(d,J=8.3Hz,1H),4. 03(t,J=6.1Hz,1H),3.68-3.61(m,1H),3.54(dd,J=8.2,11.4Hz,1H),3.45(dd,J=5.3,11.0Hz,1H),2.64(s,3H).

[0330] I-99a: 1 H NMR (400MHz, acetone-d6)δ=7.48-7.35(m,2H),6.99-6.88(m,2H),5.30(dt,J=4.7,9.0Hz,1H),5.07(d,J=4.8Hz,1H),4. 27(dd,J=2.3,6.6Hz,1H),3.52-3.38(m,2H),3.23(dd,J=6.5,10.5Hz,1H),3.07(dd,J=2.1,10.5Hz,1H),2.72(s,3H).

[0331] Example 31: (4R)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0332] Synthesis of I-100. CH of 20 mg of I-98 and 30 mg of I-99 3 CN / H 2The 0 (3 / 1, 4 mL) solution was shaken for 2 min to give a clear solution. The solution was then lyophilized for 48 h to give 42.56 mg of I-100 (100%, 59.5+40.49% purity, stereochemical ratio: 58.48:41.38). (ES, m / z): [M+1]+339.1.

[0333] 1 H NMR(400MHz,acetone-d6)δ =7.48-7.37(m,3H),6.94(br dd,J=4.1,7.9Hz,3H),5.22(dt,J=5.4,8.9Hz,1H),5.03(q,J=8.3Hz,0.61H),4.64(d,J=5.5Hz,1H),4.56(d,J=8.4Hz,0.5 4H), 4.27(t,J=6.5Hz,0.65H),3.77-3.63(m,2H),3.54-3.43(m,2.83H),3.28-3.17(m,3H),2.65(s,3H),2.51(s,1.62H).

[0334] Example 32: (4R)-N-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxamide [ka]

[0335] Synthesis of I-138. To a solution of (4R)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (I-100, 20 mg, 61.65 μmol, 1 eq.) and 2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethanamine (16.91 mg, 123.30 μmol, 2 eq.) in DMF (1.5 mL) was added EDCI (17.73 mg, 92.47 μmol, 1.5 eq.), DIEA (39.84 mg, 308.24 μmol, 53.69 uL, 5 eq.) and HOBt (12.50 mg, 92.47 μmol, 1.5 eq.). The mixture was stirred at 15° C. for 16 h. The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-70%, 8 min) to give 17.96 mg of I-138 (64%, stereochemical ratio: 61:38) as a yellow gum. (ES, m / z): [M+1] + 444.0. 1 H NMR(400MHz,chloroform-d)δ=12.67(br s,0.93H),12.17(s,0.61H),7.46-7.30(m,4.22H),7.03-6.98(m,1.55H),6.94-6.84(m,2.24H),5.03(q,J=8.6Hz,0.62H ),4.86(q,J=8.4Hz,1H),4.48(d,J=8.8Hz,0.59H),4.29(d,J=8.4Hz,1H),3.89(dd,J=3.6,8Hz,0.83H),3.69(t,J=7.6Hz ,1H),3.64-3.48(m,2.97H),3.39-3.31(m,1.98H),3.30-3.22(m,1.81H),3.22-3.15(m,1H),3.15-3.05(m,1.85H),3.02 (dd,J=7.2,13.8Hz,0.58H),2.65(s,3H),2.52(s,1.75H),2.03-1.95(m,4.73H),1.75(m,1.29H),1.71-1.60(m,6.70H).

[0336] Example 33: (4S)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0337] Synthesis of A-6. CH of (2R,4S)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-2, 307.01 mg) and (2S,4S)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-3, 460.51 mg) 3 CN / H 2 The 0 (3 / 1, 7 mL) solution was shaken for 2 min to give a clear solution. The solution was then lyophilized for 48 h to give 732.43 mg of I-121 (95%). (ES, m / z): [M+1]+ 325.1.

