Compounds, pharmaceutical compositions and methods for treating inflammatory bowel disease

Abstract

The present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprises 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; the present invention relates to a pharmaceutical composition comprising a dose unit 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 a pharmaceutical composition described herein, a method of treating inflammatory bowel disease in a subject in need thereof, and a pharmaceutical composition 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 methods of modulating an inflammatory bowel disease marker in a subject in need thereof. # imgabs0 # imgabs1 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to the following U.S. provisional patent applications: U.S. provisional patent application No. 63 / 324,741 filed on March 29, 2022; U.S. provisional patent application No. 63 / 324,801 filed on March 29, 2022; U.S. provisional patent application No. 63 / 324,897 filed on March 29, 2022; and U.S. provisional patent application No. 63 / 324,934 filed on March 29, 2022, the disclosures of which are incorporated herein by reference. Technical Field

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

[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 lining of the digestive tract, and can often spread deeply into the affected tissues. Ulcerative colitis is a condition that causes persistent inflammation and sores (ulcers) in the innermost wall 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 may develop and increase the risk of subject suffering from colon cancer, primary sclerosing cholangitis and thrombosis. 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, colon perforation and severe dehydration. Although various methods for the management of inflammatory bowel disease have been developed, these methods are typically systemic and rely on inflammation suppression rather than the treatment of underlying conditions.

[0004] There is a need for small molecule-based therapeutic approaches to treat inflammatory bowel disease. Summary of the invention

[0005] In some aspects, the disclosure provides a compound which is Compound A or Compound G or a pharmaceutically acceptable salt thereof:

[0006] In other aspects, the disclosure provides a compound, which is Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharmaceutically acceptable salt thereof:

[0007] In yet other aspects, the present disclosure provides a compound that is Compound H, Compound J, Compound K, Compound L, Compound M, Compound N, Compound O, Compound P, or a pharmaceutically acceptable salt thereof.

[0008] In additional aspects, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein and a pharmaceutically acceptable excipient.

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

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

[0011] In further embodiments, the present disclosure provides methods of modulating inflammatory bowel disease markers in a subject in need thereof, the methods 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 be readily apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is a bar graph showing the dectin-1b activity of compound A-3. In this figure, Syki is Syk inhibitor IV (BAY 61-3606), and the OD650 nM value is adjusted according to the cell number.

[0014] Figure 2 is a bar graph of the Luminex assay of compound A-3.

[0015] Figure 3 is a graph showing the dose response of the combination of compounds A-2 and A-3.

[0016] Figure 4 is a bar graph showing the dectin-1b activity of compounds A1, B1, and E1.

[0017] Figure 5 is a bar graph of Luminex assays of compounds A1 and B1 at concentrations of 0.125 μM, 0.25 μM, 0.5 μM, and 1 μM, and shows the inhibition of zymosan-induced IL-12p40 expression in monocyte-derived dendritic cells.

[0018] Fig. 6A , Figure 6B and Figure 6C is a bar graph of Luminex assays of compounds A1, A2 and A3 at concentrations of 15.6 nM, 62.5 nM, 250 nM and 1 μM for 3 donors and shows the inhibitory effect of zymosan-induced pro-inflammatory cytokine IL-12p40 production in monocyte-derived dendritic cells.

[0019] Fig. 7A , Figure 7B and Figure 7C The IC values ​​of compounds A1, A2 and A3 are 50 The curves are shown and show the inhibitory effect of zymosan-induced pro-inflammatory cytokine IL-12p40 production in monocyte-derived dendritic cells.

[0020] Fig. 8A and Figure 8B The bar graphs are for compounds 1-100 and A6, respectively, and show the inhibition of LPS-induced IRF reporter activity.

[0021] Figure 9A-9H is a bar graph of compounds 1-100 and A6 and shows the inhibitory effects of pro-inflammatory cytokines in LPS-stimulated monocyte-derived dendritic cells.

[0022] Figures 10A-10H is a bar graph of compounds 1-100 and A6 and shows the inhibition of pro-inflammatory cytokines in R848 stimulated monocyte-derived dendritic cells.

[0023] Fig.11 A and Fig.11 B is a bar graph of Luminex assays of compounds A3 and C3 at a concentration of 0.5 μM.

[0024] Fig.12 is a bar graph of the inhibitory effects of compounds A6, C2 and C3 at concentrations of 1 μM, 10 μM and 30 μM on BGP-induced Dectin-1b signaling in HEK cells. DETAILED DESCRIPTION

[0025] In this disclosure, unless the context indicates otherwise, the singular forms "a", "an", and "the" include plural referents, and references to specific values ​​include at least that specific value. For example, reference to "a material" is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, etc.

[0026] When a value is expressed as an approximation by using the descriptor "about" or "approximately", it should be understood that the specific value forms another embodiment. Generally, the use of the term "about" or "approximately" indicates an approximation, which can vary according to the desired characteristics sought to be obtained by the disclosed subject matter, and should be interpreted in the specific context in which it is used based on its function. Those skilled in the art will be able to interpret it conventionally. In some cases, the number of significant figures for a specific value can be a non-limiting method for determining the degree of the word "about" or "approximately". In other cases, the rank used in a series of values ​​can be used to determine the expected range available for the term "about" or "approximately" for each value. Where present, all ranges include the end value and are combinable. That is, the reference to the value stated in the range includes each value in the range.

[0027] When presenting a list, unless otherwise stated, it should be understood that each individual element and each combination should be interpreted as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0028] It should be understood that certain features of the invention described herein in the context of separate embodiments for clarity may also be provided in a single embodiment in combination. That is, unless clearly incompatible or excluded, each separate embodiment is deemed to be combined with any other one or more embodiments, and such a combination is considered to be another embodiment. On the contrary, the various features of the invention described in the context of a single embodiment for brevity may also be provided individually or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a premise basis for the use of exclusive terms such as "alone", "only", etc. or the use of "negative" limitations related to the narration of claim elements. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each of the steps itself may also be considered as an independent embodiment.

[0029] The compounds disclosed herein may exist in one or more specific chiral forms such as R-form and S-form. In some embodiments, the compound is an enantiomer. In other embodiments, the compound is a diastereomer. In certain embodiments, one, two, three or four carbon atoms are in (R)-configuration. In other embodiments, one, two, three or four carbon atoms are in (S)-configuration. The compounds described herein may also be enriched in isomers of compounds with selected stereochemistry (e.g., R or S). In some embodiments, the compound has 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% enantiomeric excess (ee%). In other embodiments, the compound is racemic, ie, the ee is 0%. In other embodiments, the compound is a single enantiomer, ie, the ee is 100%.

[0030] The terms "subject" and "patient" are used interchangeably and include, without limitation, mammals. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or farm animal, livestock or pet, or an animal used in clinical research.

[0031] "Treatment" or variations thereof refers to improving or reducing the development of a disease or disorder, i.e., delaying the onset of a disease. In certain embodiments, "treating" refers to improving or reducing at least one physical parameter of a disease or disorder. In other embodiments, "treating" involves ameliorating a disease or disorder. In further embodiments, "treating" involves the cause of a disease or disorder. In yet other embodiments, "treating" involves alleviating the symptoms of a disease or disorder. In still further embodiments, "treating" involves treating a disease or disorder as a supplement to another therapy.

[0032] The term "halogen" means chlorine, fluorine, bromine, or iodine.

[0033] As used herein, the term "alkyl" refers to a straight or branched chain alkyl group. In some embodiments, the alkyl group has from 1 to 20 carbon atoms, i.e., C 1-20 In other embodiments, the alkyl group has from 1 to 6 carbon atoms, i.e., C 1-6Alkyl. Examples of alkyl include methyl (C1 alkyl), ethyl (C2 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), etc. In some embodiments, the alkyl is methyl. In other embodiments, the alkyl is ethyl. In other embodiments, the alkyl is n-propyl or isopropyl. In still other embodiments, the alkyl is n-butyl, isobutyl, sec-butyl, or tert-butyl. In other embodiments, the alkyl is pentyl. In other embodiments, the alkyl is hexyl. The alkyl is optionally substituted by one, two or three selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0034] As used herein, the term "alkoxy" refers to an OC 1-6 wherein alkyl is as defined herein and the point of attachment is through the oxygen atom of the alkoxy group. In some embodiments, the alkoxy group has from 1 to 20 carbon atoms, i.e., C 1-20 In other embodiments, the alkoxy group has from 1 to 6 carbon atoms, i.e., C 1-6 Alkoxy. Examples of alkoxy include methoxy (C1 alkoxy), ethoxy (C2 alkoxy), n-propoxy (C3 alkoxy), isopropoxy (C3 alkoxy), etc. In some embodiments, the alkoxy is methoxy. In other embodiments, the alkoxy is ethoxy. In other embodiments, the alkoxy is n-propoxy or isopropoxy. In still other embodiments, the alkoxy is n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. In other embodiments, the alkoxy is pentyloxy. In other embodiments, the alkoxy is hexyloxy. The alkoxy is optionally substituted by one, two or three selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0035] As used herein, the term "alkylene" or "-alk-" refers to a straight or branched alkyl group connecting two groups, i.e., an internal group. In some embodiments, the alkylene group has from 1 to 6 carbon atoms, i.e., C 1-6 Examples of alkylene groups include C1 alkyl (-CH2-), C2 alkyl (-CH2CH2- or CH(CH3)-), C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. The alkylene group is optionally substituted by one, two or three alkyl radicals selected from halogen, OH, OC1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0036] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 20 carbon atoms, which has at least one unsaturated point as a double bond. In other embodiments, the alkenyl group has from 2 to 6 carbon atoms, i.e., C 2-6 Alkenyl. Examples of alkenyl include vinyl (C2 alkenyl), propenyl (C3 alkenyl), etc. In some embodiments, the alkenyl is -CH=CH2. In some embodiments, the alkenyl is a straight chain hydrocarbon. In other embodiments, the alkenyl is a branched 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 as described herein. For example, the alkenyl is optionally substituted with one, two or three selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0037] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon group having from 2 to 20 carbon atoms, which has at least one point of unsaturation that is a triple bond. In other embodiments, the alkynyl group has from 2 to 6 carbon atoms, i.e., C 2-6 Alkynyl. Examples of alkynyl include ethynyl (C2 alkynyl), propynyl (C3 alkynyl), etc. 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 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 as described herein. For example, alkenyl is optionally substituted with one, two or three selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0038] As used herein, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon group. In some embodiments, the cycloalkyl group has from 3 to 8 carbon atoms ("C 3-8”). In some embodiments, the cycloalkyl group has from 3 to 6 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), 1-methylcyclopropyl (C4), or 2-methylcyclopentyl (C4). The cycloalkyl group is optionally substituted by one, two or three cycloalkyl radicals selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0039] The term "heterocyclyl" refers to a stable 3- to 14-membered non-aromatic ring radical containing two to twelve carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl contains 3 ring atoms, 4 ring atoms, etc., up to and including 14 ring atoms. The heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain a fused or bridged ring system. The heteroatoms in the heterocyclyl group may be optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclyl group is unsaturated, partially saturated, or fully saturated. The heterocyclyl may be attached to the rest of the molecule by any atom of one or more rings. "Heterocyclyl" also includes such a bicyclic ring system, in which a non-aromatic ring contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen and a combination containing at least one of the above heteroatoms; and the other ring optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and is not aromatic. In some embodiments, the heterocyclic group is indolyl. Examples of heterocyclic groups include, but are not limited to, azepanyl, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, triaz ... trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl, azepanyl, 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, benzopyrone, benzofuranyl, benzofuranone, benzofurazanyl, benzothiazolyl, benzothiophenyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopentadienyl [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]cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazoline 1,6-naphthyridinyl, 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-cycloheptyl[4 ,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). The heterocyclic group is optionally substituted by one, two or three selected from halogen, OH, OC, 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent.

[0040] The term "aryl" refers to a radical having from 6 to 10 carbon atoms ("C 6-10 ”) carbocyclic aromatic groups, such as phenyl, naphthyl, etc. The aryl group is optionally substituted by one, two or three selected from halogen, OH, OC 1-6 Alkyl, CN, NH2, NH(C 1-6 Alkyl), NH(C 1-6 Alkyl)2, C 3-8 The cycloalkyl group, the heterocyclic group, or the aryl group is substituted by a substituent. Compound

[0041] The present disclosure provides compounds having Formula I:

[0042] According to this disclosure, R 1 , R 2 , R 3 , and R 4 is independently H or optionally substituted C 1-6 In some embodiments, R 1 , R 2 , R 3 , and R 4 are independently H. In other embodiments, R 1 , R 2 , R 3 , and R 4 is independently optionally substituted C 1-6 In another embodiment, R 1 , R 2 , R 3 , and R 4 R is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1 , R 2 , R 3 , and R 4 is independently methyl. In still other embodiments, R 1 In other embodiments, R 2 In another embodiment, R 3 In yet other embodiments, R 4 In still other embodiments, R 1 is H. In other embodiments, R 2 is H. In another embodiment, R 3 is H. In still other embodiments, R 4 It's H.

[0043] According to this disclosure, R 5 is OH, optionally substituted C 1-6 Alkoxy, -N(R A )(Optionally substituted 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 an optionally substituted C 1-6 In another embodiment, R 5 is an optionally substituted C 5-6 In yet other embodiments, R 5is an optionally substituted C5 alkyl. In still other embodiments, R 5 is an optionally substituted C6 alkyl. 5 Yes-N(R A )(Optionally substituted C 1-6 In other embodiments, R 5 Yes-N(R A )(Optionally substituted C 5-6 In yet other embodiments, R 5 Yes-N(R A )(optionally substituted C5 alkyl). In still further embodiments, R 5 Yes-N(R A )(optionally substituted C6 alkyl). In other embodiments, R 5 Yes-X(R A )-R 13 -CH(X 6 )(X 7 )R 11 R 12 In other embodiments, R 5 yes

[0044] According to this disclosure, R 15 Yes-C 1-6 In some embodiments, R 15 In other embodiments, R 15 In another embodiment, R 15 In yet other embodiments, R 15 In still other embodiments, R 15 In other embodiments, R 15 In another embodiment, R 15 It is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0045] 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 1-6 In another embodiment, R A It's methyl.

[0046] According to the present disclosure, X is O or NH. In some embodiments, X is O. In other embodiments, X is NH.

[0047] According to this disclosure, X 1 Yes CR 6 or N. In some embodiments, X 1 Yes CR 6 In other embodiments, X 1 It is N.

[0048] According to this disclosure, X 2 Yes CR 7 or N. In some embodiments, X 2 Yes CR 7 In other embodiments, X 2 It is N.

[0049] According to this disclosure, X 3 Yes CR 8 or N. In some embodiments, X 3 Yes CR 8 In other embodiments, X 3 It is N.

[0050] According to this disclosure, X 4 Yes CR 9 or N. In some embodiments, X 4 Yes CR 9 In other embodiments, X 4 It is N.

[0051] According to this disclosure, X 5 Yes CR 10 or N. In some embodiments, X 5 Yes CR 10 In other embodiments, X 5 It is N.

[0052] In certain embodiments, X 1 -X 5 Only one of them is N.

[0053] According to this disclosure, X 6 and X 7 is independently H or optionally substituted C 1-6 alkyl, or both are N and are linked to form a diazolidinyl ring. 6 and X 7 are independently H. In other embodiments, X 6 is H. In other embodiments, X 7 is H. In yet other embodiments, X 6 and X 7is independently optionally substituted C 1-6 In still other embodiments, X 6 and X 7 X is independently such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In other embodiments, X 6 and X 7 In another embodiment, X 6 and X 7 is N and is linked to form an optionally substituted diazolidinyl ring.

[0054] According to this disclosure, R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, OH, halogen, 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 are independently H. In other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 are independently OH. In another embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 is independently a halogen, such as F, Cl or Br. In still other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 is independently optionally substituted C 1-6 In yet another embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 R is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. 6 , R 7 , R 8 , R 9 , and R 10In another embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 is independently optionally substituted C 1-6 In yet other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 R is independently methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy. 6 , R 7 , R 8 , R 9 , and R 10 In other embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 Independently is - (OC 1-6 alk) n -C 1-6 In another embodiment, R 6 , R 7 , R 8 , R 9 , and R 10 One of them is independently OCH2CH2OCH2CH2OCH3.

[0055] According to this disclosure, R 11 and R 12 is independently 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, NH2, or N(R 13 )(R 14 ). In some embodiments, R 11 and R 12 is independently optionally substituted C 1-6 In other embodiments, R 11 and R 12 R is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. 11 and R 12 is independently optionally substituted C 2-6 In yet other embodiments, R 11 and R 12R is independently vinyl, propenyl, butenyl, pentenyl, or hexenyl. In still other embodiments, R 11 and R 12 is independently optionally substituted C 2-6 In other embodiments, R 11 and R 12 R is independently ethynyl, propynyl, butynyl, pentynyl, or hexynyl. 11 and R 12 is independently optionally substituted C 1-6 In still other embodiments, R 11 and R 12 R is independently methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy. 11 and R 12 is independently OH. In other embodiments, R 11 and R 12 are independently NH2. In another embodiment, R 11 and R 12 Independently N(R 13 )(R 14 In still other embodiments, R 11 and R 12 is independently NHCH3. In other embodiments, R 11 and R 12 independently N(CH3)2.

[0056] According to this disclosure, R 13 and R 14 independently H or C 1-6 In some embodiments, R 13 and R 14 are independently H. In other embodiments, R 13 and R 14 Independently C 1-6 In another embodiment, R 13 and R 14 are independently methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0057] According to the present disclosure, n is 2-8. In some embodiments, n is 2. In other embodiments, n is 3. In further embodiments, n is 4. In still further embodiments, n is 5. In still further embodiments, n is 6. In other embodiments, n is 7. In further embodiments, n is 8.

[0058] The present disclosure also provides 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 pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the present disclosure provides Compound A or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof. In certain aspects, compound A is or a pharmaceutically acceptable salt thereof. In other aspects, Compound A is or a pharmaceutically acceptable salt thereof. In another aspect, compound A is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound A is or a pharmaceutically acceptable salt thereof. In still another aspect, Compound A is or a pharmaceutically acceptable salt thereof.

[0060] In other embodiments, the present disclosure provides Compound B or a pharmaceutically acceptable salt thereof: In certain aspects, compound B is or a pharmaceutically acceptable salt thereof. In other aspects, compound B is or a pharmaceutically acceptable salt thereof. In another aspect, compound B is Or a pharmaceutically acceptable salt thereof. In yet other aspects, compound B is or a pharmaceutically acceptable salt thereof. In still another aspect, compound B is or a pharmaceutically acceptable salt thereof.

[0061] In further embodiments, the present disclosure provides Compound C or a pharmaceutically acceptable salt thereof: In certain aspects, compound C is or a pharmaceutically acceptable salt thereof. In other aspects, compound C is or a pharmaceutically acceptable salt thereof. In another aspect, compound C is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound C is or a pharmaceutically acceptable salt thereof. In still another aspect, compound C is or a pharmaceutically acceptable salt thereof. In other aspects, compound C is or a pharmaceutically acceptable salt thereof. In another aspect, compound C is or a pharmaceutically acceptable salt thereof. In other aspects, compound C is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound C is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound C is or a pharmaceutically acceptable salt thereof.

[0062] In yet other embodiments, the present disclosure provides Compound D or a pharmaceutically acceptable salt thereof: In certain aspects, compound D is or a pharmaceutically acceptable salt thereof. In other aspects, compound D is or a pharmaceutically acceptable salt thereof. In another aspect, compound D is Or a pharmaceutically acceptable salt thereof. In yet other aspects, compound D is or a pharmaceutically acceptable salt thereof. In still another aspect, compound D is or a pharmaceutically acceptable salt thereof.

[0063] In other embodiments, the present disclosure provides Compound E or a pharmaceutically acceptable salt thereof: In some aspects, compound E is or a pharmaceutically acceptable salt thereof. In another aspect, compound E is or a pharmaceutically acceptable salt thereof. In other aspects, compound E is or a pharmaceutically acceptable salt thereof. In still another aspect, compound E is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound E is or a pharmaceutically acceptable salt thereof.

[0064] In further embodiments, the present disclosure provides Compound F or a pharmaceutically acceptable salt thereof: In certain aspects, compound F is or a pharmaceutically acceptable salt thereof. In other aspects, compound F is In another aspect, compound F is or a pharmaceutically acceptable salt thereof. In yet other aspects, compound F is or a pharmaceutically acceptable salt thereof. In still another aspect, compound F is or a pharmaceutically acceptable salt thereof.

