Inhibitors of YAP / TAZ-TEAD oncoproteins

Abstract

Provided are YAP / TAZ-TEAD oncoprotein inhibitors of formula (I), or stereoisomers, and / or pharmaceutically acceptable salts, and / or solvates thereof, pharmaceutical compositions thereof, and methods of treatment.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates generally to cancer therapy, and more specifically to the synthesis of covalent inhibitors of the YAP / TAZ-TEAD oncoprotein and their use for the treatment of cancer. [Background technology]

[0002] background TEA domain transcription factors (TEAD proteins) are effectors of oncogenic YAP / TAZ signaling in cancers where Hippo tumor suppressor pathway signaling is deregulated. Interactions between Yes1 Associated Transcriptional Regulator (YAP1, also known as YAP), the YAP transcriptional coactivator paralog WW domain-containing Transcription Regulator 1 (WWTR1, also known as TAZ), and TEAD proteins have been demonstrated both in vitro and in vivo. In both cases, protein interactions lead to increased TEAD transcriptional activity and expression of genes involved in proliferation, survival, angiogenesis, and other hallmarks of cancer. In normal tissues, intact Hippo signaling via MST1 / 2 and LATS1 / 2 kinases results in the phosphorylation, cytoplasmic sequestration, and proteasomal degradation of YAP / TAZ. Inactivation of Hippo signaling as a result of somatic mutations in NF2, MST, or LATS stabilizes YAP / TAZ, leading to its nuclear translocation, association with TEAD, and activation of TEAD target genes. Genomic amplification of YAP / TAZ or gene fusions resulting in constitutively active YAP / TAZ are alternative mechanisms of Hippo pathway deregulation. Furthermore, activation of YAP / TAZ signaling has been described as a mechanism of resistance to other targeted cancer therapies, such as inhibitors of EGFR and MEK.

[0003] Therefore, inhibitors of TEAD1, 2, 3, and / or 4 may have great potential in cancer therapeutic applications, both as monotherapy and in combination with other targeted agents, in cancers where Hippo pathway signaling is deregulated. Summary of the Invention

[0004] overview This application is based on the discovery of a class of small molecule compounds that are effective as covalent inhibitors of the YAP / TAZ-TEAD oncoprotein. These compounds can be used in cancer therapy.

[0005] In a first aspect, a compound according to formula (I): TIFF2025532584000001.tif51128 or a stereoisomer thereof, and / or a pharmaceutically acceptable salt, and / or solvate thereof is provided, During the ceremony: Bond b is a double or triple bond; R 1 is H, C 1~3 Alkyl, morpholin-4-yl, and -CHN(C 1~3 alkyl)2; If bond b is a triple bond, R 1a is absent; if bond b is a double bond, R 1a is H; R 2 are H, F, -OH, C 1~3 Alkyl, -OC 1~3 selected from the group consisting of alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl; R 3 H and C 1~3 alkyl; and If bond b is a triple bond, R 8 is absent; if bond b is a double bond, R 8 are H, F, CN, and C 1~3 alkyl; and i) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: Bond a is a double or triple bond; X 1 is absent or selected from the group consisting of O, CH(OH), CH(OCH), CH, CHCH, CH(CH), and C(CH), and R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7 is selected from the group consisting of H and C1-C3 alkyl; or X 1 and R 4 together with the carbon to which they are attached form a C4-C6 cycloalkylene; X 2 is X 2a and X 2a is C; If bond a is a triple bond, R 5 is absent; or, if bond a is a double bond, R 5 is selected from the group consisting of H, F, and C1-C3 alkyl; If bond a is a triple bond, R 6 is absent; or, if bond a is a double bond, R 6 is selected from the group consisting of H, F, and C1-C3 alkyl; A is absent or selected from the group consisting of O, CH2, CH2CH2, CH(OH), CH(OCH3), C(CH3)2 and CH(CH3); and Ar is aryl or heteroaryl, each of which may contain 1, 2, 3, or 4 R 9 or ii) In the formula, bonds a, X 1 , X2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000002.tif23128 is formed, and X 2 is X 2a and X 2a is C;R 4 and R 6 together -(CH2) m -; m is 0, 1, or 2; X 1 is absent or selected from the group consisting of CH, CHCH, CH(CH), O, CHO, and OCH; R 5 is selected from the group consisting of H, F, and C1-C3 alkyl; A is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); and Ar is aryl or heteroaryl, each of which may be selected from 1, 2, 3, or 4 R 9 or iii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000003.tif17128 is formed, and X 1 is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); X 2 is X 2b and X 2b is N;R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7 is selected from the group consisting of H and C1-C3 alkyl; R 5 and Ar together TIFF2025532584000004.tif15128; and R 6 and A does not exist; or iv) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000005.tif11128 is formed, and X 1 is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); X 2 is X 2c and X 2c is N or CR 6 and R 6 is selected from the group consisting of H, F, and C1-C3 alkyl; R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7 is selected from the group consisting of H and C1-C3 alkyl; A is absent; and R 5 and Ar together Form TIFF2025532584000006.tif13128, where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused arylene or fused heteroarylene ring, where Ar 1 The ring may contain 1, 2, 3, or 4 R 9 optionally substituted with a group; Here, each R 9 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, C1-C6 alkoxy, and CN; However, the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)ethenyl]-1-piperidinyl]-2-propen-1-one.

[0006] In a second aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present application (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, and a pharmaceutically acceptable carrier.