[0338] 1 H NMR(400MHz,acetone-d6)δ =7.46-7.38(m,2.94H),7.01-6.88(m,3.05H),5.22(dt,J=5.4,8.9Hz,0.99H),5.06(m,0.52H),4.63(d,J=5.4Hz,0.99H),4.60-4.51(m, 0.56H), 4.24(t,J=6.5Hz,0.52H),3.74-3.64(m,1.52H),3.55-3.44(m,2.56H),3.28-3.17(m,3.09H),2.65(s,3.00H),2.50(s,1.53H).

[0339] Example 34: (4S)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid. [ka]

[0340] Synthesis of A-7. CHCH of (2R,4S)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-5, 46.41 mg) and (2S,4S)-2-((R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-4, 15.47 mg) 3 CN / H 2 The 0 (3 / 1, 3 mL) solution was shaken for 2 min to give a clear solution. The solution was then lyophilized for 48 h to give 50.36 mg of A-7 (81%). (ES, m / z): [M+1]+ 325.1.

[0341] 1 H NMR(400MHz, acetone-d6)δ =7.50-7.33(m,2.76H),7.02-6.86(m,2.78H),5.28(dt,J=4.8,9.1Hz,0.35H),5.06(br d,J=4.1Hz,0.31H),4.92-4.80(m,1.02H),4.34(br d,J=8.1Hz,1.06H),4.25(br d,J=5.0Hz,0.38H),4.00(br s,1.07H),3.69-3.59(m,1.22H),3.58-3.48(m,1.17H),3.48-3.38(m,1.75H),3.35-3.26(m,1.07H),3.22(br dd,J=6.4,10.3Hz,0.41H),3.06(br d,J=11.0Hz,0.37H),2.71(s,1.05H),2.63(s,3.00H).

[0342] Example 35: Biological Assays A. Dectin-1 Assay: Compounds described herein are added to mammalian cells for bioactivity assessment. The HEK-Blue Dectin-1b cell line (InVivoGen) releases a reporter protein (secreted embryonic alkaline phosphatase, SEAP) into the culture supernatant in response to Dectin-1 activation. HEK-Blue reporter cells were cultured in DMEM culture medium with 10% uncomplemented fetal bovine serum (InvivoGen), 1% Pen / Strep antibiotics (InvivoGen), 0.2% Normocin antibiotics (InvivoGen). The day before the assay, cells were seeded at 50,000 cells / well in flat-bottom 96-well plates and incubated for an additional 20 hours. On the day of the assay, cells were incubated with 1 μM, 10 μM, or 30 μM of a compound described herein, or 1 μM SYKi IV Dectin-1b inhibitor (Millipore), or DMSO (vehicle control) for 6 h, after which beta-glucan peptide (BGP, Dectin-1 ligand at 30 μg / mL) was added and incubated for 16–18 h. After the end of incubation, culture supernatants were collected and Dectin-1-associated activity was assessed by measuring the presence of SEAP reporter protein using the Quanti-Blue assay (Invivogen), and these values ​​were adjusted by cell viability levels assessed using Cell-Titer-Glo2 reagent (Promega).

[0343] Results represent cell number-adjusted SEAP levels in triplicate for each condition, reflecting less than 5% correction in cell number and viability. For compound A-3, see, e.g., FIG. 1.

[0344] [Table 2]

[0345] Compounds A1 and B1 inhibit BGP-induced Dectin-1b reporter gene activity in a concentration-dependent manner over the range of 1 μM to 30 μM, with maximal inhibition at 30 μM, the highest concentration tested. Compound E1 is less active in this HEK-Dectin-1b assay at these concentrations. See Figure 4.

[0346] Compounds A6, C2 and C3 showed dose-dependent inhibition of BGP-induced Dectin-1b signaling in HEK cells over the range of 1 μM to 30 μM, with maximal inhibition at 30 μM, the highest concentration tested. See FIG. 12.