[0065] In yet other embodiments, the present disclosure provides Compound G or a pharmaceutically acceptable salt thereof: In certain aspects, compound G is or a pharmaceutically acceptable salt thereof. In other aspects, compound G is or a pharmaceutically acceptable salt thereof. In another aspect, compound G is Or a pharmaceutically acceptable salt thereof. In yet other aspects, compound G is or a pharmaceutically acceptable salt thereof. In still another aspect, compound G is or a pharmaceutically acceptable salt thereof.

[0066] In still further embodiments, the disclosure provides compounds that are or a pharmaceutically acceptable salt thereof. In certain aspects, the compound is or a pharmaceutically acceptable salt thereof. In other aspects, the compound is or a pharmaceutically acceptable salt thereof. In another aspect, the compound is or a pharmaceutically acceptable salt thereof. In yet other aspects, the compound is or a pharmaceutically acceptable salt thereof.

[0067] In other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some aspects, Compound H is or a pharmaceutically acceptable salt thereof. In certain aspects, compound H is or a pharmaceutically acceptable salt thereof. In other aspects, compound H is or a pharmaceutically acceptable salt thereof. In another aspect, the compound is or a pharmaceutically acceptable salt thereof. In yet other aspects, compound H is or a pharmaceutically acceptable salt thereof.

[0068] In still other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, compound J is or a pharmaceutically acceptable salt thereof. In other aspects, compound J is or a pharmaceutically acceptable salt thereof. In another aspect, compound J is or a pharmaceutically acceptable salt thereof. In other aspects, compound J is Or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound J is or a pharmaceutically acceptable salt thereof.

[0069] In yet further embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, compound K is or a pharmaceutically acceptable salt thereof. In some aspects, compound K is or a pharmaceutically acceptable salt thereof. In other aspects, compound K is or a pharmaceutically acceptable salt thereof. In another aspect, compound K is or a pharmaceutically acceptable salt thereof. In yet other aspects, compound K is or a pharmaceutically acceptable salt thereof.

[0070] In other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, compound L is or a pharmaceutically acceptable salt thereof. In another aspect, compound L is Or a pharmaceutically acceptable salt thereof. In yet other aspects, compound L is or a pharmaceutically acceptable salt thereof. In still another aspect, compound L is or a pharmaceutically acceptable salt thereof. In other aspects, compound L is or a pharmaceutically acceptable salt thereof.

[0071] In other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, compound M is or a pharmaceutically acceptable salt thereof. In other aspects, compound M is or a pharmaceutically acceptable salt thereof. In another aspect, compound M is Or a pharmaceutically acceptable salt thereof. In yet other aspects, compound M is or a pharmaceutically acceptable salt thereof. In still another aspect, compound M is or a pharmaceutically acceptable salt thereof.

[0072] In still other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, compound N is or a pharmaceutically acceptable salt thereof. In other aspects, compound N is or a pharmaceutically acceptable salt thereof. In another aspect, compound N is or a pharmaceutically acceptable salt thereof. In yet other aspects, compound N is In still further aspects, compound N is or a pharmaceutically acceptable salt thereof.

[0073] In yet further embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, Compound O is or a pharmaceutically acceptable salt thereof. In other aspects, compound O is or a pharmaceutically acceptable salt thereof. In another aspect, compound O is or a pharmaceutically acceptable salt thereof. In yet other aspects, Compound O is or a pharmaceutically acceptable salt thereof. In still another aspect, compound O is or a pharmaceutically acceptable salt thereof.

[0074] In other embodiments, the compound is or a pharmaceutically acceptable salt thereof. In certain aspects, the compound is or a pharmaceutically acceptable salt thereof. In other aspects, compound P is or a pharmaceutically acceptable salt thereof. In another aspect, compound P is or a pharmaceutically acceptable salt thereof. In still other aspects, compound P is or a pharmaceutically acceptable salt thereof. In yet another aspect, compound P is or a pharmaceutically acceptable salt thereof.

[0075] The compounds described herein may be prepared synthetically, i.e., products not found in nature. Alternatively, such compounds may be isolated.

[0076] As used herein, the term "pharmaceutically acceptable salt" includes salts suitable for administration to a subject as defined herein. Pharmaceutically acceptable salts are well known in the art. See, for example, Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (PH Stahl and CG Wermuth, eds.), Wiley-VCH Publishers, 2008. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Pharmaceutical composition

[0077] The present 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 compositions may also contain 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 compositions comprise Compound A or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical compositions contain or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0078] In other embodiments, the present disclosure provides a pharmaceutical composition comprising Compound B or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises In another aspect, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0079] In another embodiment, the present disclosure provides a pharmaceutical composition comprising Compound C or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises Or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition contains one or more of the following: or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0080] In yet other embodiments, the present disclosure provides a pharmaceutical composition comprising Compound D or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises D-5. In other aspects, the pharmaceutical composition contains one or more of the following: or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0081] In another embodiment, the pharmaceutical composition contains Compound E or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises E-4 or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition contains In other aspects, the pharmaceutical composition comprises In still another aspect, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0082] In yet other embodiments, the pharmaceutical composition contains Compound F. In certain aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0083] In still other embodiments, the present disclosure provides a pharmaceutical composition comprising Compound G. In some aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises and or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0084] In other embodiments, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0085] In another embodiment, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0086] In yet another embodiment, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises In some aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0087] In other embodiments, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0089] In still other embodiments, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0090] In yet another embodiment, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0091] In other embodiments, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In certain aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises P-2 or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In still another aspect, the pharmaceutical composition comprises In other aspects, the pharmaceutical composition contains or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises In still other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition comprises or a pharmaceutically acceptable salt thereof.

[0092] When the pharmaceutical composition contains two or more stereoisomers of Compound A, the stereoisomers may be present in equal ratios or in different ratios. In certain embodiments, the composition contains an excess (S, S, 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. In other embodiments, the composition contains an excess (R, S, 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.

[0093] In further embodiments, the composition contains one of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G in excess of the (S, R, S) ratio. In yet other embodiments, the composition contains 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 excess of the (R, R, S) ratio.

[0094] In certain aspects, the pharmaceutical composition contains a higher ratio of In other embodiments, the pharmaceutical composition contains 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 to 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 still further embodiments, the molar ratio of A-2 to A-3 is about 35: about 65.

[0095] In other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of G-4 to G-5 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of G-4 to G-5 is about 40: about 60. In further embodiments, the molar ratio of G-4 to G-5 is about 25: about 75. In yet other embodiments, the molar ratio of G-4 to G-5 is about 30: about 70. In still further embodiments, the molar ratio of G-4 to G-5 is about 35: about 65.

[0096] In other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of F-4 to F-5 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of F-4 to F-5 is about 40: about 60. In further embodiments, the molar ratio of F-4 to F-5 is about 25: about 75. In yet other embodiments, the molar ratio of F-4 to F-5 is about 30: about 70. In still further embodiments, the molar ratio of F-4 to F-5 is about 35: about 65.

[0097] In yet other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of G-9 to G-10 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of G-9 to G-10 is about 40: about 60. In further embodiments, the molar ratio of G-9 to G-10 is about 25: about 75. In yet other embodiments, the molar ratio of G-9 to G-10 is about 30: about 70. In still further embodiments, the molar ratio of G-9 to G-10 is about 35: about 65.

[0098] In other embodiments, the pharmaceutical composition contains a molar ratio of about 25 to about 55: about 45 to about 75 or a pharmaceutically acceptable salt thereof. 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 other embodiments, the molar ratio of C-7 to C-8 is about 40: about 60. In other 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 still other embodiments, the molar ratio of C-7 to C-8 is about 35: about 65.

[0099] In other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of H-2 to H-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of H-2 to H-3 is about 40: about 60. In further embodiments, the molar ratio of H-2 to H-3 is about 25: about 75. In yet other embodiments, the molar ratio of H-2 to H-3 is about 30: about 70. In still further embodiments, the molar ratio of H-2 to H-3 is about 35: about 65.

[0100] In still other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of J-2 to J-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of J-2 to J-3 is about 40: about 60. In further embodiments, the molar ratio of J-2 to J-3 is about 25: about 75. In yet other embodiments, the molar ratio of J-2 to J-3 is about 30: about 70. In still further embodiments, the molar ratio of J-2 to J-3 is about 35: about 65.

[0101] In yet other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of K-2 to K-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of K-2 to K-3 is about 40: about 60. In further embodiments, the molar ratio of K-2 to K-3 is about 25: about 75. In yet other embodiments, the molar ratio of K-2 to K-3 is about 30: about 70. In still further embodiments, the molar ratio of K-2 to K-3 is about 35: about 65.

[0102] In other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. Or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of L2 to L-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of L-2 to L-3 is about 40: about 60. In further embodiments, the molar ratio of L-2 to L-3 is about 25: about 75. In yet other embodiments, the molar ratio of L-2 to L-3 is about 30: about 70. In still further embodiments, the molar ratio of L-2 to L-3 is about 35: about 65.

[0103] In other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of O-2 to O-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of O-2 to O-3 is about 40: about 60. In further embodiments, the molar ratio of O-2 to O-3 is about 25: about 75. In yet other embodiments, the molar ratio of O-2 to O-3 is about 30: about 70. In still further embodiments, the molar ratio of O-2 to O-3 is about 35: about 65.

[0104] In yet other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of P-2 to P-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of P-2 to P-3 is about 40: about 60. In further embodiments, the molar ratio of P-2 to P-3 is about 25: about 75. In yet other embodiments, the molar ratio of P-2 to P-3 is about 30: about 70. In still further embodiments, the molar ratio of P-2 to P-3 is about 35: about 65.

[0105] In still other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. Or a pharmaceutically acceptable salt thereof. In further embodiments, the molar ratio of M-2 to M-3 is about 25 to about 55: about 45 to about 75. In other embodiments, the molar ratio of M-2 to M-3 is about 40: about 60. In further embodiments, the molar ratio of M-2 to M-3 is about 25: about 75. In yet other embodiments, the molar ratio of M-2 to M-3 is about 30: about 70. In still further embodiments, the molar ratio of M-2 to M-3 is about 35: about 65.

[0106] In still other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In another embodiment, the molar ratio of M-5 to M-4 is about 50: about 50.

[0107] In still other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In other embodiments, the molar ratio of N-2 to N-3 is about 25 to about 55: about 45 to about 75. In other embodiments, In some embodiments, the molar ratio of N-2 to N-3 is about 40: about 60. In other embodiments, the molar ratio of N-2 to N-3 is about 25: about 75. In still other embodiments, the molar ratio of N-2 to N-3 is about 30: about 70. In still other embodiments, the molar ratio of N-2 to N-3 is about 35: about 65.

[0108] In still other embodiments, the pharmaceutical composition contains a molar ratio of about 10: about 90, or about 50: about 50, or about 90: about 10. or a pharmaceutically acceptable salt thereof. In another embodiment, the molar ratio of N-5 to N-4 is about 75:about 25.

[0109] In addition to the compounds described herein, the pharmaceutically acceptable composition also contains one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient is selected based on the mode of administration and route. Suitable pharmaceutical carriers and pharmaceutical necessities for use in pharmaceutical formulations are described in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippencott Williams & Wilkins (2005); Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., ed., Pharmaceutical Press (2009); and USP / NF (United States Pharmacopeia and the National Formulary).

[0110] In some embodiments, the pharmaceutically acceptable excipient is one or more of the following: an antioxidant, a binder, a buffer, a colorant, a diluent (e.g., solid or liquid), a disintegrant, a dispersant, a dye, a filler, an emulsifier, a flavoring agent, a lubricant, a pH adjuster, a pigment, a preservative, a stabilizer, a solubilizer, a solvent, a suspending agent, a sweetener, or a wetting agent, or a combination thereof.

[0111] Examples of suitable excipients include, but are not limited to, acacia gum, alginate, calcium phosphate, calcium carbonate, calcium silicate, carbomer gel, carboxymethylcellulose, carnauba wax, cellulose, crospovidone, dextrose, diacetylated monoglycerides, ethylcellulose, gelatin, glyceryl monostearate 40-50, acacia gum, gum arabic, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, lactose, lecithin, magnesium stearate, kaolin, C-methacrylic acid polymer, mannose alcohol, methylcellulose, methyl hydroxybenzoate, microcrystalline cellulose, povidone, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone, propyl hydroxybenzoate, sodium carboxymethylcellulose, sodium hydroxide, sodium stearyl fumarate, sodium starch glycolate, starch, sorbitan monooleate, sorbitol, sorbic acid, sucrose, talc, tragacanth, talc, triethyl citrate, titanium dioxide, yellow iron oxide, talc, oily medium (e.g., peanut oil, liquid paraffin, mineral oil, olive oil, almond oil, glycerin, propylene glycol), or water.

[0112] When the excipient acts as a diluent, the excipient may be a solid, semisolid or liquid material (e.g., saline) that acts as a vehicle, carrier or medium for the active ingredient. As known in the art, the type of diluent may vary depending on the intended route of administration.

[0113] The pharmaceutical composition can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding, or lyophilizing methods. Methods for preparing formulations well known in the art are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippencott Williams & Wilkins (2005); and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and JC Boylan, eds., 1988-1999, Marcel Dekker, New York. Dosage Unit

[0114] The disclosure also provides dosage units containing one or more compounds or pharmaceutical compositions disclosed herein. Those skilled in the art will be able to select dosage forms 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 some aspects, the dosage unit is a solid dosage form. In other aspects, the dosage form is a liquid dosage form.

[0115] The dosage unit can be formulated for delivery that is most useful to the subject. In some embodiments, the dosage unit is for enteral or parenteral administration. Examples of enteral administration include, but are not limited to, oral, rectal, sublingual, or buccal. In certain embodiments, the dosage unit is orally administered.

[0116] In other embodiments, the dosage unit is used for parenteral administration, i.e., parenteral dosage unit. As used herein, the term "parenteral" refers to the route of administration except enteral administration. The example of parenteral administration includes but is not limited to through the cheek, epidermis, extradural, extra-amniotic, intra-arterial, intra-articular, intracardiac, intra-cavernous, intracerebral, intraventricular, intradermal, intralesional, intramuscular, intraocular, intraosseous infusion, intraperitoneal, intrapulmonary, intrathecal, intrauterine, intravaginal, intravenous, intravesical, intravitreal, nasal, perivascular, subcutaneous, sublingual, transdermal, local, epithelial or transmucosal. Parenteral administration can be by continuous infusion in a selected time period. In certain embodiments, the dosage unit is intravenous, intraperitoneal, intramuscular or subcutaneous. In further embodiments, the dosage unit is oral, intravenous, intraperitoneal, intramuscular or subcutaneous. In further embodiments, the dosage unit is orally administered.

[0117] Parenteral dosage units are known in the art, and include but are not limited to injectable solutions, inhalants, infusions, patches and suppositories. In some aspects, the parenteral dosage unit is an injectable solution. In other embodiments, the dosage unit is formulated for oral delivery, i.e., oral dosage units. In some 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, membrane, liquid / solution (e.g., suspension, emulsion), lollipop, lozenge, paste, powder, capsule or syrup. In other aspects, the oral dosage unit is a pill, tablet, capsule, syrup, liquid solution, powder, paste, patch, pump or membrane. In other aspects, the oral dosage unit is a dry product for reconstructing with water or other suitable vehicles before use.

[0118] When 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 (eg, in the stomach) and soluble at higher pH (eg, in the small intestine).

[0119] The dosage form can also be a modified release dosage form. As used herein, the term "modified release" refers to a dosage form containing one or more controlled release excipients. The modified release dosage form can be an immediate release, delayed release, extended release, sustained release, pulsed release, controlled release, extended release, accelerated release, rapid release, targeted release, programmed release, or gastric retention dosage form. Suitable modified release dosage form vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, dosage forms containing water-soluble isolation layer coatings, dosage forms containing enteric coatings, osmotic devices, multi-particle devices, and combinations thereof. These dosage forms can be prepared according to known methods and techniques. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 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 herein by reference in their entirety.

[0120] Regardless of the type of dosage unit, it can 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.

[0121] One skilled 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 be incorporated 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 mg 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 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1750 mg, about 2000 mg, about 2250 mg, about 2500 mg, about 2750 mg, about 3000 mg, about 3500 mg, about 4000 mg, about 4500 mg, about 50 ... 0 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, 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 contains from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 100 mg, from about 0.01 mg to about 50 mg, from about 0.01 mg to about 25 mg, from about 0.01 mg to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.01 mg to about 0.1 mg, from about 0.1 mg to about 1000 mg, from about 0.1 mg to about 750 mg, from about 0.1 mg to about 500 mg, from about 0.1 mg to about 250 mg, from about 0.1 mg to about 1000 mg. g to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 1 mg, about 1 mg to about 1000 mg, about 1 mg to about 750 mg, about 1 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 1000 mg, about 5 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 250 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg to about 25 mg, about 5 mg to about 10 mg, about 10 mg to about 1000 mg, about 10 mg to about 750 mg, about 10 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg, about 25 mg to about 1000 mg, about 25 mg to about 750 mg, about 25 mg to about 500 mg, about 25 mg to about 250 mg, about 25 mg to about 100 mg, about 25 mg to about g to about 50 mg, about 50 mg to about 1000 mg, about 50 mg to about 750 mg, about 50 mg to about 500 mg, about 50 mg to about 250 mg, about 50 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 750 mg, about 100 mg to about 500 mg, about 100 mg to about 250 mg, about 250 mg to about 1000 mg, about 250 mg to about 750 mg, about 250 mg to about 500 mg, about 500 mg to about 1000 mg, about 500 mg to about 750, or about 750 mg to about 100 mg. Treatment

[0122] The compounds, pharmaceutical compositions, and dosage units discussed herein can be used in methods for regulating inflammatory bowel disease markers. In some embodiments, methods for regulating inflammatory bowel disease markers are provided, and the methods include administering one or more compounds disclosed herein to a subject in need thereof. In other embodiments, methods for regulating inflammatory bowel disease markers are provided, and the methods include administering one or more pharmaceutical compositions disclosed herein to a subject in need thereof. In further embodiments, methods for regulating inflammatory bowel disease markers are provided, and the methods include administering one or more dosage forms disclosed herein to a subject in need thereof.

[0123] As used herein, the term "regulation" or its variants refers to observable changes in the level of inflammatory bowel disease markers in a subject as measured using techniques and methods known in the art for measuring inflammatory bowel disease. The inflammatory bowel disease marker level in the subject can be regulated to cause a change of at least about 1% relative to the previous marker level when the compound, pharmaceutical composition or dosage form is applied. In some embodiments, the regulation causes the inflammatory bowel disease marker to change 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 relative to the inflammatory bowel disease marker before the administration of the pharmaceutical composition. In other embodiments, regulation is to increase the level of inflammatory bowel disease markers in the subject. In further embodiments, regulation includes reducing the level of inflammatory bowel disease markers in the subject.

[0124] The term "inflammatory bowel disease marker" as used herein refers to a diagnostic marker that identifies a subject as suffering from inflammatory bowel disease. The marker can be a clinical marker (e.g., symptom), a diagnostic marker (e.g., test / scan), or a biochemical indicator (e.g., a biomarker). The methods provided herein result in a reduction in at least one inflammatory bowel disease marker. In some embodiments, the methods result in a beneficial change (e.g., reduction or increase) in a clinical marker, a diagnostic marker, a biochemical indicator, or a combination thereof.

[0125] In certain embodiments, the inflammatory bowel disease marker is a diagnostic marker. The example of diagnostic marker includes the result obtained from laboratory test (for example, blood test, stool study), endoscopic procedure (for example, colonoscopy, flexible sigmoidoscopy, upper gastrointestinal endoscopy, capsule endoscopy or balloon-assisted enteroscopy) or imaging procedure (for example, X-ray, computed tomography or magnetic resonance imaging). In some aspects, the method causes the positive change of diagnostic marker. In certain embodiments, the method causes laboratory test such as blood test (showing anemia or infection) or stool study (showing blood or organism). For example, the method can cause the reduction or absence of organisms in anemia, infection, fecal blood or feces. In other aspects, the method causes the positive change in endoscopic procedure such as colonoscopy, flexible sigmoidoscopy, upper gastrointestinal endoscopy, capsule endoscopy or balloon-assisted enteroscopy. For example, the method results in a reduction in inflammation, tumors, injuries, polyps, fistulas, or perforated colons, as diagnosed by colonoscopy, flexible sigmoidoscopy, upper gastrointestinal endoscopy, capsule endoscopy, or balloon-assisted enteroscopy. In addition, for example, the method results in a reduction in inflammation, tumors, injuries, polyps, fistulas, or perforated colons, as diagnosed by X-ray, computed tomography, or magnetic resonance imaging. In certain embodiments, the method results in a reduction in inflammation or ulcers in the intestinal lining of the subject, as observed by colonoscopy.

[0126] In other embodiments, the inflammatory bowel disease marker is a clinical marker. Examples of clinical markers of inflammatory bowel disease include, without limitation, ulcers (e.g., intestinal lining), inflammation (e.g., intestinal lining), diarrhea, fatigue, abdominal pain, cramping, blood in the stool, loss of appetite, or unintentional weight loss, or a combination thereof.