[0007] In a third aspect, methods are provided for treating a disease or disorder modulated by TEAD1, 2, 3, and / or 4, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound disclosed herein (including those of Formula (I), (II), any embodiment, and any of Compounds 1-106), or administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound disclosed herein (including those of Formula (I), (II), any embodiment, and any of Compounds 1-106) and a pharmaceutically acceptable carrier. In some or any embodiments, the method is one in which TEAD1 is selectively inhibited relative to TEAD2, 3, and 4. In some or any embodiments, the disease or disorder is selected from cancer, fibrotic diseases, neurofibromatosis type 2, and polycystic kidney disease.

[0008] In a fourth aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (including those according to any of Formulas (I), (II), any embodiment herein, and compounds 1-106), or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof; or a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, and a pharmaceutically acceptable carrier.

[0009] In a fifth aspect, provided herein are compounds useful as intermediates in the preparation of the compounds disclosed herein.

[0010] In a sixth aspect, provided herein are methods for preparing compounds of formula (I) according to either the general schemes or synthetic examples.

[0011] In another aspect, the disclosure provides a method of inhibiting TEAD1, 2, 3, and / or 4 in a subject or sample, comprising administering a compound of Formula (I) (including those according to any of Formulas (I), (II), any embodiment herein, and compounds 1-106) or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof. In certain embodiments, the compound is at least one of the compounds as set forth in Table 1, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a schematic diagram showing how compounds of the present disclosure function as covalent TEAD1 inhibitors.

[0013] [Figure 2] 1 is a graph showing the percent weight change over time in mice following treatment according to Example 5.

[0014] [Figure 3] 1 is a graph showing the percent volume change over time of tumors in mice following treatment according to Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description The present disclosure is based on the discovery of a class of small molecule compounds that inhibit the activity of TEAD1, 2, 3, and / or 4, and in some embodiments, selectively inhibit the activity of TEAD1 relative to the activity of other TEAD isoforms, which show potential in the treatment of cancer, in some embodiments, certain types of cancer. TEAD1 belongs to the TEAD family, which regulates cell growth and proliferation via the TEAD1 / YAP / TAZ complex. TEAD1 regulates glioblastoma stemness and invasiveness by regulating the expression of EGFR and AQP4 via the TEAD-EGFR / AQP4 pathway. Furthermore, through the Hippo-YAP / TAZ-TEAD pathway, YAP / TAZ-TEAD activation induces the transcription of cell cycle-promoting genes; TEAD1 controls the expression of cytoskeleton remodeling genes; TEAD1 increases the expression of other transcription factors such as Myc and SP1; the YAP / TAZ-TEAD1 axis controls cell apoptosis; blocking TEAD1 aberrant activity downregulates the expression of genes such as MYC, KRAS, BRAF, NF2, LKB1, and PD-L1. Consequently, inhibitor compounds that inhibit the activity of TEAD1, 2, 3, and / or 4 (in some embodiments, selectively for TEAD1) have potential in the treatment of cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).

[0016] It is to be understood that the aspects and embodiments disclosed herein are not limited to the particular compositions, methods, and experimental conditions described, as such compositions, methods, and experimental conditions may vary. It is also to be understood that the terminology used herein is intended for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0017] Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, it being understood that modifications and variations are within the spirit and scope of the disclosure. Preferred methods and materials are now described.

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0019] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the method" includes one or more methods, and / or steps, of the type described herein that would become apparent to those skilled in the art upon reading this disclosure.

[0020] In the event that there are multiple definitions for a term herein, the definitions in this section shall prevail unless otherwise specified.Unless otherwise specified, when a term is defined as substituted, the groups in the list of substituents are themselves unsubstituted.For example, a substituted alkyl group can be substituted with, for example, a cycloalkyl group, and unless otherwise specified, the cycloalkyl group is not further substituted.

[0021] When referring to the compounds provided herein, unless otherwise indicated, the following terms have the following meanings: Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0022] The term "about" will be understood by those of ordinary skill in the art. Regardless of whether the term "about" is explicitly used, all quantities given herein refer to the actual given value and are also meant to refer to approximations to such given value that would be reasonably estimated based on ordinary skill in the art. Reference to "about" a value or parameter herein includes (and describes) variations to the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X." As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with temperature, dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent that would be recognized by those of ordinary skill in the art as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent.

[0023] As used herein, "acyl" refers to the group --C(O)R, where R is alkyl or cycloalkyl, as defined herein.

[0024] "Alkyl" refers to a straight-chain or branched, monovalent saturated hydrocarbon, where the alkyl has 1 to 12 carbon atoms, in some embodiments 1 to 10 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 3 carbon atoms, or in some embodiments 1, 2, 3, or 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl groups. "Lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms. A "C0" alkyl (as in "C0-C6 alkyl") is a covalent bond. "C6 alkyl" refers, for example, to n-hexyl, iso-hexyl, etc. In some embodiments, alkyl is a C 1~3 Alkyl or C 1~4 It is alkyl.

[0025] "Alkylcarbonyl" refers to the group -C(O)R, where R is alkyl, as defined herein. In some embodiments, acyl is acetyl. Lower alkylcarbonyl is one where alkyl is C1-C6 alkyl.

[0026] "Alkylcarbonyloxy" refers to an -OC(O)R group, where R is alkyl, as defined herein.

[0027] "Alkylsulfonyl" refers to a -S(O)R group, where R is alkyl, as defined herein.