[0347] B. Monocyte-derived dendritic cell (MoDC) assay protocol Monocyte-derived DCs (MoDCs) were differentiated from CD14+ monocytes from healthy human donors. Commercially available freshly prepared Leukopaks were obtained from healthy blood donors and kept chilled on ice before centrifugation, and pelleted cells were washed and resuspended in MACS buffer (Miltenyi Biotec). CD14 + Monocytes were purified using a MultiMACS™ Cell24 Separator-Plus instrument and reagents according to the manufacturer's instructions (Miltenyi Biotec). + The cell fraction was washed, counted, and cryopreserved for further use. On the first day of the experiment, cryopreserved CD14 + The cells were thawed, washed with culture medium, and then resuspended in culture medium consisting essentially of RPMI (Invitrogen) supplemented with 10% v / v heat-inactivated FBS. To generate moDCs, these CD14 + Cells were counted and cultured at 75 cm in 30 mL of culture medium supplemented with GM-CSF (40–100 ng / mL) and IL-4 (25 ng / mL). 2MoDCs were seeded into tissue culture flasks at 100°C for 12 h. Every other day, half of the culture medium was replaced with fresh medium (containing the same cytokine supplements) and after 6–7 days of culture, fully differentiated and mature MoDCs were obtained, as confirmed by conventional immunophenotypic markers (levels of expression or non-expression of surface CD80, CD83, CD86, CD209, HLA-DR, CD14 and CD64) validated by flow cytometry. Fully differentiated (mature) MoDCs were seeded into flat-bottom 96-well plates and incubated for 6 h with various concentrations of the compounds described herein, or control solution (DMSO), or the pharmacological inhibitors cyclosporine A (CsA) and BAY61-3606 (known inhibitor of Syk kinase). Dectin-1 (CLEC7a1) ligand (zymosan, 5 μg / mL), or the Toll-like receptor agonist R848, were then added to the MoDC culture wells and incubated for an additional 18–20 h. After the end of incubation, culture supernatants were collected and the levels of pro-inflammatory cytokines and chemokines were measured in triplicate for each condition by Luminex® multiplex assay (Figure 2) or ELISA (Figure 3).

[0348] [Table 3]

[0349] Compounds A1 and B1 show potent inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells from healthy human donor 2. See FIG.

[0350] Compounds A1, A2 and A3 show inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells from healthy human donors 1, 2 and 3. Compounds were tested at final concentrations from 15.5 nM to 1 μM with maximum inhibition seen at the highest concentration of 1 μM. See Figures 6A-6C.

[0351] Compounds A1, A2 and A3 show dose-dependent inhibition of zymosan-induced production of the pro-inflammatory cytokine IL-12p40 in monocyte-derived dendritic cells from healthy human donor 1. See Figures 7A-7C.

[0352] Compounds A6 and I-100 inhibit several pro-inflammatory cytokines in LPS-stimulated MoDCs from healthy human donors 14. A6 causes a statistically significant decrease in IL-6 (Figure 9A), TNFα (Figure 9B), IL-23 (Figure 9C), IL-12p70 (Figure 9D), IP-10 (Figure 9E), Gro-α (Figure 9F), MCP-1 (Figure 9G), and Mip-1α (Figure 9H). I-100 causes a statistically significant decrease in IL-6, TNFα, IL-23, IL-12p70, Gro-α, MCP-1, and Mip-1α. See Figures 9A-9H.

[0353] Compounds A6 and I-100 inhibit several pro-inflammatory cytokines in R848-stimulated MoDCs from healthy human donors 14. A6 causes a statistically significant decrease in IL-6 (Figure 10A), TNFα (Figure 10B), IL-23 (Figure 10C), IL-12p70 (Figure 10D), IP-10 (Figure 10E), Gro-α (Figure 10F), MCP-1 (Figure 10G), and Mip-1α (Figure 10H). I-100 causes a statistically significant decrease in IL-6, TNFα, IL-23, IL-12p70, IP-10, Gro-α, MCP-1, and Mip-1α. See Figures 10A-10H.

[0354] Compounds A3 and C3, when tested at a final concentration of 0.5 μM, inhibit zymosan-induced IL-12p40 in primary human MoDCs from healthy donors 5 and 6. Compound C3, when tested at a final concentration of 0.5 μM, inhibits zymosan-induced IL-12p40 in primary human monocyte-derived dendritic cells from healthy donors 5 (FIG. 11A) and 6 (FIG. 11B), while compound A3 does not achieve statistically significant inhibition at a final concentration of 0.5 μM.