[0127] The method can also result in a positive change in a biochemical indicator such as a biomarker. Examples of biomarkers include, but are not limited to, 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 protein B1 (HMGB1, e.g., feces), chitinase 3-like 1 (CHI3 L1, 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 anti-neutrophil cytoplasmic antibodies (pANCA, e.g., serum, such as in subjects with ulcerative colitis), anti-Saccharomyces cerevisiae antibodies (ASCA, e.g., serum, such as in subjects with Crohn's disease), 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 intestinal lining tissue), active regulatory protein 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, clusters of differentiation (such as CD3, CD69, CD80, CD86), C4, sialic acid, C1 activity In some aspects, the biomarker is TNF-α, IL-1β, IL-6, IL-8, IL-23, IL-12, or IL-17A.In other aspects, the biomarker is NF-κB, MCP-1, CCL20 or IFN-γ level or a combination 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 another aspect, the biomarker is SAA or eotaxin-1. In another aspect, the method 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 yet other aspects, the method can be used to reduce NF-κB levels, IL-8 levels, MCP-1 levels, CCL20 levels or IFNγ levels in a subject. In still other aspects, the method can be used to reduce the NF-κB level in the intestinal lining tissue of the subject, the IL-8 level in the intestinal lining tissue, the MCP-1 level in the intestinal lining tissue, the CCL20 level in the intestinal lining tissue, or the IFNγ level in the intestinal lining tissue. In other aspects, the method described herein can be used to reduce the ulcer in the intestinal lining inflammation and / or intestinal lining, as observed by colonoscopy. In other aspects, the method described herein can be used to reduce the NF-κB, MCP-1, CCL20 or IFN-γ level in the subject. In still other aspects, the method described herein can be used to reduce the TNF-α, IL-1β, IL-6, IL-8, IL-23, IL-12 or IL-17A level in the subject. In yet another aspect, the method described herein can be used to reduce the M2-PK pyruvate kinase, osteoprotegerin, MPO, HMGB1, CHI3L1, HBD2, MMP, calprotectin, lactoferrin, pANCA or ASCA level in the subject. In other aspects, the method results in a decrease in 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 other aspects, the method results in a decrease in 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 method results in a decrease in the activity or level of M2-PK, osteoprotegerin, MPO, HMGB1, CHI3L1, HBD2, MMP, calprotectin, lactoferrin, p-ANCA or ASCA or a combination thereof in a subject. In still other aspects, the method results in a decrease in the activity or level of one or both of SAA or eotaxin-1 in a subject.

[0128] Therefore, the compounds disclosed herein can be used to treat inflammatory bowel disease. As used herein, the term "inflammatory bowel disease" or "IBD" refers to a disorder 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 of the intestinal lining. The subject may suffer from inflammatory bowel disease or may be at risk of suffering from inflammatory bowel disease. In some embodiments, the patient suffers from or has been diagnosed with inflammatory bowel disease. In other embodiments, the patient has a risk of suffering from inflammatory bowel disease.

[0129] As used herein, the term "at risk of developing inflammatory bowel disease" refers to a subject having 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 variations that can lead to a diagnosis of inflammatory bowel disease.

[0130] Therefore, the present disclosure provides a method for treating inflammatory bowel disease in a subject in need by administering one or more compounds, pharmaceutical compositions or dosage units to a subject in need. In some embodiments, the method comprises administering one or more compounds disclosed herein to the subject in need. In other embodiments, the method comprises administering one or more pharmaceutical compositions disclosed herein to the subject in need. In further embodiments, the method comprises administering one or more dosage units to the subject in need.

[0131] The method comprises 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 mg / day to about 1000 mg / day. In other embodiments, the therapeutically effective amount is about 0.01 mg / day to about 750 mg / day, about 0.01 mg / day to about 500 mg / day, about 0.01 mg / day to about 250 mg / day, about 0.01 mg / day to about 100 mg / day, about 0.01 mg / day to about 50 mg / day, about 0.01 mg / day to about 25 mg / day, about 0.01 mg / day to about 10 mg / day, about 0.01 mg / day to about 5 mg / day, about 0.01 mg / day to about 10 mg / day, about 0.01 mg / day to about 5 mg / day, about 0.01 mg / day to about 15 mg / day, about 0.01 mg / day to about 20 mg / day, about 0.01 mg / day to about 10 mg / day, about 0.01 mg / day to about 2 ... day to about 0.1 mg / day, about 0.1 mg / day to about 1000 mg / day, about 0.1 mg / day to about 750 mg / day, about 0.1 mg / day to about 500 mg / day, about 0.1 mg / day to about 250 mg / day, about 0.1 mg / day to about 100 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.1 mg / day to about 5 mg / day, about 0.1 mg / day to about 1 mg / day, about 1 mg / day to about 1000 mg / day, about 1 mg / day to about 750 mg / day, about 1 mg / day to about 500 mg / day, about 1 mg / day to about 250 mg / day, about 1 mg / day to about 100 mg / day, about 1 mg / day to about 50 mg / day, about 1 mg / day to about 25 mg / day, about 1 mg / day to about 10 mg / day, about 1 mg / day to about 5 mg / day, about 5 mg / day to about 1000 mg / day, about 5 mg / day to about 750 mg / day, about 5 mg / day about 500 mg / day, about 5 mg / day to about 250 mg / day, about 5 mg / day to about 100 mg / day, about 5 mg / day to about 50 mg / day, about 5 mg / day to about 25 mg / day, about 5 mg / day to about 10 mg / day, about 10 mg / day to about 1000 mg / day, about 10 mg / day to about 750 mg / day, about 10 mg / day to about 500 mg / day, about 10 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 50 mg / day, about 10 mg / day to about 25 mg / day, about 25 mg / day to about 1000 mg / day, about 25 mg / day to about 750 mg / day, about 25 mg / day to about 500 mg / day, about 25 mg / day to about 250 mg / day, about 25 mg / day to about 100 mg / day, about 25 mg / day to about 50 mg / day, about 50 mg / day to about 1000 mg / day, about 50 mg / day to about 750 mg / day, about 50 mg / day to about 500 mg / day, about 50 mg / day to about 250 mg / day, about 50 mg / day to about About 100 mg / day, about 100 mg / day to about 1000 mg / day, about 100 mg / day to about 750 mg / day, about 100 mg / day to about 500 mg / day, about 100 mg / day to about 250 mg / day, about 250 mg / day to about 1000 mg / day, about 250 mg / day to about 750 mg / day, about 250 mg / day to about 500 mg / day, about 500 mg / day to about 1000 mg / day, about 500 mg / day to about 750 mg / day, or about 750 mg / day to about 100 mg / day.

[0132] 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) with an additional agent known to be therapeutically useful. In some embodiments, the additional agent can be used to treat inflammatory bowel disease. In other embodiments, the additional agent is an anti-inflammatory drug, an immune system suppressant, a biological agent, an antibiotic, an antidiarrheal drug, an analgesic, or a supplement. Examples of anti-inflammatory drugs include, but are not limited to, corticosteroids and / or aminosalicylate (e.g., mesalamine, balsalazide, or olsalazine). Examples of immune system suppressants include, but are not limited to, azathioprine, mercaptopurine, and methotrexate. Examples of biological agents include, but are not limited to, infliximab, adalimumab, golimumab, certolizumab pegol, vedolizumab, and eutecticumab. Examples of antibiotics include, but are not limited to, ciprofloxacin and metronidazole. Examples of antidiarrheal drugs include fiber supplements (eg, psyllium powder or methylcellulose) or loperamide. An example of an analgesic is acetaminophen.

[0133] 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 mg / day to about 1000 mg / day. In other embodiments, the therapeutically effective amount is about 0.01 mg / day to about 750 mg / day, about 0.01 mg / day to about 500 mg / day, about 0.01 mg / day to about 250 mg / day, about 0.01 mg / day to about 100 mg / day, about 0.01 mg / day to about 50 mg / day, about 0.01 mg / day to about 25 mg / day, about 0.01 mg / day to about 10 mg / day, about 0.01 mg / day to about 5 mg / day, about 0.01 mg / day to about day to about 0.1 mg / day, about 0.1 mg / day to about 1000 mg / day, about 0.1 mg / day to about 750 mg / day, about 0.1 mg / day to about 500 mg / day, about 0.1 mg / day to about 250 mg / day, about 0.1 mg / day to about 100 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.1 mg / day to about 5 mg / day, about 0.1 mg / day to about 1 mg / day, about 1 mg / day to about 1000 mg / day, about 1 mg / day to about 750 mg / day, about 1 mg / day to about 500 mg / day, about 1 mg / day to about 250 mg / day, about 1 mg / day to about 100 mg / day, about 1 mg / day to about 50 mg / day, about 1 mg / day to about 25 mg / day, about 1 mg / day to about 10 mg / day, about 1 mg / day to about 5 mg / day, about 5 mg / day to about 1000 mg / day, about 5 mg / day to about 750 mg / day, about 5 mg / day about 500 mg / day, about 5 mg / day to about 250 mg / day, about 5 mg / day to about 100 mg / day, about 5 mg / day to about 50 mg / day, about 5 mg / day to about 25 mg / day, about 5 mg / day to about 10 mg / day, about 10 mg / day to about 1000 mg / day, about 10 mg / day to about 750 mg / day, about 10 mg / day to about 500 mg / day, about 10 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 50 mg / day, about 10 mg / day to about 25 mg / day, about 25 mg / day to about 1000 mg / day, about 25 mg / day to about 750 mg / day, about 25 mg / day to about 500 mg / day, about 25 mg / day to about 250 mg / day, about 25 mg / day to about 100 mg / day, about 25 mg / day to about 50 mg / day, about 50 mg / day to about 1000 mg / day, about 50 mg / day to about 750 mg / day, about 50 mg / day to about 500 mg / day, about 50 mg / day to about 250 mg / day, about 50 mg / day to about About 100 mg / day, about 100 mg / day to about 1000 mg / day, about 100 mg / day to about 750 mg / day, about 100 mg / day to about 500 mg / day, about 100 mg / day to about 250 mg / day, about 250 mg / day to about 1000 mg / day, about 250 mg / day to about 750 mg / day, about 250 mg / day to about 500 mg / day, about 500 mg / day to about 1000 mg / day, about 500 mg / day to about 750 mg / day, or about 750 mg / day to about 100 mg / day.

[0134] The methods described herein may also 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) with additional agents known to be therapeutically useful. In some embodiments, the additional agent may be used to treat inflammatory bowel disease. In other embodiments, the additional agent is an anti-inflammatory drug, an immune system suppressant, a biological agent, an antibiotic, an antidiarrheal drug, an analgesic, or a supplement. Examples of anti-inflammatory drugs include, but are not limited to, corticosteroids and / or aminosalicylate (e.g., mesalamine, balsalazide, or olsalazine). Examples of immune system suppressants include, but are not limited to, azathioprine, mercaptopurine, and methotrexate. Examples of biological agents include, but are not limited to, infliximab, adalimumab, golimumab, certolizumab pegol, vedolizumab, and eutecticumab. Examples of antibiotics include, but are not limited to, ciprofloxacin and metronidazole. Examples of antidiarrheal drugs include fiber supplements (eg, psyllium powder or methylcellulose) or loperamide. An example of an analgesic is acetaminophen.