[0028] "C1-C6 alkylthio" refers to the group -SR, where R is alkyl, as defined herein.

[0029] "Alkoxy" refers to the group -OR, where R is alkyl, as defined herein. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and hexyloxy groups. In some embodiments, the alkoxy is methoxy. "Lower alkoxy" refers to -OR, where R is alkyl having 1 to 6 carbon atoms.

[0030] "C1-C6 alkoxycarbonyl" refers to a -C(O)R group, where R is C1-C6 alkoxy, as defined herein.

[0031] "Haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogens, e.g., 1, 2, 3, 4, or 5 halo atoms. Representative examples include 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl. "Lower haloalkyl" means that the alkyl has 1 to 6 carbon atoms. In some embodiments, the haloalkyl is trifluoromethyl. "Lower perhaloalkyl" means that all hydrogens in the alkyl have been replaced with halo.

[0032] "C1-C6 haloalkylthio" refers to the radical -SR, where R is a C1-C6 haloalkyl group, as defined herein.

[0033] "Haloalkenyl" refers to an alkenyl group, as defined herein, substituted with one or more halogens, e.g., 1, 2, 3, 4, or 5 halo atoms. "Lower haloalkenyl" means the alkenyl has 2 to 6 carbon atoms.

[0034] "Haloalkynyl" refers to an alkynyl group, as defined herein, substituted with one or more halogens, e.g., 1, 2, 3, 4, or 5 halo atoms. "Lower haloalkynyl" means the alkynyl has 2 to 6 carbon atoms.

[0035] "Haloalkoxy" refers to the group -OR, where R is haloalkyl, as defined herein. "Lower perhaloalkoxy" means that all hydrogens in the alkyl have been replaced with halo.

[0036] "Cycloalkyl" refers to a monocyclic or bicyclic monovalent hydrocarbon group having 3 to 14 carbon ring atoms. Cycloalkyls can be saturated or partially saturated, but cannot contain aromatic rings. Cycloalkyls include fused, bridged, and spiro ring systems. In some embodiments, cycloalkyls have 3 to 12, 3 to 10, 3 to 8, 4 to 6, or 3, 4, 5, 6, or 7 carbon atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of bicyclic cycloalkyls include, but are not limited to, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, spiro[2.2]pentanyl, and the like.

[0037] "Cycloalkylene" refers to a divalent cycloalkyl, as defined herein. Examples of monocyclic cycloalkylenes include, but are not limited to, cyclopropa-diyl, cyclobuta-diyl, cyclopenta-diyl, and cyclohexa-diyl groups. Examples of bicyclic cycloalkylenes include, but are not limited to, bicyclo[4.4.0]decane-diyl, bicyclo[2.2.1]heptane-diyl, spiro[2.2]pentane-diyl, and the like. In some embodiments, the cycloalkylene is a C4-C6 cycloalkylene.

[0038] "Alkenyl" refers to a straight-chain or branched, monovalent hydrocarbon group containing 2 to 12 carbon atoms and one or more double bonds between two carbon atoms. In some embodiments, an alkenyl has 2 to about 10 carbon atoms, 2 to 8 carbon atoms, 2 to about 6 carbon atoms, or 2, 3, or 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others. "Lower alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms.

[0039] "Alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more triple bonds between two carbon atoms and 2 to 12 carbon atoms, in some embodiments 2 to 10 carbon atoms, in some embodiments 2 to 6 carbon atoms, or 2, 3, or in some embodiments 4 carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH), among others. "Lower alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms.

[0040] "Aryl" means a monovalent 6- to 14-membered mono- or bi-carbon ring, where a monocyclic ring is aromatic and at least one ring in a bicyclic ring is aromatic. In some embodiments, an aryl contains 6 to 10 carbon ring atoms. Representative examples include phenyl, naphthyl, and indanyl. In some embodiments, an aryl is phenyl.

[0041] "Heteroaryl" refers to N, -N(R x )-, O, S, and S(O) n- refers to a monovalent monocyclic, fused bicyclic, or fused tricyclic group of 5 to 14 ring atoms containing one or more heteroatoms, e.g., 1, 2, 3, or 4 ring heteroatoms, independently selected from - (n is 0, 1, or 2), and the remaining ring atoms are carbon, where the rings comprising the monocyclic group are aromatic and at least one of the fused rings comprising the bicyclic or tricyclic group is aromatic. One or two ring carbon atoms of any non-aromatic ring comprising the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic groups include bridged ring systems. Unless otherwise specified, the point of attachment may be on any atom of any ring of the heteroaryl group, valence rules permitting. In particular, when the point of attachment is on a nitrogen, R xExamples of heteroaryl include isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, 1,3,5-triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl), isoindolyl, indolinyl, isoindolinyl, phthalimidyl, pyrazolopyridyl, benzofuranyl, benzimidazolyl, benzodioxol-4-yl, cinnolinyl, Examples of heteroaryl include, but are not limited to, benzoyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (e.g., including tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (e.g., including pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, and benzothienyl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl, or pyridinyl. In some embodiments, heteroaryl is pyrazolyl, pyrimidinyl, or pyridinyl. In some embodiments, heteroaryl is pyrazolyl or pyrimidinyl. In some embodiments, heteroaryl is oxazolyl, isoxazolyl, thiazolyl, or pyridinyl.