[0355] CAIRF Assay: Compounds described herein are added to mammalian cells for bioactivity assessment. The THP-1 dual reporter cell line (InVivoGen) secretes a reporter protein (Lucia luciferase or LUC) in response to activation by the pro-inflammatory bacterial component lipopolysaccharide (LPS). THP-1 dual reporter cells were cultured in RPMI1640 culture medium containing 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum, 100 μg / ml Normocin antibiotic (InvivoGen), Pen-Strep antibiotic (100 U / ml-100 μg / ml, InvivoGen). On the day of the assay, cells were seeded at 50,000 cells / well in flat-bottom 96-well plates and incubated for 2 hours. Cells were then incubated with 1 μM or 10 μM of a compound described herein, or 1 μM of IKK-16 (Selleck), a potent inhibitor of IκB kinase (IKK), or DMSO (vehicle control) for 2 h, after which LPS was added at 25 ng / mL and incubated for 24 h. After the end of incubation, culture supernatants were collected and IRF-associated activity was assessed by measuring Lucia luciferase using the Quanti-Luc assay (InvivoGen), and these values ​​were adjusted for cell viability levels assessed using Cell-Titer-Glo2 reagent (Promega).

[0356] Compound I-100 shows inhibition of LPS-induced IRF reporter activity. This inhibition does not reach statistical significance when tested at 1 μM and 10 μM. See Figure 8A. Compound A6 shows inhibition of LPS-induced IRF reporter activity in cell assay. This inhibition reaches statistical significance when tested at 1 μM. See Figure 8B.

[0357] Example 36: Compound Interconversion This example provides the kinetics of compounds A-2 and A-3. More specifically, A-6 is a mixture of compounds A-2 and A-3, which interconvert in solution.

[0358] In this example, A-6 is mixed with 12 nM Na 3 PO 4 , DCl, and D 2 The solution was then monitored using 1H-NMR at 37 °C. [ka] Interconversion between compounds A-2 and A-3 was observed and was monitored for 5 days, see Table 1.

[0359] [Table 1]

[0360] These data show that the conversion of A-2 to A-3 reaches approximately a 1 / approximately 1.5 equilibrium in approximately 3 hours in neutral aqueous buffer at 37° C. The conversion of A-3 to A2 reaches approximately a 1.5 / 1 equilibrium in approximately 7 hours.

[0361] While the present invention has been described in conjunction with its preferred specific embodiments, it is to be understood that the foregoing description and the following examples are intended to illustrate, not to limit, the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents substituted without departing from the scope of the invention, and further that other aspects, advantages, and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present disclosure contemplates and claims inventions resulting from combinations of features of the invention cited herein with features of the cited prior art documents that are complementary to the features of the invention. Similarly, it will be understood that the materials, features, or articles described may be used in combination with other materials, features, or articles, and such combinations are considered to be within the scope of the invention.

[0362] The disclosures of each patent, patent application, and publication cited or described in this document are incorporated herein by reference in their entirety for all purposes.

Claims

1. Compounds of Formula I: 【Chemistry 460】 (In the formula: R １ , R ２ , R ３ , and R ４ is independently H or optionally substituted C １－６ is alkyl; R ５ is OH, optionally substituted C １－６ Alkoxy, -N(R Ａ ) (optionally substituted C １－６ alkyl), or -X(R Ａ )-R １５ -CH(X ６ ) (X ７ ) R １１ R １２ and R １５ is -C １－６ alk-; R Ａ is H or optionally substituted C １－６ is alkyl; X is O or NH; X １ is CR ６ or N; X ２ is CR ７ or N; X ３ is CR ８ or N; X ４ is CR ９ or N; X ５ is CR １０ or N; X ６ and X ７ are independently H or optionally substituted C １－６ alkyl or both are N and are joined to form a diazirinyl ring; R ６ , R ７ , R ８ , R ９ , and R １０ are independently H, OH, halo, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, or -(OC １－６ alk) ｎ -C １－６ is alkyl; R １１ and R １２ is independently an optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ Alkoxy, OH, NH ２ , or N(R １３ ) (R １４ ) and R １３ and R １４ are independently H or C １－６ is alkyl; n is 2 to 8; However, X １ ~X ５ is N) or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1 , wherein R １ , R ２ , R ３ , and R ４ is independently H.