[0135] In certain embodiments, the additional agent may be a therapy, i.e., a non-pharmacological therapy. For example, the subject may require nutritional support, i.e., a special diet, or enteral (e.g., feeding tube) or parenteral (e.g., nutrient injection) administration of food. Aspect A Aspect A1. A compound, which is Compound A or Compound G: or a pharmaceutically acceptable salt thereof. Aspect A2. The compound according to Aspect A1, which is Compound A or a pharmaceutically acceptable salt thereof. Aspect A3. A compound according to Aspect A1 or A2, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect A4. A compound according to any one of Aspects A1 to A3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect A5. A compound according to any one of Aspects A1 to A3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect A6. A compound according to any one of Aspects A1 to A3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect A7. A compound according to any one of Aspects A1 to A3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect A8. The compound according to Aspect A1, which is Compound G or a pharmaceutically acceptable salt thereof. Aspect A9. A compound according to Aspect A1 or A38, which is a compound or a pharmaceutically acceptable salt thereof. Aspect A10. A compound according to any one of Aspects A1, A8 or A9, which is or a pharmaceutically acceptable salt thereof. Aspect A11. A compound according to any one of Aspects A1, A8 or A9, which is or a pharmaceutically acceptable salt thereof. Aspect A12. A compound according to any one of Aspects A1, A8 or A9, which is or a pharmaceutically acceptable salt thereof. Aspect A13. A compound according to any one of Aspects A1, A8 or A9, which is or a pharmaceutically acceptable salt thereof. Aspect A14. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any of Aspects A1 to A13 and a pharmaceutically acceptable excipient. Aspect A15. The pharmaceutical composition according to Aspect A14, comprising: Aspect A16. The pharmaceutical composition according to Aspect A15, wherein The molar ratio is about 40 to about 60. Aspect A17. The pharmaceutical composition according to Aspect A44, comprising Aspect A18. The pharmaceutical composition according to Aspect A48, wherein The molar ratio is about 40 to about 60. Aspect A19. A dosage unit comprising a compound according to any of Aspects A1 to A13 or a pharmaceutical composition according to any 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, liquid solution, powder, paste, or film, or a parenteral dosage unit, such as an injection solution. Aspect A21. The dosage unit according to Aspect A19 or A20, comprising from about 0.01 mg to about 1000 mg of the compound. Aspect A22. The dosage unit according to any of Aspects A19-A21, which is a solid dosage form. Aspect A23. The dosage unit according to any of Aspects A19-A21, which is a liquid dosage form. Aspect A24. The method according to any of Aspects A24 to A26, wherein the composition is administered orally, intravenously, intraperitoneally, intramuscularly or subcutaneously. Aspect A25. The method according to Aspect A27, wherein the composition is administered orally. Aspect A26. The method according to any of Aspects A24 to A28, wherein bradykinesia frequency, bradykinesia intensity, resting tremor, muscle rigidity, or a combination thereof is reduced in the subject. Aspect A27. The method according to any of Aspects A24 to A29, wherein after administration of said pharmaceutical composition or said dosage unit, the subject's score on the MDS-UPDRS scale is improved. Aspect B Aspect B1. A compound, which is Compound A or Compound G: or a pharmaceutically acceptable salt thereof. Aspect B2. The compound according to Aspect B1, which is Compound A or a pharmaceutically acceptable salt thereof. Aspect B3. A compound according to aspect B1 or B2, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect B4. A compound according to any one of Aspects B1 to B3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect B5. A compound according to any one of Aspects B1 to B3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect B6. A compound according to any one of Aspects B1 to B3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect B7. A compound according to any one of Aspects B1 to B3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect B8. The compound according to Aspect B1, which is Compound G or a pharmaceutically acceptable salt thereof. Aspect B9. A compound according to aspect B1 or B8, which is or a pharmaceutically acceptable salt thereof. Aspect B10. A compound according to any one of Aspects B1, B8 or B9, which is or a pharmaceutically acceptable salt thereof. Aspect B11. A compound according to any one of Aspects B1, B8 or B9, which is or a pharmaceutically acceptable salt thereof. Aspect B12. A compound according to any one of Aspects B1, B8 or B9, which is or a pharmaceutically acceptable salt thereof. Aspect B13. A compound according to any one of Aspects B1, B8 or B9, which is or a pharmaceutically acceptable salt thereof. Aspect B14. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to any of Aspects B1 to B13 and a pharmaceutically acceptable excipient. Aspect B15. The pharmaceutical composition according to Aspect B14, comprising: Aspect B16. The pharmaceutical composition according to Aspect B15, wherein The molar ratio is about 40 to about 60. Aspect B17. The pharmaceutical composition according to Aspect B14, comprising Aspect B18. The pharmaceutical composition according to Aspect B14, comprising Aspect B19. The pharmaceutical composition according to Aspect B18, wherein The molar ratio is about 40 to about 60. Aspect B20. A dosage unit comprising a compound according to any of Aspects B1 to B13 or a pharmaceutical composition according to any of Aspects B14 to B19. Aspect B21. The dosage unit according to Aspect B20, which is an oral dosage unit, such as a pill, tablet, capsule, syrup, liquid solution, powder, paste, or film, or a parenteral dosage unit, such as an injection solution. Aspect B22. The dosage unit according to Aspect B20 or B21, comprising from about 0.01 mg to about 1000 mg of the compound. Aspect B23. The dosage unit according to any of Aspects B20-B22, which is a solid dosage form. Aspect B24. The dosage unit according to any of Aspects B20-B22, which is a liquid dosage form. Aspect B25. A method of modulating inflammatory bowel disease (IBD) markers in a subject in need thereof, the method comprising administering to the subject in need thereof a compound as described in any of Aspects B1-B13, a pharmaceutical composition as described in any of Aspects B14-B19, or a dosage form as described in any of Aspects B20-B24. Aspect B26. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, the method comprising administering to the subject in need thereof a compound as described in any of Aspects B1-B13, a pharmaceutical composition as described in any of Aspects B14-B19, or a dosage form as described in any of Aspects B20-B24. Aspect B27. The method of Aspect B25 or B26, wherein the subject suffers from or is at risk of developing IBD. Aspect B28. The method according to any of Aspects B25 to 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 of Aspects B25 to B29, wherein the IBD is ulcerative colitis. Aspect B31. The method according to any of Aspects B25 to 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 are reduced as observed by colonoscopy. Aspect B33. A method as described in any of Aspects B25-B32, wherein the level of tumor necrosis factor α (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. A method as described in any of Aspects B25 to B33, wherein the level of nuclear factor κB (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. A method as described in any of Aspects B25-B34, wherein the level of M2 pyruvate kinase (M2-PK), osteoprotegerin, myeloperoxidase (MPO), high mobility group protein 1 (HMGB1), chitinase 3-like 1 (CHI3L1), human beta defensin 2 (HBD2), metalloproteinases (MMPs), calprotectin, lactoferrin, peripheral anti-neutrophil cytoplasmic antibodies (p-ANCA) or anti-Saccharomyces cerevisiae antibodies (ASCA) or a combination thereof is reduced in the subject. Aspect B36. The method of any one of Aspects B25 to B35, wherein one or both serum amyloid A protein (SAA) or eotaxin-1 levels are reduced in the subject. Aspect C Aspect C1. A compound, said compound being Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G: or a pharmaceutically acceptable salt thereof. Aspect C2. The compound according to Aspect C1, which is Compound A or a pharmaceutically acceptable salt thereof. Aspect C3. A compound according to Aspect C1 or C2, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C4. A compound according to any one of Aspects C1 to C3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C5. A compound according to any one of Aspects C1 to C3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C6. A compound according to any one of Aspects C1 to C3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C7. A compound according to any one of Aspects C1 to C3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C8. The compound according to Aspect C1, which is Compound B or a pharmaceutically acceptable salt thereof. Aspect C9. A compound according to aspect C8, wherein the compound is B-1 or a pharmaceutically acceptable salt thereof. Aspect C10. A compound according to any one of Aspects C1, C8 or C9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C11. A compound according to any one of Aspects C1, C8 or C9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C12. A compound according to any one of Aspects C1, C8 or C9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C13. A compound according to any one of Aspects C1, C8 or C9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect C14. The compound according to Aspect C1, which is Compound C or a pharmaceutically acceptable salt thereof. Aspect C15. The compound according to Aspect C1 or C14, wherein the compound is: or a pharmaceutically acceptable salt thereof. Aspect C16. A compound according to any one of Aspects C1, C14 or C15, which is or a pharmaceutically acceptable salt thereof. Aspect C17. A compound according to any one of Aspects C1, C14 or C15, which is: or a pharmaceutically acceptable salt thereof. Aspect C18. A compound according to any one of Aspects C1, C14 or C15, which is: or a pharmaceutically acceptable salt thereof. Aspect C19. A compound according to any one of Aspects C1, C14 or C15, which is: or a pharmaceutically acceptable salt thereof. Aspect C20. The compound according to Aspect C1, which is Compound D or a pharmaceutically acceptable salt thereof. Aspect C21. A compound according to aspect C1 or C20, which is or a pharmaceutically acceptable salt thereof. Aspect C22. A compound according to any one of Aspects C1, C20 or C21, which is: or a pharmaceutically acceptable salt thereof. Aspect C23. A compound according to any one of Aspects C1, C20 or C21, which is: or a pharmaceutically acceptable salt thereof. Aspect C24. A compound according to any one of Aspects C1, C20 or C21, which is: or a pharmaceutically acceptable salt thereof. Aspect C25. A compound according to any one of Aspects C1, C20 or C21, which is: or a pharmaceutically acceptable salt thereof. Aspect C26. The compound according to Aspect C1, which is Compound E or a pharmaceutically acceptable salt thereof. Aspect C27. A compound according to aspect C1 or C26, which is or a pharmaceutically acceptable salt thereof. Aspect C28. A compound according to any one of Aspects C1, C26 or C27, which is or a pharmaceutically acceptable salt thereof. Aspect C29. A compound according to any one of Aspects C1, C26 or C27, which is or a pharmaceutically acceptable salt thereof. Aspect C30. A compound according to any one of Aspects C1, C26 or C27, which is or a pharmaceutically acceptable salt thereof. Aspect C31. A compound according to any one of Aspects C1, C26 or C27, which is or a pharmaceutically acceptable salt thereof. Aspect C32. The compound according to Aspect C1, which is Compound F or a pharmaceutically acceptable salt thereof. Aspect C33. A compound according to aspect C1 or C32, which is or a pharmaceutically acceptable salt thereof. Aspect C34. A compound according to any one of Aspects C1, C32 or C33, which is or a pharmaceutically acceptable salt thereof. Aspect C35. A compound according to any one of Aspects C1, C32 or C33, which is or a pharmaceutically acceptable salt thereof. Aspect C36. A compound according to any one of Aspects C1, C32 or C33, which is or a pharmaceutically acceptable salt thereof. Aspect C37. A compound according to any one of Aspects C1, C32 or C33, which is or a pharmaceutically acceptable salt thereof. Aspect C38. The compound according to Aspect C1, which is Compound G or a pharmaceutically acceptable salt thereof. Aspect C39. A compound according to aspect C1 or C38, which is or a pharmaceutically acceptable salt thereof. Aspect C40. A compound according to any one of Aspects C1, C38 or C39, which is or a pharmaceutically acceptable salt thereof. Aspect C41. A compound according to any one of Aspects C1, C38 or C39, which is or a pharmaceutically acceptable salt thereof. Aspect C42. A compound according to any one of Aspects C1, C38 or C39, which is or a pharmaceutically acceptable salt thereof. Aspect C43. A compound according to any one of Aspects C1, C38 or C39, which is or a pharmaceutically acceptable salt thereof. Aspect C44. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any of Aspects C1 to C43 and a pharmaceutically acceptable excipient. Aspect C45. The pharmaceutical composition according to Aspect C44, comprising: Aspect C46. The pharmaceutical composition according to Aspect C45, wherein The molar ratio is about 40 to about 60. Aspect C47. The pharmaceutical composition according to Aspect C44, comprising Aspect C48. The pharmaceutical composition according to Aspect C44, comprising Aspect C49. The pharmaceutical composition according to Aspect C48, wherein The molar ratio is about 40 to about 60. Aspect C50. A dosage unit comprising a compound according to any of Aspects C1 to C43 or a pharmaceutical composition according to any 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, liquid solution, powder, paste, or film, or a parenteral dosage unit, such as an injection solution. Aspect C52. The dosage unit according to Aspect C50 or C51, comprising from about 0.01 mg to about 1000 mg of the compound. Aspect C53. The dosage unit according to any of Aspects C50 to C52, which is a solid dosage form. Aspect C54. The dosage unit according to any of Aspects C50 to C52, which is a liquid dosage form. Aspect C55. The method according to any of Aspects C55 to 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 according to any of Aspects C55 to C59, wherein bradykinesia frequency, bradykinesia intensity, resting tremor, muscle rigidity, or a combination thereof is reduced in the subject. Aspect C58. The method according to any of Aspects C55 to C60, wherein after administration of said pharmaceutical composition or said dosage unit, the subject's score on the MDS-UPDRS scale is improved. Aspect D Aspect D1. A compound, said compound being Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G: or a pharmaceutically acceptable salt thereof. Aspect D2. The compound according to Aspect D1, which is Compound A or a pharmaceutically acceptable salt thereof. Aspect D3. A compound according to aspect D1 or D2, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D4. A compound according to any one of Aspects D1 to D3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D5. A compound according to any one of Aspects D1 to D3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D6. A compound according to any one of Aspects D1 to D3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D7. A compound according to any one of Aspects D1-D3, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D8. The compound according to Aspect D1, which is Compound B or a pharmaceutically acceptable salt thereof. Aspect D9. A compound according to aspect D8, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D10. A compound according to any one of Aspects D1, D8 or D9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D11. A compound according to any one of aspects D1, D8 or D9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D12. A compound according to any one of aspects D1, D8 or D9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D13. A compound according to any one of aspects D1, D8 or D9, wherein the compound is or a pharmaceutically acceptable salt thereof. Aspect D14. The compound according to Aspect 1, which is Compound C or a pharmaceutically acceptable salt thereof. Aspect D15. The compound according to Aspect D1 or D14, wherein the compound is: or a pharmaceutically acceptable salt thereof. Aspect D16. A compound according to any one of Aspects D1, D14 or D15, which is or a pharmaceutically acceptable salt thereof. Aspect D17. A compound according to any one of Aspects D1, D14 or D15, which is: or a pharmaceutically acceptable salt thereof. Aspect D18. A compound according to any one of Aspects D1, D14 or D15, which is: or a pharmaceutically acceptable salt thereof. Aspect D19. A compound according to any one of Aspects D1, D14 or D15, which is: or a pharmaceutically acceptable salt thereof. Aspect D20. The compound according to Aspect D1, which is Compound D or a pharmaceutically acceptable salt thereof. Aspect D21. A compound according to aspect D1 or D20, which is or a pharmaceutically acceptable salt thereof. Aspect D22. A compound according to any one of Aspects D1, D20 or D21, which is: or a pharmaceutically acceptable salt thereof. Aspect D23. A compound according to any one of Aspects D1, D20 or D21, which is: or a pharmaceutically acceptable salt thereof. Aspect D24. A compound according to any one of Aspects D1, D20 or D21, which is: or a pharmaceutically acceptable salt thereof. Aspect D25. A compound according to any one of Aspects D1, D20 or D21, which is: or a pharmaceutically acceptable salt thereof. Aspect D26. The compound according to Aspect D1, which is Compound E or a pharmaceutically acceptable salt thereof. Aspect D27. A compound according to aspect D1 or D26, which is or a pharmaceutically acceptable salt thereof. Aspect D28. A compound according to any one of aspects D1, D26 or D27, which is or a pharmaceutically acceptable salt thereof. Aspect D29. A compound according to any one of aspects D1, D26 or D27, which is or a pharmaceutically acceptable salt thereof. Aspect D30. A compound according to any one of aspects D1, D26 or D27, which is or a pharmaceutically acceptable salt thereof. Aspect D31. A compound according to any one of aspects D1, D26 or D27, which is or a pharmaceutically acceptable salt thereof. Aspect D32. The compound according to Aspect D1, which is Compound F or a pharmaceutically acceptable salt thereof. Aspect D33. A compound according to aspect D1 or D32, which is or a pharmaceutically acceptable salt thereof. Aspect D34. A compound according to any one of aspects D1, D32 or D33, which is or a pharmaceutically acceptable salt thereof. Aspect D35. A compound according to any one of aspects D1, D32 or D33, which is or a pharmaceutically acceptable salt thereof. Aspect D36. A compound according to any one of aspects D1, D32 or D33, which is or a pharmaceutically acceptable salt thereof. Aspect D37. A compound according to any one of aspects D1, D32 or D33, which is or a pharmaceutically acceptable salt thereof. Aspect D38. The compound according to Aspect D1, which is Compound G or a pharmaceutically acceptable salt thereof. Aspect D39. A compound according to aspect D1 or D38, which is or a pharmaceutically acceptable salt thereof. Aspect D40. A compound according to any one of aspects D1, D38 or D39, which is or a pharmaceutically acceptable salt thereof. Aspect D41. A compound according to any one of aspects D1, D38 or D39, which is or a pharmaceutically acceptable salt thereof. Aspect D42. A compound according to any one of aspects D1, D38 or D39, which is or a pharmaceutically acceptable salt thereof. Aspect D43. A compound according to any one of aspects D1, D38 or D39, which is or a pharmaceutically acceptable salt thereof. Aspect D44. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any of Aspects D1 to D43 and a pharmaceutically acceptable excipient. Aspect D45. The pharmaceutical composition according to Aspect D44, comprising: Aspect D46. The pharmaceutical composition according to Aspect D45, wherein The molar ratio is about 40 to about 60. Aspect D47. A pharmaceutical composition according to aspect D44, comprising Aspect D48. The pharmaceutical composition according to aspect D44, comprising Aspect D49. The pharmaceutical composition according to Aspect D48, wherein The molar ratio is about 40 to about 60. Aspect D50. A dosage unit comprising a compound according to any of aspects D1 to D43 or a pharmaceutical composition according to any 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, liquid solution, powder, paste, or film, or a parenteral dosage unit, such as an injection solution. Aspect D52. The dosage unit according to aspect D50 or D51, comprising from about 0.01 mg to about 1000 mg of the compound. Aspect D53. The dosage unit according to any of Aspects D50-D52, which is a solid dosage form. Aspect D54. The dosage unit according to any of Aspects D50 to D52, which is a liquid dosage form. Aspect D55. A method of modulating inflammatory bowel disease (IBD) markers in a subject in need thereof, the method comprising administering to the subject in need thereof a compound as described in any of Aspects D1-D43, a pharmaceutical composition as described in any of Aspects D44-D49, or a dosage form as described in any of Aspects D50-D54. Aspect D56. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, the method comprising administering to the subject in need thereof a compound as described in any of Aspects D1-D43, a pharmaceutical composition as described in any of Aspects D44-D49, or a dosage form as described in any of Aspects D50-D54. Aspect D57. The method of aspect D55 or D56, wherein the subject suffers from or is at risk of developing IBD. Aspect D58. The method according to any of Aspects D55 to 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. Aspect D60. The method according to any of aspects D55 to D59, wherein the IBD is ulcerative colitis. Aspect D61. The method of any one of aspects D55 to D59, wherein the IBD is Crohn's disease. Aspect D62. The method of any one of aspects D55 to D61, wherein inflammation or ulcers in the intestinal lining of the subject are reduced as observed by colonoscopy. Aspect D63. A method as described in any of Aspects D55 to 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. Aspect D64. The method of any one of Aspects D55 to D63, wherein the level of nuclear factor κB (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. A method as described in any of Aspects D55-D64, wherein the level of M2 pyruvate kinase (M2-PK), osteoprotegerin, myeloperoxidase (MPO), high mobility group protein 1 (HMGB1), chitinase 3-like 1 (CHI3L1), human beta defensin 2 (HBD2), metalloproteinases (MMPs), calprotectin, lactoferrin, peripheral anti-neutrophil cytoplasmic antibodies (p-ANCA) or anti-Saccharomyces cerevisiae antibodies (ASCA) or a combination thereof is reduced in the subject. Aspect D66. The method of any one of aspects D55 to D65, wherein one or both serum amyloid A protein (SAA) or eotaxin-1 levels are reduced in the subject.

[0136] The following examples are provided to illustrate some of the concepts described within this disclosure. Although each example is considered to provide a specific individual embodiment of composition, method of preparation, and use, none of these examples should be considered to limit the more general embodiments described herein. Examples

[0137] 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

[0138] Synthesis of 2.2: A mixture of (2S)-2-amino-3-sulfanyl-propionic acid methyl ester (2.1, 30 g, 174.78 mmol, 1 equivalent, HCl) in acetone (600 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 60 ° C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove acetone. The residue was diluted with ethyl acetate (200 mL), washed with water, 5% sodium bicarbonate aqueous solution (3 x 200 mL) and brine (100 mL) in sequence, and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=0 / 1 to 3 / 1) to obtain 22.3 g of 2.2 (72%) as a colorless oil. (ES, m / z): [M+1] + 176.1.

[0139] Synthesis of 2.3: Me2SO4 (11.9 g, 94.2 mmol, 8.93 mL, 1.5 eq.) was added dropwise to a solution of (4S)-2,2-dimethylthiazolidine-4-carboxylic acid methyl ester (2.2, 11 g, 62.8 mmol, 1 eq.) and K2CO3 (13 g, 94.2 mmol, 1.5 eq.) in DMF (50 mL) at 0 °C with stirring. The mixture was stirred at 15 °C for 12 hours. The reaction mixture was quenched by adding 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 ( 40g Purification on silica flash column, eluent: 0% to 5% ethyl acetate / petroleum ether gradient @ 60 mL / min) afforded 6 g of 2.3 (50%) as a colorless oil. (ES, m / z): [M+1] + 190.1.

[0140] Synthesis of 2.4: A mixture of (4S)-2,2,3-trimethylthiazolidine-4-carboxylic acid methyl ester (2.3, 4 g, 21.13 mmol, 1 eq.) in HCl (6 M, 80 mL, 22.71 eq.) was degassed and purged with Ar 3 times, and then the mixture was stirred at 100 ° C. under Ar atmosphere for 8 hours. 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.

[0141] Synthesis of 2.6: To a solution of 2-hydroxybenzonitrile (2.5, 10 g, 83.95 mmol, 1 eq.) in MeOH (150 mL) and phosphate buffer (150 mL) was added (2R)-2-amino-3-sulfanyl-propionic acid (26.46 g, 167.90 mmol, 2 eq., HCl) at room temperature. The solution was adjusted to pH=6.4 by careful addition of solid K2CO3, and the reaction mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by adding solid citric acid. After extraction with dichloromethane (30 mL x 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.

[0142] 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 eq.), N-methoxymethylamine (7.76 g, 79.58 mmol, 1.1 eq., HCl) and DECP (12.98 g, 79.58 mmol, 1.57 mL, 12.02 eq.) in DMF (170 mL) was added DIPEA (14.02 g, 108.52 mmol, 18.9 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The reaction mixture was diluted with water (45 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with NaHCO (30 mL x 3), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO, petroleum ether: ethyl acetate, from 1:0 to 19:1) to give 2.7 (12.95 g, 96.48% yield) as a light yellow solid. (ES, m / z): [M+1] + 267.1.

[0143] Synthesis of 2.8: LAH (2.57 g, 67.59 mmol, 1.5 equivalents) was added 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 equivalent) in THF (240 mL) at -40 ° C under N2. The temperature was raised to -30 ° C in 0.5 hours. The reaction mixture was then hydrolyzed by continuous addition of saturated NH4Cl aqueous solution (200 mL) and 1M KHSO4 solution (200 mL). 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 and filtered, and then evaporated under reduced pressure to obtain 2.8 (9.34 g, crude product) as a yellow solid. The crude product was used in the next step without further purification. (ES,m / z):[M+1] + 208.0.

[0144] Synthesis of A-2 to A-5: To a solution of (R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (2.8, 9.34 g, 45.07 mmol, 1 eq.) in a mixture of EtOH (300 mL) and H2O (100 mL) at 20°C, (2S)-2-(methylamino)-3-sulfanyl-propionic acid (2.4, 9.28 g, 54.08 mmol, 1.2 eq., HCl) and KOAc (30.96 g, 315.47 mmol, 7 eq.) were added. The suspension was gently stirred at 20°C in the dark for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and then the solution was extracted with ethyl acetate (100 mL x 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*100mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-35%, 20 minutes) to obtain A-2 to A-5 (6.15 g, 42.06% yield) as a pale yellow solid, i.e., a mixture of four stereoisomers. (ES, m / z): [M+1] + 325.1.

[0145] Example 2: Purification of the following 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)

[0146] Two grams of the compounds of Example 1 (A-2 to A-5) (a mixture of 4 peaks) were separated and purified twice by SFC to obtain 290 mg of A-2 (14.5% yield, de value of 87.56%, peak 1), 80 mg of A-5 (4% ​​yield, de value of 94.2%, peak 2), 120 mg of A-4 (6% yield, de value of 96.22%, peak 3) and 480 mg of A-3 (24% yield, de value of 98.38%, peak 4) as light yellow solids. (ES, m / z): [M+1] + 325.1.

[0147] Method 1: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); gradient: B%=30% isocratic elution mode; flow rate: 57g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0148] Method 2: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); gradient: B%=46% isocratic elution mode; flow rate: 75g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0149] A-2: 1HNMR (400 MHz, acetone-d6) δ = 7.46-7.37 (m, 2H), 6.99-6.90 (m, 2H), 5.00 (q, J = 8.3 Hz, 1H), 4.54 (d, J = 8.5 Hz, 1H), 4.20 (t, J = 6.6 Hz, 1H), 3.67 (dd, J = 8.7, 11.3 Hz, 1H), 3.57-3.39 (m, 1H), 3.29-3.16 (m, 2H), 2.49 (s, 3H).

[0150] A-3: 1 HNMR (400MHz, acetone-d6) 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).

[0151] A-5: 1 HNMR (400 MHz, acetone-d6) δ = 7.47-7.36 (m, 2H), 7.00-6.87 (m, 2H), 4.85 (brd, J = 8.2 Hz, 1H), 4.34 (d, J = 8.2 Hz, 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, 10.8 Hz, 1H), 2.63 (s, 3H).

[0152] A-4: 1 HNMR (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). Example 3: Preparation of the following 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)

[0153] Synthesis of 11.2. To a solution of 2-hydroxy-4-methylbenzonitrile (11.1, 3 g, 22.53 mmol, 1 equivalent) in MeOH (30 mL) and phosphate buffer (150 mL) was added (2R)-2-amino-3-sulfanyl-propionic acid (5.46 g, 45.06 mmol, 2 equivalents) and phosphate buffer (30 mL). The solution was adjusted to pH=6.4 by careful addition of solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by adding solid citric acid. After extraction with dichloromethane (3 x 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 of 100.0%) as a yellow solid. (ES,m / z):[M+1] + 238.0.

[0154] 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 eq.), N-methoxymethylamine (849.54 mg, 13.91 mmol, 1.1 eq., HCl) and DECP (2.39 g, 13.91 mmol, 2.21 mL, 95% purity, 1.1 eq.) in DMF (5 mL) was added DIEA (2.45 g, 18.97 mmol, 3.30 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with NaHCO3 aqueous solution and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The organic phase was washed with NaHCO3 aqueous solution, then washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue and filter cake were purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate from 1:0 to 1:1) to give 2.05 g of 11.3 (57.84%, %ee value of 84.94%) as a light yellow solid. (ES, m / z): [M+1] + 281.1.

[0155] Synthesis of 11.4. At -40 ° C under N2, LAH (365.54 mg, 9.63 mmol, 1.5 equivalents) was added 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 equivalent) in THF (15 mL). The temperature was raised to -30 ° C in 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (30 mL) and 1M KHSO4 solution (30 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2 x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 210 mg of 11.4 (crude product) as a yellow solid. The crude product was used in the next step without further purification. (ES,m / z):[M+1] + 222.2

[0156] Synthesis of 11.5. To a solution of (R)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazole-4-carbaldehyde (11.4, 1.4 g, 6.33 mmol, 1 eq.) in a mixture of EtOH (21 mL) and H2O (7 mL) at 20°C, (2S)-2-(methylamino)-3-sulfanyl-propionic acid (1.30 g, 7.59 mmol, 1.2 eq., HCl) and KOAc (4.35 g, 44.29 mmol, 7 eq.) were added. The suspension was gently stirred at 20°C in the dark for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (2 x 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*70mm#10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 20 minutes) to obtain 150 mg of 11.5 (25.69%) as a light yellow solid (a mixture of G-2, G-3, G-4 and G-5). (ES, m / z): [M+1] + 339.0.

[0157] Separation of G-2 to G-5. 300 mg of 11.5 (a mixture of 4 peaks) was separated and purified twice by SFC to obtain 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 a light yellow solid. (ES, m / z): [M+1] + 339.0

[0158] Method 1: Instrument: Waters SFC 80Q preparative SFC; Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); Mobile phase: A is CO2 and B is IPA (0.1% NH 3· H2O); Gradient: B from 38% to 38% in 7 minutes

[0159] Method 2: Instrument: Waters SFC 80Q preparative SFC; Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); Mobile phase: A is CO2 and B is IPA (0.1% NH 3· H2O); Gradient: B from 30% to 30% in 15 min

[0160] G-4: 1 H NMR (400MHz, acetone-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)

[0161] G-5: 1 H NMR (400 MHz, acetone-d6) δ = 7.30 (d, J = 7.9 Hz, 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 = 8.9 Hz, 1H), 3.20 (br d, J = 7.0 Hz, 2H), 2.64 (s, 3H), 2.31 (s, 3H)

[0162] G-3: 1 H NMR (400 MHz, acetone-d6) δ = 7.29 (d, J = 7.9 Hz, 1H), 6.82-6.68 (m, 2H), 5.33-5.18 (m, 1H), 5.04 (d, J = 4.8 Hz, 1H), 4.26 (dd, J = 2.1, 6.5 Hz, 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)

[0163] G-2: 1 H NMR (400 MHz, acetone-d6) δ = 7.29 (d, J = 8.0 Hz, 1H), 6.82-6.64 (m, 2H), 4.81 (d, J = 8.2 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 4.03 (dd, J = 5.4, 6.7 Hz, 1H), 3.67-3.58 (m, 1H), 3.55-3.40 (m, 2H), 3.30 (dd, J = 6.9, 11.0 Hz, 2H), 2.63 (s, 3H), 2.31 (s, 3H)

[0164] Example 4: Preparation of (4S)-2-((S)-2-(2-hydroxy-4-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0165] 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 H2O (1 mL), and the mixture was lyophilized to give 15.74 mg of G-6 (100%) as a light yellow solid. (ES, m / z): [M+1] + 339.0.