[0042] "Fused arylene" refers to a divalent monocyclic aryl ring, as defined herein, that is fused to a second ring and includes one of the following rings: Ar in TIFF2025532584000007.tif11128 1In some embodiments, Ar 1 The fused arylene is TIFF2025532584000008.tif14128.

[0043] "Fused heteroarylene" refers to a divalent monocyclic heteroaryl ring, as defined herein, that is fused to a second ring and includes one of the following rings: Ar in TIFF2025532584000009.tif11128 1 In some embodiments, Ar 1 The fused heteroarylene is TIFF2025532584000010.tif13128.

[0044] "Heterocycloalkyl" means a saturated monovalent monocyclic radical of 3 to 9 ring atoms, or a saturated monovalent fused bicyclic radical of 5 to 12 ring atoms, where one or more heteroatoms, e.g., 1, 2, 3, or 4 ring heteroatoms, are independently selected from the group consisting of -O-, -S(O) n - (n is 0, 1, or 2), -N=, -N(R y )-(where R y are independently selected from hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), and the remaining ring atoms are carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Fused bicyclic groups include bridged ring systems. Unless otherwise stated, the point of attachment of a group may be located on any atom of any ring within the group, valence rules permitting. In particular, when the point of attachment is on a nitrogen, R yMore specifically, the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolidyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and N-oxides thereof.

[0045] Halogen groups include F, Cl, Br, and I; a nitro group refers to -NO2; and a cyano group refers to -CN.

[0046] "Amino" refers to -NH2.

[0047] "Lower carbamates" are -O(C=O)NR a R b where R a and R b are independently hydrogen, C1-C6 alkyl, aryl, or heterocyclyl.

[0048] The term "substituted heteroaryl" refers to heteroaryl, as defined herein, substituted with one or more (1, 2, 3, or 4) substituents independently selected from the following groups: lower alkyl, lower alkenyl, lower alkynyl, C3-C6 heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, C3-C6 cycloalkyl, phenyl, lower alkoxy, lower lower haloalkoxy, oxo, lower alkylcarbonyloxy, lower alkylcarbonyl, C1-C6 alkoxycarbonyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, cyano, halogen, hydroxy, amino, lower alkylamino, -NHC(O)R (where R is C1-C6 alkyl), nitro, C1-C6 alkylthio, C1-C6 haloalkylthio, SH, and lower carbamate.

[0049] As used herein, the term "protecting group" refers to a group that is attached to an oxygen atom, a nitrogen atom, or a phosphorus atom to prevent further reaction or for other purposes, unless otherwise specified. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis (see, for example, the protecting groups described in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference). In some or any embodiments, the "nitrogen protecting group" is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, -C(O)OCHCl(Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs), or p-toluenesulfonyl (tosyl). In some or any embodiments, the oxygen protecting group (e.g., X1 (relating to) is methoxymethyl (MOM), ethoxyethyl, methoxyethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, methyl, tert-butyl, allyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivalyl, benzoyl, dimethoxytrityl, trityl, methoxytrityl, p-methoxybenzyl, or methylthiomethyl.

[0050] "Stereoisomers" refer to compounds that have the same molecular formula and sequence (configuration) of bonded atoms but differ in the three-dimensional orientation of the atoms in space. Stereoisomers include enantiomers, diastereomers, geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers), and atropisomers. Enantiomers are a pair of molecules with identical connectivity that exist in two forms that are mirror images of each other but are not superimposable on one another. Diastereoisomers are non-identical stereoisomers that have a different configuration at one or more equivalent stereocenters and are not mirror images of each other. Geometric isomers include cis-trans isomers or configurational isomers, and refer to pairs of molecules that have the same formula but whose functional groups are in different orientations in three-dimensional space. Cis-trans stereoisomers may contain non-rotatable double bonds or ring structures that restrict or prevent bond rotation. Cis indicates that the functional groups (substituents) are on the same side of a plane, while trans indicates that they are on opposite (transverse) sides. Atropisomers are stereoisomers resulting from hindrance of rotation around a single bond, where the steric strain barrier to rotation is high enough to allow for isolation of conformers. In some or any embodiment, the stereoisomers are geometric isomers. In some or any embodiment, the stereoisomers are enantiomers. In some or any embodiment, the stereoisomers are enantiomers and geometric isomers.

[0051] The term "substantially free" of stereoisomers (e.g., geometric isomers) or "in the substantial absence" of stereoisomers, with respect to compositions, refers to a composition that comprises at least 85% or 90% by weight, and in some or any embodiments 95%, 98%, 99%, or 100% by weight of the specified stereoisomer (e.g., geometric isomer) of the compound in the composition. In some or any embodiments, in the methods and compounds provided herein, the compound is substantially free of the specified stereoisomer (e.g., geometric isomer) of the compound.

[0052] Similarly, the term "isolated" with respect to a composition refers to a composition that contains at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the specified compound, with the remainder containing other species or stereoisomers (e.g., geometric isomers) thereof.

[0053] As used herein, the term "solvate" refers to a compound provided herein or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, unless otherwise specified. When the solvent is water, the solvate is a hydrate.

[0054] Pharmaceutically acceptable salts of the compounds described herein (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) include the conventional non-toxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like. In other cases, the compounds described may contain one or more acidic functional groups, and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable bases.These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine.Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts.Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc.