3. 2. The compound of claim 1 , wherein R １ , R ２ , R ３ , and R ４ is independently an optionally substituted C １－６ alkyl, for example methyl, ethyl, propyl, butyl, pentyl, or hexyl, or for example methyl; for example R １ is methyl; for example, R ２ is methyl; for example, R ３ is methyl; for example, R ４ is methyl; for example, R １ is H; for example, R ２ is H; for example, R ３ is H; for example, R ４ is H.

4. The compound according to any one of claims 1 to 3, wherein R ５ is OH.

5. The compound according to any one of claims 1 to 3, wherein R ５ is optionally substituted C １－６ Alkoxy, for example optionally substituted C ５ - ６ Alkyl, or for example optionally substituted C ５ Alkyl, or for example optionally substituted C ６ A compound which is an alkyl.

6. The compound according to any one of claims 1 to 3, wherein R ５ But -N(R Ａ ) (optionally substituted C １－６ alkyl), for example -N(R Ａ ) (optionally substituted C ５ - ６ alkyl), or for example -N(R Ａ ) (optionally substituted C ５ alkyl), or for example -N(R Ａ ) (optionally substituted C ６ The compound,

7. The compound according to any one of claims 1 to 3, wherein R ５ But -X(R Ａ )-R １３ -CH(X ６ ) (X ７ ) R １１ R １２ A compound.

8. A compound according to any one of claims 1 to 7, wherein R １８ But -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ - or -CH ２ CH ２ CH ２ CH ２ A compound which is -.

9. A compound according to any one of claims 1 to 8, wherein R Ａ is H or optionally substituted C １－６ A compound which is an alkyl.

10. The compound according to any one of claims 1 to 9, wherein X is O.

11. 10. The compound according to any one of claims 1 to 9, wherein X is NH.

12. A compound according to any one of claims 1 to 11, wherein X １ is CR ６ A compound.

13. A compound according to any one of claims 1 to 11, wherein X １ The compound wherein:

14. A compound according to any one of claims 1 to 13, comprising X ２ But, CR ７ or N.

15. A compound according to any one of claims 1 to 13, comprising X ２ The compound wherein:

16. A compound according to any one of claims 1 to 15, comprising X ３ But, CR ８ or N.

17. A compound according to any one of claims 1 to 15, comprising X ３ The compound wherein:

18. A compound according to any one of claims 1 to 17, comprising X ４ But, CR ９ or N.

19. A compound according to any one of claims 1 to 17, comprising X ４ The compound wherein:

20. A compound according to any one of claims 1 to 19, comprising X ５ But, CR １０ or N.

21. A compound according to any one of claims 1 to 19, comprising X ５ The compound wherein:

22. A compound according to any one of claims 1 to 21, comprising X ６ and X ７ are independently H or, for example, X ６ is H; or for example, X ７ is H.

23. A compound according to any one of claims 1 to 21, comprising X ６ and X ７ is independently an optionally substituted C １－６ A compound which is alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl, or for example, methyl.

24. A compound according to any one of claims 1 to 21, comprising X ６ and X ７ is N and is linked to form a diazirinyl ring.

25. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ is independently H.

26. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ is OH.

27. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ A compound in which:

28. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ is optionally substituted C １－６ A compound which is an alkyl.

29. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ is optionally substituted C １－６ The compound, which is an alkoxy.

30. A compound according to any one of claims 1 to 24, wherein R ６ , R ７ , R ８ , R ９ , and R １０ But - (OC １－６ alk) ｎ -C １－６ A compound which is an alkyl.

31. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independently an optionally substituted C １－６ A compound which is an alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl.

32. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independently an optionally substituted C ２－６ A compound which is an alkenyl, for example, ethenyl, propenyl, butenyl, pentenyl, or hexenyl.

33. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independently an optionally substituted C ２－６ A compound which is an alkynyl, for example, ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

34. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independently an optionally substituted C １－６ A compound that is an alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

35. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independently OH.

36. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ became independent and established NH ２ A compound.

37. A compound according to any one of claims 1 to 30, wherein R １１ and R １２ is independent of N(R １３ ) (R １４ ), for example NHCH ３ or for example N(CH ３ ) ２ A compound.

38. A compound according to any one of claims 1 to 37, wherein R １３ and R １４ is independently H.

39. A compound according to any one of claims 1 to 37, wherein R １３ and R １４ became independent and C １－６ A compound which is an alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl.

40. 40. The compound of any one of claims 1 to 39, wherein n is 3 to 6, or 2, or 3, or 4, or 5, or 6, or 7, or 8.

41. 2. The compound of claim 1 , 【Chemistry 461】 or a pharma- ceutically acceptable salt thereof.

42. 42. The compound of claim 41, 【Chemistry 462】 for example, 【Chemistry 463】 or a pharma- ceutically acceptable salt thereof.

43. 42. The compound of claim 41, 【Chemistry 464】 for example 【Chemistry 465】 A compound.

44. 2. The compound of claim 1 , 【Chemistry 466】 or a pharma- ceutically acceptable salt thereof.

45. 45. The compound of claim 44, 【Chemistry 467】 for example, 【Chemistry 468】 or a pharma- ceutically acceptable salt thereof.

46. 2. The compound of claim 1 , 【Chemistry 469】 or a pharma- ceutically acceptable salt thereof.

47. 47. The compound of claim 46, 【Chemistry 470】 for example, 【Chemistry 471】 or a pharma- ceutically acceptable salt thereof.

48. 47. The compound of claim 46, 【Chemistry 472】 for example, 【Chemistry 473】 A compound.

49. 2. The compound of claim 1 , 【Chemical 474】 or a pharma- ceutically acceptable salt thereof.

50. 50. The compound of claim 49, 【Chemistry 475】 for example, 【Chemistry 476】 or a pharma- ceutically acceptable salt thereof.

51. 2. The compound of claim 1 , 【Chemistry 477】 or a pharma- ceutically acceptable salt thereof.

52. 52. The compound of claim 51 , 【Chemistry 478】 for example, 【Chemical 479】 or a pharma- ceutically acceptable salt thereof.

53. 2. The compound of claim 1 , 【Chemistry 480】 or a pharma- ceutically acceptable salt thereof.

54. 54. The compound of claim 53, 【Chemistry 481】 for example, 【Chemistry 482】 or a pharma- ceutically acceptable salt thereof.

55. 2. The compound of claim 1 , 【Chemistry 483】 or a pharma- ceutically acceptable salt thereof.

56. 56. The compound of claim 55, 【Chemistry 484】 for example, 【Chemistry 485】 or a pharma- ceutically acceptable salt thereof.

57. 2. The compound of claim 1 , 【Chemistry 486】 or a pharma- ceutically acceptable salt thereof.

58. 58. The compound of claim 57, 【Chemistry 487】 for example, 【Chemistry 488】

59. 2. The compound of claim 1 , 【Chemistry 489】 or a pharma- ceutically acceptable salt thereof.

60. 60. The compound of claim 59, 【Chemistry 490】 for example, 【Chemistry 491】 or a pharma- ceutically acceptable salt thereof.

61. 2. The compound of claim 1 , 【Chemistry 492】 or a pharma- ceutically acceptable salt thereof.

62. 62. The compound of claim 61 , 【Chemistry 493】 for example, 【Chemistry 494】 or a pharma- ceutically acceptable salt thereof.

63. 2. The compound of claim 1 , 【Chemistry 495】 or a pharma- ceutically acceptable salt thereof.

64. 64. The compound of claim 63, 【Chemistry 496】 for example, 【Chemistry 497】 A compound.