[0166] G-6: 1H NMR (400 MHz, acetone) δ = 7.30 (d, J = 7.7 Hz, 1.74 H), 6.81-6.71 (m, 3.48 H), 5.25-5.12 (m, 1.02 H), 5.07-4.92 (m, 0.78 H), 4.61 (d, J = 5.4 Hz, 0.98 H), 4.54 (d, J = 8.3 Hz, 0.74 H), 4.2 5(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)

[0167] 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

[0168] To a mixture of (4S)-2-(2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid (A-2-A-5, 40 mg, 123.30 μmol, 1 eq), 2-(3-but-3-ynyldiazirin-3-yl)ethylamine (4.1, 16.91 mg, 123.30 μmol, 1 eq) in DMF (2 mL) at 25° C., HATU (93.76 mg, 246.60 μmol, 2 eq) and DIEA (31.87 mg, 246.60 μmol, 42.95 μL, 2 eq) were added. The mixture was degassed and purged with Ar 3 times, and then stirred at 25° C. under Ar atmosphere for 12 hours. The reaction mixture was filtered to give a solution. The solution was purified by preparative HPLC (neutral conditions; column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 40%-70%, 8 minutes) to obtain 15 mg of C-2 to C-5 (27% yield) as a black jelly, i.e., a mixture of four stereoisomers. (ES, m / z): [M+1] + 444.1.

[0169] Example 6: Preparation of Compound C-3-(2S,4S)-N-(2-(3-(but-3-yn-1-yl)-3H-diazolyl-3-yl)ethyl)-2-((S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxamide

[0170] To a mixture of (4S)-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methyl-thiazolidine-4-carboxylic acid (A-3, 25 mg, 0.077 mmol, 1 eq), 2-(3-but-3-ynyldiazirin-3-yl)ethylamine (4.1, 10.57 mg, 0.077 mmol, 1 eq) in DMF (1 mL) was added HATU (58.60 mg, 0.154 mmol, 2 eq) and DIEA (19.92 mg, 0.154 mmol, 26.84 μL, 2 eq). The mixture was degassed and purged with Ar 3 times, and then stirred at 25° C. under Ar atmosphere for 12 h. The reaction mixture was filtered to give a solution. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%-70%, 10 minutes) to obtain 19 mg of C-3 (52.8%) obtained 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)

[0171] Example 7: Preparation of Compound C-2-(4S)-N-[2-(3-but-3-ynyldiazolyl-3-yl)ethyl]-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methyl-thiazolidine-4-carboxamide

[0172] To a mixture of (4S)-2-[(4S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl]-3-methyl-thiazolidine-4-carboxylic acid (A-2, 15 mg, 0.046 mmol, 1 eq), 2-(3-but-3-ynyldiazirin-3-yl)ethylamine (4.1, 6.34 mg, 0.046 mmol, 1 eq) in DMF (1 mL) was added HATU (35.16 mg, 0.092 mmol, 2 eq) and DIEA (11.95 mg, 0.092 μmol, 16.11 μL, 2 eq). The mixture was degassed and purged with Ar 3 times, and then stirred at 25° C. under Ar atmosphere for 12 h. The reaction mixture was filtered to give a solution. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 45%-75%, 8 minutes) to obtain 13 mg of C-2 (62.7%) as a yellow oil. (ES, m / z): [M+1] + 444.1. 1 H NMR (400 MHz, acetone-d6) δ = 7.65-7.53 (m, 1H), 7.52-7.31 (m, 2H), 6.96 (quin, J = 7.5 Hz, 2H), 5.25-4.92 (m, 1H), 4.70-4.45 (m, 1H), 4.11 (dd, J = 4.3, 7.2 Hz, 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).

[0173] 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

[0174] 7.3 Synthesis. To (2S)-2-amino-3-sulfanyl-propionic acid methyl ester (7.1, 20g, 116.52mmol, 1 equivalent, HCl) in toluene (300mL) solution was added 2,2-dimethyl propanal (7.2, 12.04g, 139.82mmol, 15.46mL, 1.2 equivalents), then TEA (17.69g, 174.78mmol, 24.33mL, 1.5 equivalents) was added, the mixture was heated to reflux (oil bath temperature: 110 ° C) and water was removed by Dean Stark (Dean-Stark) for 18 hours. The mixture was cooled to room temperature, then filtered, the filter cake was washed with ethyl acetate (2x 50mL), and the filtrate was concentrated in vacuo to obtain 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 in vacuo. The residue was purified by flash silica gel chromatography ( 330g Purification on silica flash column, eluent: 0% to 30% ethyl acetate / petroleum ether gradient @150 mL / min) afforded 20 g of 7.3 (84%) as a colorless oil. (ES, m / z): [M+1] + 204.1.

[0175] Synthesis of 7.4. To a solution of (4S)-2-tert-butylthiazolidine-4-carboxylic acid methyl ester (7.4, 10 g, 49.19 mmol, 1 eq.) in HCOOH (150 mL) was added Ac2O (15.06 g, 147.56 mmol, 13.82 mL, 3 eq.) and HCOONa (4.01 g, 59.03 mmol, 3.19 mL, 1.2 eq.) at 0°C to 5°C with stirring. The reaction mixture was warmed to 15°C and stirred for 18 hours. The solvent was removed under reduced pressure, and the obtained oil was treated with saturated NaHCO3 solution (100 mL) at 0°C, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated NaHCO3 solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was combined with another batch and purified by flash silica gel chromatography ( 330g Purification on silica flash column, eluent: 0% to 50% ethyl acetate / petroleum ether gradient @150 mL / min) afforded 22 g of 7.4 as a white solid. (ES, m / z): [M+1] + 232.1.

[0176] Synthesis of 7.5. To a stirred solution of i-PrNH2 (6.52 g, 110.24 mmol, 9.47 mL, 1.5 eq.) in THF (150 mL) was added dropwise n-BuLi (2.5 M, 32.34 mL, 1.1 eq.) at -65 °C under a nitrogen atmosphere. DMPU (37.68 g, 293.98 mmol, 35.55 mL, 4 eq.) was added dropwise at this temperature. After the addition, the reaction mixture was stirred at -65 °C for 1 hour, and a solution of (4S)-2-tert-butyl-3-formyl-thiazolidine-4-carboxylic acid methyl ester (7.4, 17 g, 73.49 mmol, 1 eq.) in THF (100 mL) was added dropwise at -65 °C. The reaction mixture was stirred for 1 hour, and then MeI (12.52 g, 88.19 mmol, 5.49 mL, 1.2 eq.) was added dropwise. The reaction mixture was stirred at this temperature for another 1 hour. After the reaction was complete, at 0°C to 5°C, the reaction mixture was quenched with saturated NH4Cl solution (20mL) and extracted with ethyl acetate (3x 100mL), the organic phases were combined, and washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography ( 330g Purification on silica flash column, eluent: 0% to 25% ethyl acetate / petroleum ether gradient @100 mL / min) afforded 12 g of 7.5 (65%) as a yellow solid. (ES, m / z): [M+1] + 246.1.

[0177] Synthesis of 7.6. A solution of (4S)-2-tert-butyl-3-formyl-4-methyl-thiazolidine-4-carboxylic acid methyl ester (7.5, 1 g, 4.08 mmol, 1 equivalent) in HCl (10.04 g, 101.90 mmol, 9.84 mL, 37% purity, 25 equivalents) was degassed and purged 3 times with Ar, then heated to 100 ° C and stirred for 5 days. The reaction mixture was dried in a vacuum to obtain 700 mg of 7.6 (crude product) as a yellow solid. The crude product was used directly in the next step without further purification.

[0178] Synthesis of E-2 to E-5. At 20 ° C, to a solution of (R)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (2.8, 200 mg, 965.02 μmol, 1 eq.) in a mixture of EtOH (24 mL) and H2O (8 mL), (2S)-2-amino-2-methyl-3-sulfanyl-propionic acid (7.6, 364.41 mg, 2.12 mmol, 2.2 eq., HCl) and KOAc (662.95 mg, 6.76 mmol, 7 eq.) were added. The suspension was gently stirred in the dark at 20 ° C for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid and then extracted with ethyl acetate (2x30 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 conditions; column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 10%-30%, 8 minutes) to give 150 mg of E-2, E-3, E-4 and E-5 (43% yield) as a mixture of four stereoisomers as a pale yellow solid. (ES, m / z): [M+1] + 325.1.

[0179] 1 HNMR (400 MHz, acetone-d6) 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=10.13 Hz, 1H), 3.11 (d, J=10.25 Hz, 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 =7.91Hz,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).

[0180] 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

[0181] To 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 eq) and formaldehyde (I10, 40.02 mg, 493.19 μmol, 36.72 μL, 37% purity, 4 eq) in MeOH (5 mL) was added NaBH3CN (30.99 mg, 493.19 μmol, 4 eq). The mixture was stirred at 15 °C for 16 hours. 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 C18100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 15%-45%, 8 minutes) to obtain 36 mg of B-2 to B-5 (83%) as a white solid, i.e., a mixture of four stereoisomers. (ES, m / z): [M+1] + 339.1.

[0182] 1 HNMR (400MHz, chloroform-d) δ = 1.46-1.62 (m, 3H), 2.52 (s, 1H), 2.58 (s, 1H), 2.6 1(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),5.1 6-5.29(m,1H),6.85-6.94(m,1H),6.96-7.04(m,1H),7.32-7.45(m,2H).

[0183] 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

[0184] To 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 eq) in DMF (5 mL) under Ar was added 3-but-3-ynyl-3-(2-iodoethyl)diazirine (41.29 mg, 166.45 μmol, 1.2 eq), K2CO3 (23 mg, 166.45 μmol, 1.2 eq). The mixture was stirred at 15° C. under Ar 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*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50%-80%, 8 minutes) to obtain 18 mg of D-2 to D-5 (29%) as a yellow gum, i.e., a mixture of four stereoisomers. (ES, m / z): [M+1] + 445.1. 1 HNMR (400 MHz, chloroform-d) δ = 1.70 (br t, J = 7.19 Hz, 2H), 1.77-1.88 (m, 2H), 1.97-2.09 (m, 3H), 2.54 (s, 1H), 2.62 (d, J = 2.00 Hz, 2H), 2.71 (s, 1H), 3.07-3.13 (m, 1H), 3.15-3.34 (m, 2H), 3.38-3.59 (m, 2H), 3.68 (dd, J = 9.07, 6.44 Hz, 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).

[0185] Example 11: Preparation of the following 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)

[0186] Synthesis of I-1.

[0187] To a solution of benzonitrile (1.1, 1.0 g, 9.70 mmol, 990 μL, 1 eq) and (R)-2-amino-3-mercaptopropionic acid hydrochloride (1.2, 2.29 g, 14.6 mmol, 1.5 eq) in MeOH (45.0 mL) and H2O (17.5 mL) was added NaHCO3 (2.04 g, 24.2 mmol, 943 μL, 2.5 eq) and NaOH (2 mg, 48.5 μmol, 0.005 eq) in a single portion at 25°C. The mixture was stirred at 40°C for 12 hours. The mixture was then concentrated in vacuo to remove most of the MeOH. The residue was extracted with ethyl acetate (2 x 20 mL), the pH of the aqueous phase was adjusted to about 3 with 2M HCl (aq), then extracted with ethyl acetate (3 x 30 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give 1.5 g of I-1 as a white solid (74%, %ee value 100.0%). (ES, m / z): [M+1] + 208.0.

[0188] Synthesis of 10.1. To a solution of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (900.00 mg, 4.34 mmol, 1 eq.), N-methoxymethylamine (465.95 mg, 4.78 mmol, 1.1 eq., HCl salt) and DECP (820.17 mg, 4.78 mmol, 759.42 μL, 95% purity, 1.1 eq.) in DMF (10 mL) was added DIPEA (1.12 g, 8.69 mmol, 1.51 mL, 2 eq.) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes, and then the reaction mixture was stirred at 25 °C for 11.5 hours. After the reaction was complete, 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 retained, 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 a NaHCO3 aqueous solution, then washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue and filter cake were purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate from 1: 0 to 1: 1) to obtain 900 mg of 10.1 (82%, ee value was 100.0%) as a light yellow solid. (ES, m / z): [M+1] + 251.1.

[0189] Synthesis of 10.2. At -40 ° C, under N2, LAH (159.19 mg, 4.19 mmol, 1.5 equivalents) was added to a solution of (R)-N-methoxy-N-methyl-2-phenyl-4,5-dihydrothiazole-4-carboxamide (10.1, 700 mg, 2.80 mmol, 1 equivalent) in THF (20 mL). The temperature was raised to -30 ° C in 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (20 mL), and then adding 1M KHSO4 solution (10 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with dichloromethane (2x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 534 mg of 10.2 (crude product) as a yellow solid. The crude product was used in the next step without further purification. (ES,m / z):[M+1] + 192.0.

[0190] Synthesis of F-1. To a solution of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxaldehyde (10.2, 534 mg, 2.79 mmol, 1 eq.) in a mixture of EtOH (60 mL) and H2O (20 mL) was added (2S)-2-(methylamino)-3-sulfanyl-propionic acid (575.12 mg, 3.35 mmol, 1.2 eq., HCl salt) and KOAc (1.92 g, 19.55 mmol, 7 eq.) at 20 °C under Ar. The suspension was gently stirred in the dark at 20 °C for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH=5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (2 x 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*70mm#10μm; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 15%-45%, 20 minutes) to give 300 mg of a mixture of F-1 (34%, 4 desired isomers and 2 aromatized isomers) as a light yellow solid. (ES, m / z): [M+1] + 309.1.

[0191] Separation of F-2 to F-5. 500 mg of F-1 was separated and purified twice by SFC 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 a light yellow solid. (ES, m / z): [M+1] + 339.0.

[0192] SFC separation method:

[0193] Method 1: Instrument: Waters SFC 80Q preparative SFC; Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); Mobile phase: A is CO2 and B is MeOH (0.1% NH 3· H2O); gradient: B from 40% to 40% in 10 min.

[0194] Method 2: Instrument: Waters SFC 80Q preparative SFC; Column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); Mobile phase: A is CO2 and B is MeOH (0.1% NH3· H2O); gradient: B% from 35% to 35% in 16 min.

[0195] F-4: 1 H NMR (400 MHz, acetone-d6) δ = 7.85-7.79 (m, 2H), 7.55-7.43 (m, 3H), 4.92 (d, J = 8.0 Hz, 1H), 4.57 (d, J = 7.7 Hz, 1H), 4.30 (t, J = 6.3 Hz, 1H), 3.66 (dd, J = 8.7, 11.2 Hz, 1H), 3.46 (dd, J = 8.6, 11.1 Hz, 1H), 3.25-3.18 (m, 3H), 2.48 (s, 3H)

[0196] F-5: 1 H NMR (400MHz, acetone-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)

[0197] F-3: 1 H NMR (400 MHz, acetone-d6) δ = 7.95-7.69 (m, 2H), 7.65-7.33 (m, 3H), 5.01 (dt, J = 5.4, 9.2 Hz, 1H), 4.49 (d, J = 5.2 Hz, 1H), 3.89 (br t, J = 6.4 Hz, 1H), 3.62 (dd, J = 8.7, 11.1 Hz, 1H), 3.42-3.16 (m, 3H), 2.68 (s, 3H)

[0198] F-2: 1 H NMR (400 MHz, 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, 6.5 Hz, 1H), 3.50-3.37 (m, 2H), 3.19 (dd, J = 6.6, 10.4 Hz, 1H), 3.01 (br d, J = 10.6 Hz, 2H), 2.72 (s, 3H)

[0199] 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.

[0200] Synthesis of 95.2. Anhydrous magnesium chloride (5.28 g, 55.48 mmol, 2.28 mL, 2 eq.), TEA (8.42 g, 83.23 mmol, 11.58 mL, 3 eq.) and paraformaldehyde (2.5 g, 83.23 mmol, 3 eq.) were added to a mixture of p-cresol (95.1, 3 g, 27.74 mmol, 2.91 mL, 1 eq.) in anhydrous THF (70 mL) in a 100 mL sealed tube. The mixture was stirred at 80 ° C for 16 hours. The reactant was used in the next step without further purification. At 0 ° C, NH3.H2O (254.83 g, 1.82 mol, 280.03 mL, 25% purity, 65.47 equivalents) and I2 (8.46 g, 33.32 mmol, 6.71 mL, 1.2 equivalents) were added to the above mixture, and the resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched by saturated Na2SO3 aqueous solution (40 mL). The resulting mixture was extracted with ethyl acetate (3 x 40 mL), and then the organic layers were combined and dried over Na2SO4. Afterwards, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 40g Purification by silica flash column, eluent: 0% to 100% ethyl acetate / petroleum ether gradient @ 36 mL / min) afforded 1.6 g of 95.2 (43%) as a yellow solid.

[0201] Synthesis of 95.3. At 25 ° C, L-cysteine ​​(1.66 g, 10.51 mmol, 2 equivalents, HCl salt) and phosphate buffer (10 mL) were added to a solution of 2-hydroxy-5-methylbenzonitrile (95.2, 0.7 g, 5.26 mmol, 1 equivalent) in MeOH (10 mL). The solution was adjusted to pH = 6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (20 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with dichloromethane (3x 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.

[0202] 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 eq.), N,O-dimethylhydroxylamine (2A, 474.82 mg, 4.87 mmol, 1.1 eq., HCl) and DECP (793.99 mg, 4.87 mmol, 735.18 uL, 1.1 eq.) in DMF (11 mL) was added DIPEA (857.90 mg, 6.64 mmol, 1.16 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The residue was poured into water (10 mL) and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with aqueous NaHCO3, then with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 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.

[0203] Synthesis of 95.5. At -30 ° C under N2, LAH (243.69 mg, 6.42 mmol, 1.5 equivalents) was added to 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 equivalent) in THF (14.5 mL). The temperature was raised to -30 ° C in 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (20 mL) and 1M KHSO4 solution (100 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (3x 50 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 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.

[0204] Synthesis of 95.6. To a solution of (R)-2-(2-hydroxy-5-methylphenyl)-4,5-dihydrothiazole-4-carbaldehyde (95.5, 947 mg, 4.28 mmol, 1 eq.) in a mixture of EtOH (30 mL) and H2O (10 mL) at 25°C, (2S)-2-(methylamino)-3-sulfanyl-propionic acid (A-3S, 881.52 mg, 5.14 mmol, 1.2 eq., HCl) and KOAc (2.94 g, 29.96 mmol, 7 eq.) were added. The suspension was gently stirred at 25°C in the dark for 2.5 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH=5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (2 x 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*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-40%, 20 minutes) to obtain 320 mg of 95.6 (22%) as a yellow solid. (ES, m / z): [M+1] + 339.2.

[0205] Synthesis of I-95, I-96, I-95a and I-96a. 320 mg of 95.6 (a mixture of 4 peaks) was separated and purified by SFC to obtain 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 a light yellow solid. (ES, m / z): [M+1]+339.1.

[0206] Method 1: Instrument: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); Mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); Gradient: B%=50% isocratic elution mode; Flow rate: 80 g / min; Wavelength: 220 nm; Column temperature: 40°C; System back pressure: 100 bar

[0207] I-95: 1 H NMR (400MHz, acetone-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).

[0208] I-96: 1 H NMR (400MHz, acetone-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).

[0209] I-95a: 1H NMR (400 MHz, acetone-d6) δ = 7.29-7.17 (m, 2H), 6.84 (d, J = 9.0 Hz, 1H), 4.83 (br d, J = 8.1 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 4.01 (br t, J = 5.8 Hz, 1H), 3.68-3.57 (m, 1H), 3.56-3.39 (m, 2H), 3.30 (dd, J = 6.9, 11.0 Hz, 1H), 2.63 (s, 3H), 2.28 (s, 3H).

[0210] I-96a: 1 H NMR (400 MHz, acetone-d6) δ = 7.28-7.14 (m, 2H), 6.92-6.76 (m, 1H), 5.26 (dt, J = 4.6, 9.1 Hz, 1H), 5.05 (d, J = 4.6 Hz, 1H), 4.25 (dd, J = 1.7, 6.3 Hz, 1H), 3.48-3.33 (m, 2H), 3.21 (dd, J = 6.5, 10.4 Hz, 1H), 3.12-2.96 (m, 1H), 2.70 (s, 3H), 2.27 (s, 3H).