[0055] compound The aspects and embodiments described herein include the described compounds, as well as pharmaceutically acceptable salts, and / or hydrates, and / or solvates, and / or stereoisomers, and / or tautomers, and / or mixtures, or any combination thereof. In some embodiments, the described compounds are provided as pharmaceutically acceptable salts, and / or stereoisomers, and / or tautomers, and / or mixtures, or any combination thereof. In some embodiments, the described compounds are provided as pharmaceutically acceptable salts, and / or stereoisomers, and / or tautomers. In some embodiments, the described compounds are provided as pharmaceutically acceptable salts thereof.

[0056] Certain polycyclic structures provided herein are depicted with one or more variable substituents. Unless otherwise specified or clear from the context, a substituent may be present on any atom of the polycyclic ring, as long as it is chemically feasible and valence rules permit. For example, the structure: In TIFF2025532584000011.tif18128, R 9 Substituents can be present on either the benzo portion of the bicyclic ring or the furanyl portion of the bicyclic ring.

[0057] Embodiment A: In some or any embodiments, the compound of formula (I) is as follows: TIFF2025532584000012.tif17128 is TIFF2025532584000013.tif21128; Bond b is a double or triple bond; R 1 is H or C 1~3 alkyl (in some embodiments, methyl); If bond b is a triple bond, R 1a is absent; if bond b is a double bond, R 1a is H; R 2 is H, C1~2 selected from the group consisting of alkyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), and 5-membered heteroaryl (in some embodiments, pyrazolyl); R 3 is H or methyl; and If bond b is a triple bond, R 8 is absent; if bond b is a double bond, R 8 is selected from the group consisting of H and F; and i) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: Bond a is a double or triple bond; X 1 is absent or is CH, CH(OH), or C(CH), and R 4 is selected from the group consisting of H, methyl, F, —OH, methoxy, and CN; or X 1 and R 4 together with the carbon to which they are attached form a C4-C6 cycloalkylene; X 2 is X 2a and X 2a is C; If bond a is a triple bond, R 5 is absent; or, if bond a is a double bond, R 5 is H, If bond a is a triple bond, R 6 is absent; or, if bond a is a double bond, R 6 is H; A is absent or selected from the group consisting of CH2, CH(OH), CH(OCH3), and C(CH3)2; and Ar is phenyl, oxazolyl, thiazolyl, or pyridinyl, each of which is selected from the group consisting of one or two R 9or ii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000014.tif23128 is formed, and X 2 is X 2a and X 2a is C;R 4 and R 6 together -(CH2) m -; m is 0, 1, or 2; X 1 is absent or selected from the group consisting of CH, O, CHO and OCH; R 5 is H; A is absent; and Ar is one R 9 phenyl optionally substituted by a group; provided that X 1 is not present, then m is 1 or 2; or iii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000015.tif17128 is formed, and X 1 does not exist;X 2 is X 2b and X 2b is N;R 4 is H;R 5 and Ar together Form TIFF2025532584000016.tif17128; and R 6 and A does not exist; or iv) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6, A, and Ar together TIFF2025532584000017.tif11128 is formed, and X 1 does not exist;X 2 is X 2c and X 2c is CR 6 and R 6 is H;R 4 is H; A is absent; and R 5 and Ar together TIFF2025532584000018.tif12128, where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is one R 9 substituted fused phenylene; Here, each R 9 is independently selected from the group consisting of ethynyl, F, —CF3, and methoxy; However, the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)ethenyl]-1-piperidinyl]-2-propen-1-one.

[0058] Embodiment B: In some or any embodiments, the compound of formula (I) is as follows: TIFF2025532584000019.tif17128 is TIFF2025532584000020.tif21128; Bond b is a double or triple bond; R 1 is H; If bond b is a triple bond, R 1a is absent; if bond b is a double bond, R 1a is H; R 2 is H, C 1~2 selected from the group consisting of alkyl, methoxy, and 5-membered heteroaryl (in some embodiments, pyrazolyl); R 3is H or methyl; and If bond b is a triple bond, R 8 is absent; if bond b is a double bond, R 8 is selected from the group consisting of H and F; and i) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: Bond a is a double or triple bond; X 1 is absent or is CH2, and R 4 is selected from the group consisting of H, methyl, F, —OH, methoxy, and CN; or X 1 and R 4 together with the carbon to which they are attached form a C4-C6 cycloalkylene; X 2 is X 2a and X 2a is C; If bond a is a triple bond, R 5 is absent; or, if bond a is a double bond, R 5 is H; If bond a is a triple bond, R 6 is absent; or, if bond a is a double bond, R 6 is H; A does not exist; and Ar is phenyl, oxazolyl, thiazolyl, or pyridinyl, each of which is selected from the group consisting of one or two R 9 or ii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000021.tif23128 is formed, and X 2 is X 2a and X 2a is C;R 4 and R 6 together -(CH2) m -; m is 1 or 2; X 1 is absent or selected from the group consisting of CH; R 5 is selected from the group consisting of H; A is absent; and Ar is selected from the group consisting of one R 9 phenyl optionally substituted with a group; or In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000022.tif17128 is formed, and X 1 does not exist;X 2 is X 2b and X 2b is N;R 4 is selected from the group consisting of H; R 5 and Ar together Form TIFF2025532584000023.tif17128; and R 6 and A does not exist; or iii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000024.tif11128 is formed, and X 1 does not exist;X 2 is X 2c and X 2c is CR 6 and R 6 is selected from the group consisting of H; R 4 is H; A is absent; and R 5and Ar together TIFF2025532584000025.tif12128, where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is one R 9 substituted fused phenylene; Here, each R 9 is independently selected from the group consisting of ethynyl, F, —CF3, and methoxy; However, the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)ethenyl]-1-piperidinyl]-2-propen-1-one.