65. 2. The compound of claim 1 , 【Chemistry 498】 or a pharma- ceutically acceptable salt thereof.

66. 66. A compound according to claim 65, 【Chemistry 499】 for example, 【Chemical 500】 or a pharma- ceutically acceptable salt thereof.

67. 2. The compound of claim 1 , 【Chemistry 501】 or a pharma- ceutically acceptable salt thereof.

68. 68. The compound of claim 67, 【Chemistry 502】 for example, 【Chemistry 503】 or a pharma- ceutically acceptable salt thereof.

69. 2. The compound of claim 1 , 【Chemistry 504】 or a pharma- ceutically acceptable salt thereof.

70. 70. The compound of claim 69, 【Chemistry 505】 for example, 【Chemistry 506】 or a pharma- ceutically acceptable salt thereof.

71. 2. The compound of claim 1 , 【Chemistry 507】 or a pharma- ceutically acceptable salt thereof.

72. 72. The compound of claim 71, 【Chemistry 508】 for example, 【Chemistry 509】 or a pharma- ceutically acceptable salt thereof.

73. 10. The compound of claim 1, having formula II: 【Chemistry 510】 A compound represented by the formula:

74. 10. The compound of claim 1, having formula III: 【Chemistry 511】 A compound represented by the formula:

75. 10. The compound of claim 1, having formula IV: 【Chemistry 512】 A compound represented by the formula:

76. 10. The compound of claim 1, having the formula V: 【Chemistry 513】 A compound represented by the formula:

77. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any one of claims 1 to 76 and a pharma- ceutically acceptable excipient.

78. 78. The pharmaceutical composition of claim 77, comprising two diastereomers of the compound, wherein the ratio of the first diastereomer to the second diastereomer is about 10:about 90, or about 25:about 75, or about 40:about 60, or about 50:about 50, or about 60:about 40, or about 75:about 25, or about 90:about 10.

79. A dosage unit comprising a compound according to any one of claims 1 to 76, or a pharmaceutical composition according to claim 77 or 78.

80. 80. The dosage unit of claim 79, comprising from about 0.01 to about 1000 mg of the compound.

81. 13. A method of modulating an inflammatory bowel disease (IBD) marker in a subject in need thereof, comprising administering to said subject in need thereof a compound according to any one of claims 1 to 76, a pharmaceutical composition according to claim 77 or 78, or a dosage form according to claim 79 or 80.

82. 13. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to said subject a compound according to any one of claims 1 to 76, a pharmaceutical composition according to claim 77 or 78, or a dosage form according to claim 79 or 80.

83. 83. The method of claim 81 or 82, wherein the subject has or is at risk of developing IBD.

84. 84. The method of any one of claims 81 to 83, wherein the IBD is ulcerative colitis.

85. 84. The method of any one of claims 81 to 83, wherein the IBD is Crohn's disease.

86. 86. The method of any one of claims 81-85, wherein the level of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-23 (IL-23), interleukin-12 (IL-12), or interleukin-17A (IL-17A), or a combination thereof, is reduced in the subject.

87. 87. The method of any one of claims 81-86, wherein the level of nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), cysteine-cysteine ​​motif chemokine ligand 20 (CCL20), or interferon-γ (IFN-γ), or a combination thereof, is reduced in the subject.

88. 88. The method of any one of claims 81-87, wherein the level of M2 pyruvate kinase (M2-PK), osteoprotegerin, myeloperoxidase (MPO), high mobility group box protein 1 (HMGB1), chitinase 3-like 1 (CHI3L1), human beta defensin 2 (HBD2), metalloproteinases (MMPs), calprotectin, lactoferrin, peripheral antineutrophil cytoplasmic antibody (p-ANCA), or anti-Saccharomyces cerevisiae antibody (ASCA), or a combination thereof, is reduced in the subject.

89. 89. The method of any one of claims 81 to 88, wherein inflammation or ulcers in the intestinal lining of the subject are reduced as observed by colonoscopy.

90. 90. The method of any one of claims 81-89, wherein the level of one or both of serum amyloid A protein (SAA) or eotaxin-1 is reduced in the subject.

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