[0211] Example 13: (4S)-2-((S)-2-(2-Hydroxy-5-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0212] Synthesis of I-97. A solution of 50 mg of I-95 and 75 mg of I-96 in CH3CN / H2O (3 / 1, 2.5 mL) was shaken for 2 minutes to obtain a clear solution. The mixture was then lyophilized for 24 hours to obtain 85.52 mg of I-97 (68%). (ES, m / z): [M+1] + 339.1. 1 H NMR (400 MHz, acetone) δ = 7.23 (br s, 2.93H), 6.85 (dd, J = 2.7, 8.8 Hz, 1.52H), 5.24-5.14 (m, 0.86H), 5.04-4.96 (m, 0.61H), 4.62 (d, J = 5.4 Hz, 0.87H), 4.55 (d, J = 8.4 Hz, 0.68H), 4.25 (t, J = 6.5 Hz, 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).

[0213] 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.

[0214] Synthesis of 89.2. At room temperature, L-cysteine ​​(7.10 g, 45.06 mmol, 2 equivalents, HCl salt) and phosphate buffer (30 mL) were added to a solution of 2-hydroxy-3-methylbenzonitrile (89.1, 3 g, 22.53 mmol, 1 equivalent) in MeOH (30 mL). The solution was adjusted to pH = 6.4 by careful addition of solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (500 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with ethyl acetate (3 x 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.

[0215] 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 eq.), N,O-dimethylhydroxylamine (2A, 1.36 g, 13.91 mmol, 1.1 eq., HCl) and DECP (2.27 g, 13.91 mmol, 2.10 mL, 1.1 eq.) in DMF (30 mL) was added dropwise DIPEA (2.45 g, 18.97 mmol, 3.30 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with aqueous NaHCO3 and then with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue and the filter cake were purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate from 1:0 to 1:1) to obtain 2.5 g of 89.3 (67%, ee value: 91.0%) as a light yellow solid. (ES, m / z): [M+1] + 281.1.

[0216] Synthesis of 89.4. At -40 ° C under N2, LAH (446.72 mg, 11.77 mmol, 1.5 equivalents) was added 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 equivalent) in THF (22 mL). The temperature was raised to -30 ° C and stirred for 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (25 mL) and 1M KHSO4 solution (25 mL). The mixture was vigorously stirred and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2x 200 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 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.

[0217] Synthesis of 89.5. At 25 ° C under Ar, to a solution of 2-(2-hydroxy-3-methylphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (89.4, 1.74 g, 7.86 mmol, 1 eq.) in a mixture of EtOH (51 mL) and H2O (17 mL), (S)-3-mercapto-2-(methylamino)propionic acid (A-3S, 1.62 g, 9.44 mmol, 1.2 eq., HCl) and KOAc (5.40 g, 55.04 mmol, 7 eq.) were added. The suspension was gently stirred in the dark at 25 ° C for 16 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (2 x 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*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-40%, 20 minutes) to obtain 1 g of 89.5 (37%) as a light yellow solid. (ES, m / z): [M+1] + 339.2.

[0218] Synthesis of I-89, I-90, I-89a and I-90a. 500mg 89.5 (mixture of 4 peaks) was purified by two SFC separations (method 1, then method 2) and 1 preparative HPLC to give 2mg I-89a (0.4%, de value: 41.8%, peak 1), 10mg I-90a (2.0%, de value: 94.1%, peak 2), 38mg I-90 (7.6%, de value: 94.4%, peak 3) and 14mg I-89 (2.8%, de value: 97.4%, peak 4) as a light yellow solid.

[0219] SFC separation method:

[0220] Method 1 (first SFC separation): Instrument: Waters SFC80Q preparative SFC; Column: DAICELCHIRALPAK ID (250mm*30mm, 10um); Mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); Gradient: B%=56% isocratic elution mode; Flow rate: 72g / min; Wavelength: 220nm; Column temperature: 40°C; System back pressure: 100 bar.

[0221] Method 2 (second SFC separation): Instrument: Waters SFC80Q preparative SFC; Column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 10 um); Mobile phase: A is CO2 and 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.

[0222] Preparative HPLC purification:

[0223] Column: Phenomenex C18 80*40mm*3um; Mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes.

[0224] I-90: 1 H NMR (400MHz, acetone-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).

[0225] I-89: 1H NMR (400MHz, acetone-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), 4.2 3(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).

[0226] I-89a: 1 H NMR (400 MHz, acetone-d6) δ = 7.28 (d, J = 7.6 Hz, 2H), 6.82 (t, J = 7.4 Hz, 1H), 5.29 (dt, J = 4.8, 9.3 Hz, 1H), 5.07 (d, J = 4.6 Hz, 1H), 4.27 (dd, J = 2.3, 6.6 Hz, 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).

[0227] I-90a: 1 H NMR (400MHz, acetone-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).

[0228] Example 15: (4S)-2-((S)-2-(2-Hydroxy-3-methylphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0229] Synthesis of I-91. A solution of (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) in ACN / H2O (3 / 1, 2 mL) was shaken for 2 minutes to obtain a clear solution. The clear solution was then lyophilized for 48 hours to obtain 27.10 mg of I-91 (82%) as a light yellow solid. (ES, m / z): [M+1] + 339.1.

[0230] 1 H NMR (400 MHz, acetone-d6) δ = 7.28 (d, J = 7.7 Hz, 3.12 H), 6.83 (t, J = 7.6 Hz, 1.60 H), 5.21 (dt, J = 5.5, 8.9 Hz, 0.95 H), 5.02 (q, J = 8.3 Hz, 0.64 H), 4.64 (d, J = 5.5 Hz, 0.93 H), 4.56 (d, J = 5.7 Hz, 0.94 H). =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).

[0231] 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.

[0232] Synthesis of 112.2. At room temperature, L-cysteine ​​(10.35 g, 65.64 mmol, 2 equivalents, HCl salt) and phosphate buffer (45 mL) were added to a mixture of 5-fluoro-2-hydroxybenzonitrile (112.1, 4.5 g, 32.82 mmol, 1 equivalent) in MeOH (45 mL). The solution was adjusted to pH = 6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (40 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with ethyl acetate (3x 60 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, giving 7.47 g of 112.2 (94%, ee value: 89.0%) as a yellow solid. (ES, m / z): [M+1] + 242.0.

[0233] 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 eq.), N-methoxymethylamine (1.27 g, 13.00 mmol, 1.1 eq., HCl) and DECP (2.12 g, 13.00 mmol, 1.96 mL, 1.1 eq.) in DMF (30 mL) was added DIEA (2.29 g, 17.72 mmol, 3.09 mL, 1.5 eq.) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes and then at 25 °C for another 2 hours. The reaction mixture was diluted with water (45 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with NaHCO3 (30 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to obtain 1.74 g of 112.3 (49%, ee value: 79.0%) as a light yellow solid. (ES, m / z): [M+1] + 285.1.

[0234] Synthesis of 112.4. At -40 ° C under N2, LAH (400.45 mg, 10.55 mmol, 1.5 equivalents) was added 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 equivalent) in THF (20 mL). The temperature was raised to -30 ° C in 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (42 mL) and 1M KHSO4 solution (42 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (3x 30 mL), the organic layer was collected, dried over Na2SO4 and filtered, and then evaporated under reduced pressure to obtain 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.

[0235] Synthesis of I-112.5. To a solution of (R)-2-(5-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carbaldehyde (112.4, 1.58 g, 7.01 mmol, 1 eq.) in a mixture of EtOH (45 mL) and H2O (15 mL) was added (2S)-2-(methylamino)-3-sulfanyl-propionic acid (A-3S, 1.14 g, 8.42 mmol, 1.2 eq., HCl) and KOAc (4.82 g, 49.10 mmol, 7 eq.). The suspension was gently stirred at 25 °C in the dark for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (3x80 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 20 minutes) to obtain 690 mg of I-112.5 (29%) as a light yellow solid. I-110 and I-111 were not recovered in the preparative HPLC purification. (ES, m / z): [M+1] + 343.1.

[0236] Synthesis of I-110 and I-111. 600 mg of I-112.5 (mixture of 2 peaks) was purified by two SFC separations (same separation method) to obtain 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 light yellow solids. (ES, m / z): [M+1]+343.1.

[0237] Method 1: Instrument: Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A is CO2 and B is EtOH (0.1% NH3H2O); gradient: B%=50% isocratic elution mode; flow rate: 80g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0238] I-110: 1 H NMR (400 MHz, acetone-d6) δ = 7.29-7.12 (m, 2H), 6.98 (dd, J = 4.6, 9.0 Hz, 1H), 5.05 (q, J = 8.2 Hz, 1H), 4.56 (d, J = 8.2 Hz, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.71 (dd, J = 8.7, 11.2 Hz, 1H), 3.51 (dd, J = 8.0, 11.3 Hz, 1H), 3.28-3.19 (m, 2H), 2.51 (s, 3H).

[0239] I-111: 1 H NMR (400 MHz, acetone-d6) δ = 7.26-7.12 (m, 2H), 6.97 (dd, J = 4.6, 9.0 Hz, 1H), 5.26 (dt, J = 5.2, 9.0 Hz, 1H), 4.61 (d, J = 5.1 Hz, 1H), 3.67-3.50 (m, 3H), 3.19 (d, J = 7.6 Hz, 2H), 2.63 (s, 3H).

[0240] Example 17: (4S)-2-((S)-2-(5-Fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0241] Synthesis of I-112. A solution of 148.88 mg of I-110 and 223.32 mg of I-111 in ACN / H2O (3 / 1, 4 mL) was shaken for 2 minutes to obtain a clear solution. The solution was then lyophilized for 24 hours to obtain 337.12 mg of I-112 (91%). (ES, m / z): [M+1] = 343.1.

[0242] 1 H NMR (400 MHz, acetone-d6) δ = 7.26-7.13 (m, 3.10H), 6.98 (ddd, J = 3.1, 4.6, 9.0 Hz, 1.55H), 5.24 (dt, J = 5.5, 8.9 Hz, 0.99H), 5.05 (q, J = 8.3 Hz, 0.57H), 4.64 (d, J = 5.4 Hz, 0 .98H),4.57(d,J=8.3Hz,0.55H),4.26(t,J=6.5Hz,0.56H),3.77-3.66(m,1.68H ),3.58-3.48(m,2.68H),3.28-3.18(m,3.26H),2.65(s,3.00H),2.51(s,1.67H).

[0243] 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.

[0244] Synthesis of 101.2. At room temperature, L-cysteine ​​(37.94 g, 240.68 mmol, 1 equivalent) was added to a solution of 2-fluoro-6-hydroxybenzonitrile (101.1, 3.3 g, 24.07 mmol, 1 equivalent) in MeOH (33 mL) and phosphate buffer (33 mL). The solution was adjusted to pH = 6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (500 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with ethyl acetate (3 x 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.

[0245] 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 eq.), N,O-dimethylhydroxylamine (2A, 1.82 g, 18.70 mmol, 1.1 eq., HCl) and DECP (3.05 g, 18.70 mmol, 2.82 mL, 1.1 eq.) in DMF (30 mL) was added DIPEA (3.29 g, 25.49 mmol, 4.44 mL, 1.5 eq.) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes and then at 25 °C for another 2 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate from 1:0 to 1:1) to obtain 4.58 g of 101.3 (94%, ee value: 56.0%) as a light yellow solid. (ES, m / z): [M+1] + 285.3.

[0246] Synthesis of 101.4. At -40 ° C under N2, LAH (800.90 mg, 21.10 mmol, 1.5 equivalents) was added 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 equivalent) in THF (40 mL). The temperature was raised to -30 ° C and stirred for 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (50 mL) and 1M KHSO4 solution (50 mL). The mixture was vigorously stirred and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2 x 200 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 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.

[0247] Synthesis of 101.5. At 25 ° C, to a solution of 2-(2-fluoro-6-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (101.4, 2.5 g, 11.10 mmol, 1 equivalent) in a mixture of EtOH (75 mL) and H2O (25 mL), (S)-3-mercapto-2-(methylamino)propionic acid (A-3S, 1.80 g, 13.32 mmol, 1.2 equivalents, HCl) and KOAc (7.63 g, 77.70 mmol, 7 equivalents) were added. The suspension was gently stirred in the dark at 25 ° C for 16 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and then the solution was extracted with ethyl acetate (2 x 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*70mm / 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-50%, 20 minutes) to obtain 695 mg of 101.5 (18%) as a light yellow solid. (ES, m / z): [M+1] + 343.3.

[0248] Synthesis of I-101, I-102, I-101a, I-102a. 500 mg of 101.5 (a mixture of 4 peaks) was purified by three SFC separations (method 1, followed by methods 2 and 3) to obtain 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 a yellow solid.

[0249] Method 1: Instrument: Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); gradient: B%=60% isocratic elution mode; flow rate: 80g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0250] Method 2: Instrument: Waters SFC80Q preparative SFC; column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 10 um); mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); gradient: B%=42% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar.

[0251] Method 3: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A is CO2 and B is IPA (0.1% NH3H2O); gradient: B%=44% isocratic elution mode; flow rate: 72g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0252] 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).

[0253] I-102a: 1 H NMR (400MHz, acetone-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).

[0254] I-102: 1H NMR (400MHz, acetone-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).

[0255] I-101: 1 H NMR (400MHz, acetone-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).

[0256] Example 19: (4S)-2-((S)-2-(2-Fluoro-6-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0257] Synthesis of I-103. A solution 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) in CH3CN / H2O (3 / 1, 5 mL) was shaken for 2 minutes to obtain a clear solution. The mixture was then freeze-dried for 48 hours to obtain 101.05 mg of I-103 (82%) as a light yellow solid. (ES, m / z): [M+1] + 343.1.

[0258] 1H NMR (400 MHz, acetone-d6) δ = 7.44-7.36 (m, 1.64H), 6.80 (td, J = 1.2, 8.4 Hz, 1.62H), 6.70 (dd, J = 8.3, 11.7 Hz, 1.65H), 5.16-5.05 (m, 0.98H), 4.93 (q, J = 8.6 Hz, 0.66H), 4.61 (d, J = 5.5 Hz, 0.96H), 4.5 4(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).

[0259] 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

[0260] Synthesis of 104.2. To a solution of 3-fluoro-2-hydroxybenzonitrile (104.1, 4.7 g, 34.13 mmol, 1 equivalent) in MeOH (47 mL) was added L-cysteine ​​(10.76 g, 68.27 mmol, 2 equivalents, HCl salt) and phosphate buffer (47 mL). The solution was adjusted to pH=6.4 by careful addition of solid K2CO3 (5.19 g, 37.55 mmol, 1.1 equivalents), and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (50 mL). The solution was adjusted to pH=2.0 by adding solid citric acid. After extraction with dichloromethane (3 x 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.

[0261] 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 eq.), N,O-dimethylhydroxylamine hydrochloride (2A, 2.22 g, 22.80 mmol, 1.1 eq., HCl) and diethoxyphosphorylcarbonitrile (3.91 g, 22.80 mmol, 3.62 mL, 95% purity, 1.1 eq.) in DMF (50 mL) was added DIEA (4.02 g, 31.09 mmol, 5.42 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 20°C for another 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with aqueous NaHCO3 and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate from 1:0 to 1:1) to give 4.68 g of 104.3 (79%, ee value: 91.0%) as a light yellow solid. (ES, m / z): [M+1] + 285.3.

[0262] Synthesis of 104.4. At -40 ° C under N2, LAH (600.67 mg, 15.83 mmol, 1.5 equivalents) was added 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 equivalent) in THF (50 mL). The temperature was raised to -30 ° C and stirred for 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (30 mL) and 1M KHSO4 solution (30 mL). The mixture was vigorously stirred and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2x 50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then evaporated under reduced pressure to obtain 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

[0263] Synthesis of 104.5. At 20 ° C, to a solution of 2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (104.4, 2.25 g, 9.99 mmol, 1 equivalent) in a mixture of EtOH (66 mL) and H2O (22 mL), (S)-3-mercapto-2-(methylamino)propionic acid (A-3S, 2.06 g, 11.99 mmol, 1.2 equivalents, HCl) and KOAc (6.86 g, 69.93 mmol, 7 equivalents) were added sequentially. The suspension was gently stirred in the dark at 20 ° C for 16 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and then the solution was extracted with ethyl acetate (2 x 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*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 20 minutes) to obtain 485 mg of 104.5 (14%) as a light yellow solid. (ES, m / z): [M+1] + 343.1.

[0264] Synthesis of I-104, I-105, I-104a and I-105a. 523 mg of 104.5 (a 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 a light yellow solid. (ES, m / z): [M+1] + 343.1

[0265] Method 1: Instrument: Waters SFC 80 preparative SFC; column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 10 um); mobile phase: A is CO2 and B is MeOH (0.2% NH3H2O); gradient: B%=45% isocratic elution mode; flow rate: 60 g / min; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar.

[0266] Method 2: Instrument: Waters SFC 80 preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A is CO2 and B is IPA (0.1% NH3H2O); gradient: B%=35% isocratic elution mode; flow rate: 65g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0267] 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)

[0268] I-105: 1 H NMR (400 MHz, acetone-d6) δ = 7.36-7.23 (m, 2H), 6.97-6.86 (m, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.64 (d, J = 5.5 Hz, 1H), 3.74 (t, J = 7.4 Hz, 1H), 3.54 (d, J = 8.9 Hz, 2H), 3.27-3.19 (m, 2H), 2.65 (s, 3H)

[0269] I-105a: 1 H 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)

[0270] I-104: 1H NMR (400 MHz, acetone-d6) δ = 7.34-7.23 (m, 2H), 6.97-6.88 (m, 1H), 5.06 (q, J = 8.3 Hz, 1H), 4.57 (d, J = 8.1 Hz, 1H), 4.26 (t, J = 6.4 Hz, 1H), 3.71 (dd, J = 8.8, 11.3 Hz, 1H), 3.51 (dt, J = 8.5, 11.3 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H), 2.66-2.65 (m, 1H), 2.52 (s, 3H)

[0271] Example 21: (4S)-2-((S)-2-(3-Fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid

[0272] Synthesis of I-106. A solution 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) in CH3CN / H2O (3 / 1, 4 mL) was shaken for 2 minutes to give a clear solution. The mixture was then freeze-dried for 24 hours to give 94.65 mg of I-106 (78%) as a light yellow solid. (ES, m / z): [M+1] + 343.1.

[0273] I-106: 1 H NMR (400 MHz, acetone-d6) δ = 7.37-7.21 (m, 3H), 6.92 (dt, J = 4.6, 8.0 Hz, 1.59H), 5.24 (dt, J = 5.5, 8.9 Hz, 0.95H), 5.06 (d, J = 8.5 Hz, 0.54H), 4.64 (d, J = 5.6 Hz, 0.95H), 4.57 (d, J = 8.1 Hz, 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)

[0274] Example 22: (4S)-2-((R)-2-(3-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid

[0275] Synthesis of I-118. A solution 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) in CH3CN / H2O (3 / 1, 3 mL) was shaken for 2 minutes to give a clear solution. The mixture was then freeze-dried for 48 hours to give 40.88 mg of I-118 (51%) as a light yellow solid. (ES, m / z): [M+1] + 343.1.

[0276] I-118: 1 H NMR (400 MHz, acetone-d6) δ = 7.51-7.23 (m, 2.69H), 6.94-6.87 (m, 1.28H), 5.33 (dt, J = 4.8, 9.1 Hz, 0.44H), 5.06 (d, J = 4.6 Hz, 0.39H), 4.87 (q, J = 8.3 Hz, 0.90H), 4.37 (d, J = 8.3 Hz, 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)

[0277] 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.

[0278] Synthesis of 107.2. At 25 ° C, L-cysteine ​​(11.50 g, 72.93 mmol, 2 equivalents, HCl salt) was added to a mixture of 4-fluoro-2-hydroxybenzonitrile (107.1, 5 g, 36.47 mmol, 1 equivalent) in phosphate buffer (50 mL) and MeOH (50 mL). The solution was adjusted to pH = 6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (20 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with dichloromethane (3x 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.

[0279] 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 eq.), N,O-dimethylhydroxylamine (2A, 5.5 g, 22.80 mmol, 1 eq., HCl) and DECP (4.09 g, 25.08 mmol, 3.79 mL, 1.1 eq.) in DMF (60 mL) was added DIPEA (4.42 g, 34.20 mmol, 5.96 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The mixture was poured into water (60 mL) and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (3 x 60 mL). The combined organic phases were washed with aqueous NaHCO3, then with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 4 g of 107.3 (63%, ee value: 79.8%) as a white solid. (ES, m / z): [M+1] + 285.1.