[0059] Embodiment 1: Provided is a compound of formula (I), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, as provided in the first aspect. In some or any embodiments, the compound of formula (I) is according to embodiment A or B.

[0060] Aspect 1A: A compound of formula (I), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein During the ceremony: Bond b is a double or triple bond; R 1 is H, C 1~3 Alkyl, morpholin-4-yl, and -CHN(C 1~3 alkyl)2; If bond b is a triple bond, R 1a is absent; if bond b is a double bond, R 1a is H; R 2 are H, F, -OH, C 1~3 Alkyl, -OC 1~3 selected from the group consisting of alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl; R 3 H and C 1~3alkyl; and If bond b is a triple bond, R 8 is absent; if bond b is a double bond, R 8 are H, F, CN, and C 1~3 alkyl; and i) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: Bond a is a double or triple bond; X 1 is absent or selected from the group consisting of O, CH, CHCH, and CH(CH), and R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7 is selected from the group consisting of H and C1-C3 alkyl; or X 1 and R 4 together with the carbon to which they are attached form a C4-C6 cycloalkylene; X 2 is X 2a and X 2a is C; If bond a is a triple bond, R 5 is absent; or, if bond a is a double bond, R 5 is selected from the group consisting of H, F, and C1-C3 alkyl; If bond a is a triple bond, R 6 is absent; or, if bond a is a double bond, R 6 is selected from the group consisting of H, F, and C1-C3 alkyl; A is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); and Ar can be 1, 2, 3, or 4 R 9an aryl or heteroaryl group optionally substituted with a group; or ii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000026.tif23128 is formed, and X 2 is X 2a and X 2a is C;R 4 and R 6 together -(CH2) m -; m is 1 or 2; X 1 is absent or selected from the group consisting of CH, CHCH, and CH(CH); R 5 is selected from the group consisting of H, F, and C1-C3 alkyl; A is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); and Ar is selected from 1, 2, 3, or 4 R 9 an aryl or heteroaryl group optionally substituted with a group; or iii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000027.tif17128 is formed, and X 1 is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); X 2 is X 2b and X 2b is N;R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7is selected from the group consisting of H and C1-C3 alkyl; R 5 and Ar together TIFF2025532584000028.tif15128 is formed; and R 6 and A does not exist; or iv) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together TIFF2025532584000029.tif11128 is formed, and X 1 is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); X 2 is X 2c and X 2c is N or CR 6 and R 6 is selected from the group consisting of H, F, and C1-C3 alkyl; R 4 is H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1~3 Alkyl, CN, and NHR 7 and R 7 is selected from the group consisting of H and C1-C3 alkyl; A is absent; and R 5 and Ar together Form TIFF2025532584000030.tif13128, where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 can have 1, 2, 3, or 4 R's 9 a fused arylene or fused heteroarylene ring optionally substituted with a group; Here, each R 9 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, C1-C6 alkoxy, and CN; With the proviso that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)ethenyl]-1-piperidinyl]-2-propen-1-one, Provided are compounds of formula (I), or stereoisomers, and / or pharmaceutically acceptable salts, and / or solvates thereof:

[0061] Embodiment 2. In embodiment 2, bond b is a double bond and R 1a is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0062] Embodiment 3. In embodiment 3, bond b is a triple bond and R 1a and R 8

[0023] Provided is a compound according to any one of embodiments 1, 1A, A, and B, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

[0063] Aspect 4. In aspect 4, R 1 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0064] Embodiment 5. In embodiment 5, R 1 is provided a compound according to any one of aspects A and 1-3, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

[0065] Embodiment 6. In embodiment 6, R 1 is —CH 2 N(Me) 2 , or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0066] In embodiment 7a, R 1 is H and C1~3

[0023] Provided is a compound according to any one of aspects A and 1-3, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein the compound is selected from the group consisting of alkyl.

[0067] Embodiment 7. In embodiment 7, R 1 is selected from the group consisting of H and Me, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0068] Embodiment 8. In embodiment 8, R 2 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0069] Embodiment 9. In embodiment 9, R 2 is F, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0070] Embodiment 10. In embodiment 10, R 2 is —OH, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0071] Embodiment 11. In embodiment 11, R 2 C 1~3 In an embodiment 11, R is alkyl, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof. 2 C 1~2 Provided are compounds according to any one of aspects A, B, and 1-7, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is alkyl.

[0072] Embodiment 12. In embodiment 12, R 2 is H, methyl, or ethyl, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0073] In embodiment 2, R 2 Ga-OC 1~3 Provided is a compound according to any one of aspects 1 to 7, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is alkyl.