[0280] Synthesis of 107.4. At -30 ° C under N2, LAH (2g, 7.03mmol, 1 equivalent) was added to a solution of (R)-2-(4-fluoro-2-hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide (107.3, 2g, 7.03mmol, 1 equivalent) in THF (20mL). The mixture was stirred at -30 ° C for 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (40mL) and 1M KHSO4 solution (40mL). The mixture was vigorously stirred and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2x 200mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure to obtain 1.63g of 107.4 (crude) as a yellow solid. The crude product was used in the next step without further purification.

[0281] Synthesis of 107.5. To a solution of 2-(4-fluoro-2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (107.4, 1.58 g, 7.01 mmol, 1 eq.) in a mixture of EtOH (45 mL) and H2O (15 mL) at 25°C was added (2S)-2-(methylamino)-3-sulfanyl-propionic acid (A-3S, 1.14 g, 8.42 mmol, 1.2 eq., HCl) and KOAc (4.82 g, 49.10 mmol, 7 eq.). The suspension was gently stirred at 25°C in the dark for 16 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (2 x 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*40mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-30%, 8 minutes) to obtain 730 mg of 107.5 (30%) as a yellow solid. (ES, m / z): [M+1] + 343.1.

[0282] Synthesis of I-107, I-108, I-107a and I-108a. 0.5 g of 107.5 (a mixture of 4 peaks) was purified by two SFC separations (method 1, followed by method 2) to obtain 10.06 mg of I-107 (2.0%, de value: 100.0%, peak 1), 57.79 mg of I-107a (impure, a mixture of I-107 and I-107a), 12.07 mg of I-108a (impure, a mixture of I-108 and 108a) and 163.15 mg of I-108 (32%, de value: 93.2%, peak 4) as a light yellow solid. (ES, m / z): [M+1] + 343.1.

[0283] SFC separation method:

[0284] Method 1: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: A is CO2 and B is MeOH (0.1% NH3H2O); gradient: B%=38% isocratic elution mode; flow rate: 65g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0285] Method 2: Instrument: Waters SFC80Q preparative SFC; column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 10 um); mobile phase: A is CO2 and B is EtOH (0.1% NH3H2O); gradient: B%=38% isocratic elution mode; flow rate: 65 g / min; wavelength: 220 nm; column temperature: 40°C; system back pressure: 100 bar.

[0286] I-107: 1 H NMR (400 MHz, acetone-d6) δ = 7.56-7.43 (m, 1H), 6.80-6.62 (m, 2H), 5.00 (q, J = 8.1 Hz, 1H), 4.54 (d, J = 8.3 Hz, 1H), 4.23 (br t, J = 6.4 Hz, 1H), 3.68 (dd, J = 8.9, 11.0 Hz, 1H), 3.47 (br dd, J = 7.9, 11.2 Hz, 1H), 3.31-3.10 (m, 2H), 2.50 (s, 3H).

[0287] I-108: 1H 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).

[0288] Example 24: (4S)-2-((S)-2-(4-Fluoro-2-hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0289] Synthesis of I-109. A solution of 10.06 mg of I-107 and 15.15 mg of I-108 in ACN / H2O (3 / 1, 1 mL) was shaken for 2 minutes to obtain a clear solution. The solution was then lyophilized for 48 hours to obtain 18.68 mg of I-109 (74%). (ES, m / z): [M+1] + 343.1.

[0290] I-109: 1 H 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,0.8 3H),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).

[0291] 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

[0292] Synthesis of 126.2. To a mixture of 3-hydroxypyridine carbonitrile (126.1, 4.5 g, 37.47 mmol, 1 equivalent) in MeOH (45 mL) was added L-cysteine ​​(11.81 g, 74.93 mmol, 2 equivalents, HCl salt) and phosphate buffer (45 mL). The solution was adjusted to pH = 6.4 by careful addition of solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (200 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with ethyl acetate (3 x 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.

[0293] 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 eq.), N,O-dimethylhydroxylamine hydrochloride (2A, 3.56 g, 33.6 mmol, 1.1 eq., HCl) and DECP (5.96 g, 33.6 mmol, 5.52 mL, 1.1 eq.) in DMF (75 mL) was added DIEA (6.44 g, 49.9 mmol, 99.89 mL, 1.5 eq.) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes and then at 20 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 6.7 g of 126.3 (73%, ee value: 84.2%) as a yellow solid. (ES, m / z): [M+1]+268.1.

[0294] 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 equivalent) in THF (50 mL) was added LAH (1.06 g, 28.06 mmol, 1.5 equivalents) at -40 ° C under N2. The temperature was raised to -30 ° C and stirred for 0.5 hours. The reaction mixture was then quenched by continuous addition of saturated NH4Cl aqueous solution (50 mL) and 1M KHSO4 solution (50 mL). 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 x 200 mL), the organic layer was collected, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2.99 g 126.4 (76 6%, ee value: 84.2%). (ES,m / z):[M-1] - 207.0.

[0295] Synthesis of 126.5. At 25 ° C, (S)-3-mercapto-2-(methylamino)propionic acid (A-3S, 2.75 g, 16.01 mmol, 1.2 equivalents, HCl) and KOAc (9.16 g, 93.38 mmol, 7 equivalents) were added to a solution of (R)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazole-4-carboxaldehyde (126.4, 2.78 g, 13.34 mmol, 1 equivalent) in a mixture of EtOH (30 mL) and H2O (10 mL) in sequence. This suspension was gently stirred in the dark at 20 ° C for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and then the solution was extracted with ethyl acetate (2 x 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*40mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-30%, 8 minutes) to obtain 1.21 g of 126.5 (27%) as a light yellow solid. (ES, m / z): [M+1] + 326.1.

[0296] Synthesis of I-126, I-127, I-126a, and I-127a. 1 g of 126.5 (a mixture of 4 peaks) was purified by three SFC separations (method 1, followed by methods 2 and 3) to obtain 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 (a mixture of I-127 and 127a), and 12 mg of I-126a (0.012%, de value: 100%, peak 4) as a light yellow solid. (ES, m / z): [M+1] + 326.0.

[0297] Method 1: Instrument: Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: A is CO2 and B is EtOH (0.1% NH3H2O); gradient: B%=50% isocratic elution mode; flow rate: 80g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0298] Method 2: Instrument: Waters SFC80 preparative SFC; column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); mobile phase: A is CO2 and B is EtOH (0.1% NH3H2O); gradient: B%=28% isocratic elution mode; flow rate: 56g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0299] Method 3: Instrument: Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IH (250mm*30mm, 10um); mobile phase: A is CO2 and B is IPA (0.1% NH3H2O); gradient: B%=40% isocratic elution mode; flow rate: 70g / min; wavelength: 220nm; column temperature: 40°C; system back pressure: 100 bar.

[0300] I-126: 1H 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), 4.0 3(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).

[0301] I-127: 1 H NMR (400 MHz, acetone) δ = 8.17 (dd, J = 2.1, 4.4 Hz, 1H), 7.46-7.31 (m, 2H), 5.31-5.22 (m, 1H), 4.64 (d, J = 6 Hz, 1H), 3.73 (t, J = 7.6 Hz, 1H), 3.42 (d, J = 9.2 Hz, 2H), 3.23 (d, J = 7.6 Hz, 2H), 2.65 (s, 3H).

[0302] 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, 0.9 8H), 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).

[0303] 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).

[0304] Example 26: (4S)-2-((S)-2-(3-hydroxypyridin-2-yl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid

[0305] 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 H2O (1 mL), and the mixture was lyophilized to give 125.32 mg of I-128 (83%) as a light 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)

[0306] 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

[0307] Synthesis of 123.2. At 0 ° C, thionyl chloride (77.19 g, 648.85 mmol, 47.07 mL, 2 equivalents) was added dropwise to a solution of 2,4-dihydroxybenzoic acid (123.1, 50 g, 324.42 mmol, 1 equivalent), acetone (28.26 g, 486.63 mmol, 35.78 mL, 1.5 equivalents), DMAP (2.38 g, 19.47 mmol, 0.06 equivalents) in dimethoxyethane (200 mL) for 1 hour, and then stirred at 25 ° C for 7 hours. The reaction mixture was quenched with a saturated solution of NaHCO (400 mL) and extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with a saturated NaCl aqueous solution (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a residue, and the residue was ground with dichloromethane to obtain a product as a light yellow 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.

[0308] Synthesis of 123.3. K2CO3 (24.45 g, 176.89 mmol, 3 equivalents) was added to 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 equivalent) and 1-bromo-2-(2-methoxyethoxy)ethane (11.87 g, 64.86 mmol, 1.1 equivalents) in ACN (110 mL). The mixture was stirred at 90 ° C for 5 hours. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with ethyl acetate (3 x 50 mL). The combined filtrate was concentrated to dryness to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 99: 1 to 10: 1) to obtain 14.05 g of 123.3 (80%) as a light yellow oil. (ES,m / z):[M+1] + 297.1.

[0309] Synthesis of 123.4. A solution 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 equivalent) in NH3 / i-PrOH (10 M, 60 mL) was stirred at 15 ° C for 0.5 hours. Then, the mixture was heated to 80 ° C and stirred for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3: 1 to 1: 1) to give 4.22 g of 123.4 (86%) as a light yellow oil. (ES, m / z): [M + 1] + 256.1.

[0310] 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 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3x200 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 (SiO2, 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.

[0311] Synthesis of 123.6. At room temperature, L-cysteine ​​(1.30 g, 8.26 mmol, 2 equivalents, HCl salt) and phosphate buffer (10 mL) were added to a solution of 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzonitrile (123.5, 980 mg, 4.13 mmol, 1 equivalent) in MeOH (10 mL). The solution was adjusted to pH = 6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (100 mL). The solution was adjusted to pH = 2.0 by adding solid citric acid. After extraction with dichloromethane (3x 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.

[0312] 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 eq.), N,O-dimethylhydroxylamine hydrochloride (2A, 1.11 g, 11.38 mmol, 2.1 eq., HCl) and DECP (1.95 g, 11.38 mmol, 1.81 mL, 2.1 eq.) in DMF (30 mL) was added DIEA (1.75 g, 13.55 mmol, 2.36 mL, 2.5 eq.) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes and at 20 °C for another 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x3). The combined organic layers were washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate from 1:0 to 1:1) to give 1.27 g of 123.7 (61%, ee value: 86.0%) as a light yellow solid. (ES, m / z): [M+1] + 385.2.

[0313] Synthesis of 123.8. At -40 ° C under N2, LAH (155.47 mg, 4.10 mmol, 1.5 equivalents) was added 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 equivalent) in THF (20 mL). The temperature was raised to -30 ° C and stirred for 0.5 hours. Then, the reaction mixture was quenched by continuous addition of saturated NH4Cl aqueous solution (30 mL) and 1M KHSO4 solution (30 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with ethyl acetate (2 x 50 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.

[0314] Synthesis of 123.9 To a solution of (R)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazole-4-carbaldehyde (123.8, 690 mg, 2.12 mmol, 1 eq) in a mixture of EtOH (21 mL) and H2O (7 mL) at 25°C were added (S)-3-mercapto-2-(methylamino)propanoic acid (A-3S, 436.79 mg, 2.54 mmol, 1.2 eq, HCl) and KOAc (1.46 g, 14.84 mmol, 7 eq). The suspension was gently stirred at 25°C in the dark for 12 hours. Ethanol was removed under reduced pressure, and the crude was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and then the solution was extracted with ethyl acetate (2 x 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*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-35%, 20 minutes) to give 360 ​​mg of 123.9 (38%) as a light yellow solid. (ES, m / z): [M+1] + 443.1.

[0315] 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, then method 2) to obtain 23.19 mg of I-123 (6%, de value: 100%, peak 2), 46.82 mg of I-124 (13%, de value: 97%, peak 1) and 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 a light yellow solid. (ES, m / z): [M+1] + 443.1

[0316] Method 1 (first SFC separation): Instrument: Waters SFC 80Q preparative SFC; Column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 um); Mobile phase: A is CO2 and B is EtOH (0.1% NH3H2O); Gradient: B%=44% isocratic elution mode; Flow rate: 72 g / min; Wavelength: 220 nm; Column temperature: 40°C; System back pressure: 100 bar.

[0317] Method 2 (second SFC separation): Instrument: Waters SFC 150AP preparative SFC; Column: DAICELCHIRALPAK AD (250mm*30mm, 10um) Mobile phase: A is CO2 and B is MEOH (0.1% NH3H2O); Gradient: B%=50% isocratic elution mode; Flow rate: 70g / min; Wavelength: 220nm; Column temperature: 35 degrees Celsius; System back pressure: 120 bar.

[0318] I-123: 1 H NMR (400MHz, acetone) 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= 4.8Hz2H),3.47-3.41(m,1H),3.29(s,3H),3.23(d,J=6Hz,2H),2.50(s,3H)

[0319] I-124: 1 H NMR (400MHz, acetone) 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(brdd,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)

[0320] I-123a: 1H NMR (400MHz, acetone) 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)

[0321] I-124a: 1 H 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)

[0322] Example 28: (4S)-2-((S)-2-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid

[0323] Synthesis of I-125. A solution 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) in CH3CN / H2O (3 / 1, 4 mL) was shaken for 2 minutes to give a clear solution. The mixture was then lyophilized for 24 hours to give 50.89 mg of I-125 (87%) as a light yellow solid. (ES, m / z): [M+1] + 443.1

[0324] I-125: 1 H 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)

[0325] Example 29: (4S)-3-Methyl-2-((S)-2-phenyl-4,5-dihydrothiazol-4-yl)thiazolidine-4-carboxylic acid.

[0326] 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 H2O (1 mL), and the mixture was lyophilized. 10.37 mg of F-6 (100%) was obtained as a light yellow solid. (ES, m / z): [M+1] + 339.0.

[0327] F-6: 1 H NMR (400 MHz, acetone-d6) δ = 7.82 (d, J = 8.1 Hz, 3H), 7.59-7.40 (m, 5H), 5.03 (br d, J = 5.6 Hz, 1H), 4.93 (d, J = 8.1 Hz, 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 = 9.0 Hz, 2H), 3.47-3.41 (m, 0.63H), 3.25-3.18 (m, 3H), 2.65 (s, 3H), 2.49 (s, 2H)

[0328] 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.

[0329] Synthesis of 100.2. A mixture of (R)-2-amino-3-mercaptopropionic acid methyl ester (5g, 29.13mmol, 1 equivalent, HCl) in acetone-d6 (100mL) is degassed and purged with N2 3 times, and then the mixture is stirred at 60 ° C under N2 atmosphere for 16 hours. The reaction mixture is concentrated under reduced pressure to remove acetone-d6. The residue is diluted with ethyl acetate (50mL), washed with water, 5% sodium bicarbonate aqueous solution (3x 50mL) and brine (25mL) in sequence, and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=0 / 1 to 15.6 / 1) to obtain 4.6g of 100.2 (90.11%) as a colorless oil. (ES, m / z): [M+1] +176.0.

[0330] Synthesis of 100.3. At 0 ° C, under stirring, to a solution of (R)-2,2-dimethylthiazolidine-4-carboxylic acid methyl ester (100.2, 3.08 g, 17.58 mmol, 1 equivalent) and K2CO3 (3.64 g, 26.36 mmol, 1.5 equivalents) in DMF (30 mL) was added dropwise Me2SO4 (6.65 g, 52.73 mmol, 5.00 mL, 3 equivalents). The mixture was stirred at 15 ° C for 5 hours. The reaction mixture was quenched by adding water (20 mL) at 0 ° C. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was washed with brine (30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 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.

[0331] Synthesis of A-2S. A mixture of (R)-2,2,3-trimethylthiazolidine-4-carboxylic acid methyl ester (103.3, 1.5 g, 21.13 mmol, 1 equivalent) in HCl (6M, 20 mL, 15.14 equivalent) was degassed and purged with Ar 3 times, and then the mixture was stirred at 100 ° C under Ar atmosphere for 8 hours. 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.

[0332] Synthesis of 100.5. At room temperature, (2S)-2-amino-3-sulfanyl-propionic acid (5.29 g, 33.58 mmol, 2 equivalents, HCl) was added to a solution of 2-hydroxybenzonitrile (100.4, 2 g, 16.79 mmol, 1 equivalent) in MeOH (20 mL) and phosphate buffer (20 mL). The solution was adjusted to pH=6.4 by carefully adding solid K2CO3, and the reaction mixture was stirred at 60 ° C for 12 hours. The mixture was concentrated under reduced pressure, and the yellow crude residue was diluted with water (20 mL). The solution was adjusted to pH=2.0 by adding solid citric acid. After extraction with EA (3x 30 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, giving 3.7 g of 100.5 (96.24%, %ee value 93.12%) as a yellow solid. (ES, m / z): [M+1] + 223.9.

[0333] 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 eq.), N-methoxymethylamine (2A, 958.84 mg, 9.83 mmol, 1.1 eq., HCl) and DECP (1.60 g, 9.83 mmol, 1.48 mL, 1.1 eq.) in DMF (20 mL) was added DIEA (1.73 g, 13.40 mmol, 2.33 mL, 1.5 eq.) at 0°C under N2. The mixture was stirred at 0°C for 30 minutes and then at 25°C for another 2 hours. The reaction mixture was diluted with water 45 mL and extracted with EA 180 mL (60 mL*3). The combined organic layers were washed with NaHCO3 90 mL (30 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, yielding 2 g of 100.6 (81%, ee value 83.62%) as a light yellow solid. (ES, m / z): [M+1] + 267.0.

[0334] Synthesis of 100.7. At -40 ° C under N2, LAH (448.93 mg, 11.83 mmol, 1.5 equivalents) was added 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 equivalent) in THF (42 mL). The temperature was raised to -30 ° C in 0.5 hours. Then, the reaction mixture was hydrolyzed by continuously adding saturated NH4Cl aqueous solution (42 mL) and 1M KHSO4 solution (42 mL). The mixture was stirred vigorously and allowed to warm to room temperature until two phases were formed. After distribution and extraction with EA (3x 30 mL), the organic layer was collected, dried over Na2SO4 and filtered, and then evaporated under reduced pressure to obtain 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.

[0335] Synthesis of I-100.8. To a solution of (S)-2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxaldehyde (100.7, 1.3 g, 6.27 mmol, 1 eq.) in a mixture of EtOH (60 mL) and H2O (20 mL) was added (R)-3-mercapto-2-(methylamino)propionic acid (A-2S, 1.29 g, 7.53 mmol, 1.2 eq., HCl) and KOAc (4.31 g, 43.91 mmol, 7 eq.). The suspension was gently stirred at 20 °C in the dark for 12 hours. Ethanol was removed under reduced pressure, and the crude product was diluted in water. The aqueous layer was acidified to pH = 5 by adding solid citric acid, and the solution was then extracted with ethyl acetate (3 x 100 mL). The organic layer was collected, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18250*70mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 20 minutes) to obtain 540 mg of I-100.8 (26.54%) as a light yellow solid. (ES, m / z): [M+1] + 325.1.

[0336] Synthesis of I-98, I-99, I-98a and I-99a. 200 mg of I-100.8 (a mixture of 4 peaks) was separated and purified by two SFC separations to obtain 40 mg of I-98 (20%, ee value of 77.21%, peak 4), 50 mg of I-99 (25%, ee value of 84.92%, peak 1), 23.67 mg of I-98a (11.83%, ee value of 86.04%, peak 3) and 9.73 mg of I-99a (4.86%, ee value of 56.66%, peak 2) as light yellow solids. (ES, m / z): [M+1] + 325.1.

[0337] SFC separation method:

[0338] Method 1: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​EtOH]; B%: 33%-33%, 9 minutes.

[0339] Method 2: Instrument: Waters SFC80Q preparative SFC; column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 35%-35%, 9 minutes.

[0340] I-98: 1 H NMR (400 MHz, acetone-d6) δ = 7.49-7.35 (m, 2H), 7.01-6.87 (m, 2H), 5.02 (d, J = 8.3 Hz, 1H), 4.56 (d, J = 8.3 Hz, 1H), 4.26 (t, J = 6.5 Hz, 1H), 3.67 (dd, J = 8.6, 11.3 Hz, 1H), 3.47 (dd, J = 7.9, 11.4 Hz, 1H), 3.28-3.18 (m, 2H), 2.51 (s, 3H).

[0341] I-99: 1 H NMR (400 MHz, acetone-d6) δ = 7.48-7.37 (m, 2H), 6.98-6.89 (m, 2H), 5.22 (d, J = 5.5 Hz, 1H), 4.63 (d, J = 5.4 Hz, 1H), 3.72 (dd, J = 6.8, 8.0 Hz, 1H), 3.50 (d, J = 8.9 Hz, 2H), 3.22 (dd, J = 1.8, 7.4 Hz, 2H), 2.65 (s, 3H).

[0342] I-98a: 1 H NMR (400 MHz, acetone-d6) δ = 7.48-7.35 (m, 2H), 6.99-6.87 (m, 2H), 4.85 (q, J = 8.4 Hz, 1H), 4.35 (d, J = 8.3 Hz, 1H), 4.03 (t, J = 6.1 Hz, 1H), 3.68-3.61 (m, 1H), 3.54 (dd, J = 8.2, 11.4 Hz, 1H), 3.45 (dd, J = 5.3, 11.0 Hz, 1H), 2.64 (s, 3H).

[0343] 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), 4.2 7(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).

[0344] Example 31 : (4R)-2-((R)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0345] Synthesis of I-100. A solution of 20 mg of I-98 and 30 mg of I-99 in CH3CN / H2O (3 / 1, 4 mL) was shaken for 2 minutes to obtain a clear solution. The solution was then lyophilized for 48 hours to obtain 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.

[0346] 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).

[0347] 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

[0348] 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-diaziran-3-yl)ethylamine (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 hours. The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-70%, 8 minutes) to obtain 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).

[0349] Example 33: (4S)-2-((S)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0350] Synthesis of A-6. A solution 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) in CH3CN / H2O (3 / 1, 7 mL) was shaken for 2 minutes to obtain a clear solution. The solution was then lyophilized for 48 hours to obtain 732.43 mg of I-121 (95%). (ES, m / z): [M+1]+325.1.

[0351] 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),4.6 0-4.51(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).

[0352] Example 34: (4S)-2-((R)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazol-4-yl)-3-methylthiazolidine-4-carboxylic acid.

[0353] Synthesis of A-7. A solution 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) in CH3CN / H2O (3 / 1, 3 mL) was shaken for 2 minutes to obtain a clear solution. The solution was then lyophilized for 48 hours to obtain 50.36 mg A-7 (81%). (ES, m / z): [M+1]+325.1.

[0354] 1H NMR (400 MHz, acetone-d6) δ = 7.50-7.33 (m, 2.76 H), 7.02-6.86 (m, 2.78 H), 5.28 (dt, J = 4.8, 9.1 Hz, 0.35 H), 5.06 (br d, J = 4.1 Hz, 0.31 H), 4.92-4.80 (m, 1.02 H), 4.34 (br d, J = 8.1 Hz, 1.06 H), 4.25 (br d, J = 5.0 Hz, 0.38 H), 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).

[0355] Example 35: Biological Assay

[0356] A. Dectin-1 assay:

[0357] 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) to the culture supernatant in response to Dectin-1 activation. HEK-Blue reporter cells are grown in DMEM culture medium containing 10% de-supplemented fetal bovine serum (InvivoGen), 1% Pen / Strep antibiotics (InvivoGen), and 0.2% Normocin antibiotics (InvivoGen). The day before the assay, cells were seeded in 96 flat-bottom well plates at 50,000 cells / well and further incubated for 20 hours. On the day of the assay, cells were incubated for 6 hours with 1 μM, 10 μM or 30 μM compounds described herein or with 1 μM SYKi IV Dectin-1b inhibitor (Millipore) or with DMSO (vehicle control), followed by addition of β-glucan peptide (BGP, 30 μg / mL of Dectin-1 ligand) and incubation for 16-18 hours. After the incubation, culture supernatants were collected and Dectin-1 related activity was assessed by measuring the presence of SEAP-reporter protein using Quanti-Blue assay (Invivogen), and these values ​​were adjusted by the cell viability level assessed using Cell-Titer-Glo2 reagent (Promega).

[0358] Results represent SEAP levels adjusted for cell number in triplicate for each condition, and cell number and viability corrections reflect less than 5% correction. For compound A-3, see e.g. Figure 1 .

[0359] Compounds A1 and B1 showed inhibition of BGP-induced Dectin-1b reporter activity in a concentration-dependent manner in the range from 1 μM to 30 μM, with maximal inhibition at 30 μM, the maximum concentration tested. At these concentrations, compound E1 was less active in this HEK-Dectin-1b assay. See Figure 4 .

[0360] Compounds A6, C2 and C3 demonstrated dose-dependent inhibition of BGP-induced Dectin-1b signaling in HEK cells in the range from 1 μM to 30 μM, with maximal inhibition at 30 μM, the maximum concentration tested. Fig.12 .

[0361] B. Monocyte-derived DC (MoDC) Assay Protocol

[0362] Monocyte-derived DCs (MoDCs) were distinguished from CD14+ monocytes derived from healthy human donors. Commercially available freshly prepared Leukopaks were obtained from healthy blood donors and kept frozen on ice, then spun down and the pelleted cells rinsed and resuspended in MACS buffer (Miltenyi Biotec). Next, CD14 + Monocytes using MultiMACS TM The purified CD14 was purified using the Cell24Separator-Plus instrument and reagents according to the manufacturer's instructions (Miltenyi Biotec). + The cell fractions were washed, counted and then cryopreserved for later use. + Cells were thawed, rinsed with culture medium, and then resuspended in culture medium consisting primarily of RPMI (Invitrogen) supplemented with 10% v / v heat-inactivated FBS. + Count cells and inoculate to 75 cm 230mL in tissue culture flasks are supplemented with GM-CSF (40-100ng / mL) and IL-4 (25ng / mL) culture medium. Every other day, half of the culture medium is replaced with fresh culture medium (containing the same cytokine supplement), and after 6-7 days of culture, fully differentiated and mature MoDCs are obtained, as confirmed by conventional immunophenotypic markers (surface CD80, CD83, CD86, CD209, HLA-DR, CD14 and CD64 expression levels or lack thereof) confirmed by flow cytometry. Fully differentiated (mature) MoDCs are seeded into 96 flat-well plates and incubated for 6 hours with various concentrations of compounds described herein or with control solutions (DMSO) or with pharmacological inhibitors cyclosporin-A (CsA) and BAY 61-3606 (which are known Syk kinase inhibitors). Next, Dectin-1 (CLEC7a1)-ligand (zymosan, 5 μg / mL) or Toll-like receptor agonist R848 were added to the MoDC culture wells and incubated for a further 18-20 hours. After the incubation, the culture supernatant was collected and Multiplex Assays ( Figure 2 ) or by ELISA ( Figure 3 ) The levels of inflammatory cytokines and chemokines were measured in triplicate for each condition.

[0363] Compounds A1 and B1 showed potent inhibition of zymosan-induced pro-inflammatory cytokine IL-12p40 production in monocyte-derived dendritic cells from healthy human donor 2. Figure 5 .

[0364] Compounds A1, A2 and A3 showed inhibition of zymosan-induced proinflammatory cytokine IL-12p40 production in monocyte-derived dendritic cells from healthy human donors 1, 2 and 3. Compounds were tested at final concentrations ranging from 15.5 nM to 1 μM, with maximal inhibition at the highest concentration of 1 μM. Figure 6A-6C .

[0365] Compounds A1, A2 and A3 showed dose-dependent inhibition of zymosan-induced pro-inflammatory cytokine IL-12p40 production in monocyte-derived dendritic cells from healthy human donor 1. Figure 7A-7C .

[0366] Compounds A6 and I-100 inhibited several proinflammatory cytokines in LPS-stimulated MoDCs from healthy human donors 14. A6 induced IL-6 ( Fig. 9A )、TNFα( Fig. 9B )、IL-23( Fig. 9C)、IL-12p70( Fig.9D )、IP-10( Fig.9E )、Gro-α( Fig.9F )、MCP-1( Figure 9G ) and Mip-1α( Figure 9H ). I-100 caused a statistically significant decrease in IL-6, TNFα, IL-23, IL-12p70, Gro-α, MCP-1, and Mip-1α. Figure 9A-9H .

[0367] Compounds A6 and I-100 inhibited several proinflammatory cytokines in R848-stimulated MoDCs from healthy human donors14. A6 induced IL-6 ( Fig. 10A )、TNFα( Fig. 10B )、IL-23( Fig. 10C )、IL-12p70( Fig. 10D )、IP-10( Fig. 10E )、Gro-α( Fig.10F )、MCP-1( Figure 10G ) and Mip-1α( Fig. 10H ). I-100 caused a statistically significant decrease in IL-6, TNFα, IL-23, IL-12p70, IP-10, Gro-α, MCP-1, and Mip-1α. Figures 10A-10H .

[0368] When tested at 0.5 μM final concentration, compounds A3 and C3 inhibited zymosan-induced IL-12p40 in primary human MoDCs from healthy donors 5 and 6. When tested at 0.5 μM final concentration, compound C3 inhibited IL-12p40 in primary human MoDCs from healthy donors 5 and 6. Fig.11 A) and 6( Fig.11 B) Zymosan-induced IL-12p40 in primary human monocyte-derived dendritic cells, whereas compound A3 did not achieve statistically significant inhibition at 0.5 μM final concentration.

[0369] CAIRF assay:

[0370] Compounds described herein are added to mammalian cells for bioactivity assessment.THP-1 dual reporter cell line (InVivoGen) secretes reporter protein (Lucia luciferase or LUC) in response to activation caused by pro-inflammatory bacterial component lipopolysaccharide (LPS).THP-1 dual reporter cells are grown in RPMI 1640 culture medium containing 2mM L-glutamine, 25mM HEPES, 10% heat-inactivated fetal bovine serum, 100μg / ml Normocin antibiotics (InvivoGen), Pen-Strep antibiotics (100U / ml-100μg / ml, InvivoGen).On the day of the assay, cells were seeded in 96 flat-bottomed well plates at 50,000 cells / well and incubated for 2 hours. Then, the cells were incubated with 1 μM or 10 μM of the compounds described herein or with 1 μM IKK-16 (Selleck), a potent IκB kinase inhibitor (IKK), or with DMSO (vehicle control) for 2 hours, followed by the addition of 25 ng / mL of LPS and incubation for 24 hours. After the incubation, the culture supernatant was collected and the IRF-related activity was assessed by measuring Lucia luciferase using Quanti-Luc assay (InvivoGen), and these values ​​were adjusted by the cell viability level assessed using Cell-Titer-Glo2 reagent (Promega).

[0371] Compound I-100 showed inhibition of LPS-induced IRF reporter activity. This inhibition did not meet statistical significance when tested at 1 μM and 10 μM. Fig. 8A Compound A6 showed inhibition of LPS-induced IRF reporter activity in a cell-based assay. This inhibition met statistical significance when tested at 1 μM. Figure 8B .

[0372] Example 36: Compound Interconversion

[0373] 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, and they interconvert in solution.

[0374] In this example, A-6 was combined with 12 nM Na3PO4, DCl, and D2O at pH 7-7.5. This solution was then monitored at 37°C using 1H-NMR. Interconversion between compounds A-2 and A-3 was observed and monitored for 5 days. See Table 1. These data show that in neutral aqueous buffer at 37°C, the conversion of A-2 to A-3 almost reaches a 1 / about 1.5 equilibrium in about 3 hours. The conversion of A-3 to A2 almost reaches a 1.5 / 1 equilibrium in about 7 hours.

[0375] It should be understood that, although the present invention has been described in conjunction with preferred specific embodiments of the present invention, the foregoing description and subsequent examples are intended to illustrate rather than limit the scope of the present invention. It should be understood by those skilled in the art that, without departing from the scope of the present invention, various changes may be made and may be replaced with equivalents, and further, other aspects, advantages and modifications will be apparent to those skilled in the art to which the present invention belongs. In addition to the embodiments described herein, the present disclosure contemplates and claims those inventions resulting from the combination of the features of the present invention cited herein with the features of the cited prior art references that supplement the features of the present invention. Similarly, it should be understood that any of the materials, features or articles described may be used in combination with any other materials, features or articles, and such combinations are considered to be within the scope of the present invention.

[0376] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated by reference in their respective entireties for all purposes.

Claims

1. A compound having formula I: in: R 1 , R 2 , R 3 , and R 4 is independently H or optionally substituted C 1-6 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 ; R 15 Yes-C 1-6 alk-; R A is H or optionally substituted C 1-6 alkyl; X is O or NH; X 1 Yes CR 6 or N; X 2 Yes CR 7 or N; X 3 Yes CR 8 or N; X 4 Yes CR 9 or N; X 5 Yes CR 10 or N; X 6 and X 7 is independently H or optionally substituted C 1-6 alkyl, or both are N and are linked to form a diazolidinyl ring; R 6 , R 7 , R 8 , R 9 , and R 10 are independently H, OH, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, or -(OC 1-6 alk) n -C 1-6 alkyl; R 11 and R 12 is independently 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, NH2, or N(R 13 )(R 14 ); R 13 and R 14 independently H or C 1-6 alkyl; n is 2-8; and The premise is that X 1 -X 5 Only one of them is N; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1 , R 2 , R 3 , and R 4 Independently H.

3. The compound according to claim 1, wherein R 1 , R 2 , R 3 , and R 4 is independently optionally substituted C 1-6 Alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as methyl; or such as R 1 is methyl; or such as R 2 is methyl; or such as R 3 is methyl; or such as R 4 is methyl; or such as R 1 is H; or such as R 2 is H; or such as R 3 is H; or such as R 4 It's H.

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

5. The compound according to any one of claims 1 to 3, wherein R 5 is an optionally substituted C 1-6 Alkoxy, such as optionally substituted C 5-6 Alkyl, or such as optionally substituted C5 alkyl, or such as optionally substituted C6 alkyl.

6. The compound according to any one of claims 1 to 3, wherein R 5 Yes-N(R A )(Optionally substituted C 1-6 alkyl), such as -N(R A )(Optionally substituted C 5-6 alkyl), or such as -N(R A )(optionally substituted C5 alkyl), or such as -N(R A )(optionally substituted C6 alkyl).

7. The compound according to any one of claims 1 to 3, wherein R 5 is -X(R A )-R 13 -CH(X 6 )(X 7 )R 11 R 12 。 8. A compound as claimed in any one of the preceding claims, wherein R 18 It is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

9. A compound as claimed in any one of the preceding claims, wherein R A is H or optionally substituted C 1-6 alkyl.

10. A compound as claimed in any one of the preceding claims, wherein X is O.

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

12. A compound as claimed in any one of the preceding claims, wherein X 1 Yes CR 6 .

13. The compound according to any one of claims 1 to 11, wherein X 1 It is N.

14. A compound as claimed in any one of the preceding claims, wherein X 2 Yes CR 7 or N.

15. The compound according to any one of claims 1 to 13, wherein X 2 It is N.

16. A compound as claimed in any one of the preceding claims, wherein X 3 Yes CR 8 or N.

17. The compound according to any one of claims 1 to 15, wherein X 3 It is N.

18. A compound as claimed in any one of the preceding claims, wherein X 4 Yes CR 9 or N.

19. The compound according to any one of claims 1 to 17, wherein X 4 It is N.

20. A compound as claimed in any one of the preceding claims, wherein X 5 Yes CR 10 or N.

21. The compound according to any one of claims 1 to 19, wherein X 5 It is N.

22. A compound as claimed in any one of the preceding claims, wherein X 6 and X 7 independently H, or such as X 6 is H; or such as X 7 It's H.

23. A compound according to any one of claims 1 to 21, wherein X 6 and X 7 is independently optionally substituted C 1-6 Alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as methyl.

24. The compound of any one of claims 1 to 21, wherein X 6 and X 7 is N and is linked to form a diazolidinyl ring.

25. A compound as claimed in any one of the preceding claims, wherein R 6 , R 7 , R 8 , R 9 , and R 10 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 It's 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 It's a halogen.

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 an optionally substituted C 1-6 alkyl.

29. The compound of any one of claims 1 to 24, wherein R 6 , R 7 , R 8 , R 9 , and R 10 is an optionally substituted C 1-6 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 Yes-(OC 1-6 alk) n -C 1-6 alkyl.

31. A compound as claimed in any one of the preceding claims, wherein R 11 and R 12 is independently optionally substituted C 1-6 Alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

32. A compound as described in any one of claims 1 to 30, wherein R 11 and R 12 is independently optionally substituted C 2-6 Alkenyl, such as ethenyl, propenyl, butenyl, pentenyl, or hexenyl.

33. A compound as described in any one of claims 1 to 30, wherein R 11 and R 12 is independently optionally substituted C 2-6 Alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

34. A compound as described in any one of claims 1 to 30, wherein R 11 and R 12 is independently optionally substituted C 1-6 Alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy.

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

36. A compound as described in any one of claims 1 to 30, wherein R 11 and R 12 is independently NH2.

37. A compound as described in any one of claims 1 to 30, wherein R 11 and R 12 Independently N(R 13 )(R 14 ), such as NHCH3, or such as N(CH3)2.

38. A compound as claimed in any one of the preceding claims, wherein R 13 and R 14 Independently H.

39. A compound as described in any one of claims 1 to 37, wherein R 13 and R 14 Independently C 1-6 Alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

40. A compound as claimed in any one of the preceding claims, wherein n is 3-6, or 2, or 3, or 4, or 5, or 6, or 7, or 8.

41. The compound of claim 1, which is A or a pharmaceutically acceptable salt thereof.

42. The compound of claim 41, wherein The compound is A-1, such as A-2, A-3, A-4, or A-5 or a pharmaceutically acceptable salt thereof.

43. The compound of claim 41, which is Such as 44. The compound of claim 1, which is B or a pharmaceutically acceptable salt thereof.

45. The compound of claim 44, wherein The compound is B-1, such as B-2, B-3, B-4, or B-5 or a pharmaceutically acceptable salt thereof.

46. ​​The compound of claim 1, which is C or a pharmaceutically acceptable salt thereof.

47. The compound of claim 46, wherein The compound is C-1, such as C-2, C-3, C-4, or C-5 or a pharmaceutically acceptable salt thereof.

48. The compound of claim 46, which is Such as 49. The compound of claim 1, which is D or a pharmaceutically acceptable salt thereof.

50. The compound of claim 49, which is D-1, such as D-2, D-3, D-4, or D-5 or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1, which is E or a pharmaceutically acceptable salt thereof.

52. The compound of claim 51, which is E-1, such as E-2, E-3, E-4, or E-5 or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1, which is F or a pharmaceutically acceptable salt thereof.

54. The compound of claim 53, which is F-1, such as F-2, F-3, F-4, or F-5 or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1, which is G or a pharmaceutically acceptable salt thereof.

56. The compound of claim 55, which is G-1, such as G-2, G-3, G-4, or G-5 or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1, which is H or a pharmaceutically acceptable salt thereof.

58. The compound of claim 57, which is H-1, such as H-2, H-3, H-4, or H-5.

59. The compound of claim 1, wherein the compound is J or a pharmaceutically acceptable salt thereof.

60. The compound of claim 59, which is J-1, such as J-2, J-3, J-4, or J-6 or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, which is K or a pharmaceutically acceptable salt thereof.

62. The compound of claim 61, which is K-1, such as K-2, K-3, K-4, or K-5 or a pharmaceutically acceptable salt thereof.

63. The compound of claim 1, which is L or a pharmaceutically acceptable salt thereof.

64. The compound of claim 63, which is L-1, such as L-2, L-3, L-4, or L-5.

65. The compound of claim 1, which is M or a pharmaceutically acceptable salt thereof.

66. The compound of claim 65, which is M-1, such as M-2, M-3, M-4, or M-5 or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1, which is N or a pharmaceutically acceptable salt thereof.

68. The compound of claim 67, which is N-1, such as N-2, N-3, N-4, or N-5 or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1, which is O or a pharmaceutically acceptable salt thereof.

70. The compound of claim 69, which is O-1, such as O-2, O-3, O-4, or O-5 or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1, which is P or a pharmaceutically acceptable salt thereof.

72. The compound of claim 71, which is P-1, such as P-2, P-3, P-4, or P-5 or a pharmaceutically acceptable salt thereof.

73. The compound of claim 1, wherein The compound has the formula II:

74. The compound of claim 1, wherein The compound has the formula III:

75. The compound of claim 1, wherein The compound has IV:

76. The compound of claim 1, wherein The compound has the formula V:

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

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 as described in any one of claims 1-76 or a pharmaceutical composition as described in claim 77 or 78.

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

81. A method of modulating inflammatory bowel disease (IBD) markers in a subject in need thereof, the method comprising administering to the subject in need thereof a compound as described in any one of claims 1-76, a pharmaceutical composition as described in claim 77 or 78, or a dosage form as described in claim 79 or 80.

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

83. The method of claim 81 or 82, wherein: The subject suffers from or is at risk of developing IBD.

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

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

86. The method of any one of claims 81 to 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. The method of any one of claims 81 to 86, wherein The subject has a decreased 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.

88. The method of any one of claims 81 to 87, wherein The subject has a decreased 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 anti-neutrophil cytoplasmic antibodies (p-ANCA), or anti-Saccharomyces cerevisiae antibodies (ASCA), or a combination thereof.

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

90. The method of any one of claims 81 to 89, wherein: The subject has a reduced level of one or both serum amyloid A protein (SAA) or eotaxin-1.

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