[0074] Embodiment 13. In embodiment 13, R 2 is -OMe, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0075] Embodiment 14. In embodiment 14, R 2 is —NH-heteroaryl or —NH-(substituted heteroaryl), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0076] Embodiment 15. In embodiment 15, R 2 In some embodiments, R is unsubstituted heteroaryl (in some embodiments, pyrazolyl) or substituted heteroaryl (in some embodiments, pyrazolyl), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof. 2 is an unsubstituted 5-membered heteroaryl (in some embodiments, pyrazolyl), or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0077] Embodiment 16. In embodiment 16, R 2 is H, methyl, ethyl, methoxy, —NH-heteroaryl (in some embodiments, —NH-pyrimidinyl), or unsubstituted heteroaryl (in some embodiments, pyrazolyl), or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0078] Embodiment 17. In embodiment 17, R 2 is H, methyl, ethyl, or unsubstituted pyrazolyl, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0079] Embodiment 18. In embodiment 18, R 3 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0080] Embodiment 19. In embodiment 19, R 3 is F, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0081] Embodiment 20. In embodiment 20, R 3 In aspect 20, there is provided a compound according to any one of aspects 1 to 17, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein R is methyl or ethyl. 3 is provided a compound according to any one of aspects A, B, 1, and 2-17, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

[0082] Embodiment 21. In embodiment 21, bond b is a double bond and R 8is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0083] Embodiment 22. In embodiment 22, bond b is a double bond and R 8 is F, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0084] Embodiment 23. In embodiment 23, bond b is a double bond and R 8 is CN, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0085] Embodiment 24. In embodiment 24, bond b is a double bond and R 8 is Me, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0086] Embodiment 25. In embodiment 25, bond a, X 1 , X 2 , R 4 , R 5 , R 6 A compound according to any one of embodiments A, B, and 1-24, and / or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, is provided, wherein A, A, and Ar are according to i).

[0087] In embodiment 26a, X 1is absent or is CH, CH(OH), or C(CH), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0088] Embodiment 26. In embodiment 26, X 1

[0039] Provided is a compound according to embodiment 25, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

[0089] Embodiment 27. In embodiment 27, X 1 is CH2, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0090] Embodiment 28. In embodiment 28, the compound of formula: Provided is a compound according to any one of embodiments A, B, 1, and IA, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, according to TIFF2025532584000031.tif34128.

[0091] Embodiment 29. In embodiment 29, R 4 is H, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0092] Embodiment 30. In embodiment 30, R 4 is C1-C4 alkyl(methyl), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0093] Embodiment 31. In embodiment 31, R 4is cyclopropyl.

[0094] Embodiment 32. In embodiment 32, R 4 is F, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0095] Embodiment 33. In embodiment 33, R 4 is Cl, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0096] Embodiment 34. In embodiment 34, R 4 is —OH, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0097] Embodiment 35. In embodiment 35, R 4 is -OMe, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0098] Embodiment 36. In embodiment 36, R 4 is CN, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0099] Embodiment 37. In embodiment 37, R 4 NHR 7 and R 7is selected from the group consisting of H and C1-C3 alkyl, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0100] Embodiment 38. In embodiment 38, X 1 and R 4 are taken together with the carbon to which they are attached to form a C4-C6 cycloalkylene, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0101] Embodiment 39. In embodiment 39, X 1 and R 4 are taken together with the carbons to which they are attached to form a C4 cycloalkylene or a C6 cycloalkylene, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0102] Embodiment 40. In embodiment 40, there is provided a compound according to any one of embodiments 25 to 39, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is a double bond.

[0103] Embodiment 41. In embodiment 41, bond a is a double bond and R 5 and R 6 and R are each H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0104] Embodiment 42. In embodiment 42, there is provided a compound according to any one of embodiments 25 to 41, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is a double bond and is cis.

[0105] Embodiment 43. In embodiment 43, there is provided a compound according to any one of embodiments 25 to 41, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is a double bond and is trans.

[0106] Embodiment 44. In embodiment 44, bond a is a triple bond and R 5 and R 6

[0039] There is provided a compound according to any one of aspects 25 to 39, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is absent.

[0107] Embodiment 45. In embodiment 45, bond a, X 1 , X 2 , R 4 , R 5 , R 6 There is provided a compound according to any one of aspects A, B, and 1-24, wherein A, and Ar are according to ii).

[0108] Embodiment 46. In embodiment 46, there is provided a compound according to embodiment 45, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein m is 1.

[0109] Embodiment 47. In embodiment 47, there is provided a compound according to embodiment 45, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein m is 2.

[0110] Embodiment 48. In embodiment 48, X 1

[0039] There is provided a compound according to any one of aspects 45 to 47, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is absent.

[0111] Embodiment 48a. In embodiment 48a, m is 0 and X 1is other than absent, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0112] In embodiment 48b, X 1 is absent or is selected from the group consisting of CH, O, CHO, and OCH, each of which is dependent on any one of A, 1, and 2-24.

[0113] In embodiment 48c, X 1 In a subembodiment of aspect 48c, there is provided a compound according to any one of aspects 45 to 47, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein X is CH2, CH2CH2, or CH(CH3), preferably CH2. 1 is CH2.

[0114] Embodiment 49. In embodiment 49, R 5 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0115] Embodiment 50. In embodiment 50, there is provided a compound according to any one of embodiments 25 to 49, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein A is absent.

[0116] Embodiment 51a. In embodiment 51a, there is provided a compound according to any one of embodiments 25-44 (each of which is dependent on any one of embodiments A, 1, and 2-24), or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein A is selected from the group consisting of CH2, CH(OH), CH(OCH3), and C(CH3)2.

[0117] Embodiment 51. In embodiment 51, Ar is selected from the group consisting of 1, 2, 3, or 4 R 9

[0039] Provided is a compound according to any one of aspects 25 to 50, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is aryl optionally substituted with a group.

[0118] Embodiment 52a. In embodiment 52a, Ar is selected from the group consisting of 1, 2, 3, or 4 R 9 phenyl optionally substituted with one R 9 and optionally substituted with (a) or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, according to any one of aspects 20 to 46.

[0119] Embodiment 52. In embodiment 52, Ar is selected from the group consisting of 1, 2, 3, or 4 R 9

[0033] Provided is a compound according to any one of aspects 25 to 51, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is phenyl optionally substituted with a group.

[0120] Embodiment 53a. In embodiment 53a, Ar is selected from the group consisting of 1, 2, 3, or 4 R 9 and heteroaryl (preferably oxazolyl, imidazolyl, or pyridinyl) optionally substituted with a group (in some embodiments, the heteroaryl is substituted with one R 9 and optionally substituted with (a) or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, according to any one of aspects 20 to 46.

[0121] Embodiment 53. In embodiment 53, Ar is selected from the group consisting of 1, 2, 3, or 4 R 9

[0033] Provided is a compound according to any one of Aspects 25 to 50, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is a heteroaryl group, preferably oxazolyl, imidazolyl, or pyridinyl, optionally substituted with a group.

[0122] Embodiment 54. In embodiment 54, bond a, X 1 , X 2 , R 4 , R 5 , R 6 A compound according to any one of embodiments 1 to 24 is provided, wherein, A, and Ar are according to iii).

[0123] Embodiment 55. In embodiment 55, X 1 does not exist and R 4 is H, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0124] Embodiment 56. In embodiment 56, bond a, X 1 , X 2 , R 4 , R 5 , R 6 A compound according to any one of embodiments 1 to 24 is provided, wherein, A, and Ar are according to iv).

[0125] Embodiment 57. In embodiment 57, X 2 is CH, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0126] Embodiment 58. In embodiment 58, X 2 is N, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0127] Embodiment 59. In embodiment 59, X 1 does not exist and R 4is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0128] Embodiment 60. In embodiment 60, X 3 is O, NH, N(Me), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0129] Embodiment 61. In embodiment 61, Ar 1 but 1, 2, 3, or 4 R 9

[0023] Provided is a compound according to any one of aspects 56 to 60, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein the compound is benzo or pyrido, optionally substituted with a group.

[0130] Embodiment 62. In embodiment 62, each R 9 are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; or each R 9 is independently selected from the group consisting of methyl, ethynyl, F, CF3, and methoxy, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0131] Embodiment 63. In embodiment 63, one or two R 9 is present and is independently selected, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0132] Embodiment 64. In embodiment 64, one R 9 is CF3, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

[0133] In embodiment 65a, TIFF2025532584000032.tif19128 TIFF2025532584000033.tif21128, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0134] Embodiment 65. In embodiment 65, TIFF2025532584000034.tif19128 TIFF2025532584000035.tif21128, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0135] Embodiment 66. In embodiment 66, TIFF2025532584000036.tif19128 TIFF2025532584000037.tif18128, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0136] Embodiment 67. In embodiment 67, TIFF2025532584000038.tif19128 TIFF2025532584000039.tif18128, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0137] Embodiment 68. In embodiment 68, TIFF2025532584000040.tif19128 TIFF2025532584000041.tif20128, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0138] Embodiment 69. In embodiment 69, there is provided a compound according to embodiment 1 selected from the compounds in Table 1, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0139] Embodiment 70. In embodiment 70, TIFF2025532584000042.tif64151, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

[0140] Embodiment 71. In embodiment 71, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of embodiments 1 to 106, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof; and a pharmaceutically acceptable carrier.

[0141] Embodiment 72. In embodiment 72, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 106, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof; or a pharmaceutical composition according to embodiment 71.

[0142] Embodiment 73. In embodiment 73, the cancer is selected from the group consisting of bladder cancer, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), glioblastoma, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia, non-Hodgkin's lymphoma, prostate cancer, rectal cancer, malignant melanoma, gastrointestinal / gastrointestinal tract cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye cancer, rectal cancer, colorectal cancer, cervical cancer, oral cancer, benign and malignant tumors, stomach cancer. 73. The method of embodiment 72 is provided, wherein the cancer is selected from the group consisting of: uterine cancer, endometrial cancer, testicular cancer, renal cancer, throat cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oral cavity / pharyngeal cancer, esophageal cancer, laryngeal cancer, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

[0143] Embodiment 74. In embodiment 74, there is provided the method of embodiment 72, wherein said cancer is selected from the group consisting of glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).

[0144] Embodiment 75. In embodiment 75, there is provided a method according to any one of embodiments 72 to 74, wherein the method further comprises the step of administering, simultaneously or sequentially, one or more KRAS G12C and / or G12D inhibitors; one or more CDK4 / 6 inhibitors; one or more EGFR inhibitors; one or more RAF inhibitors; one or more MEK inhibitors; one or more Wnt signaling inhibitors, such as anti-β-catenin inhibitors, GSK3 inhibitors, JNK inhibitors, and CK1 inhibitors; one or more TGF-β signaling inhibitors, such as atezolizumab, durvalumab, and avelumab; one or more PD-1 / PD-L1 inhibitors; and / or radiation therapy.

[0145] Embodiment 75. In embodiment 75, there is provided a method according to any one of embodiments 72 to 74, wherein the method further comprises the step of simultaneously or sequentially administering one or more additional anticancer therapies, wherein preferably the one or more additional therapies comprise a KRAS G12C and / or G12D inhibitor, and more preferably the KRAS G12C and / or G12D inhibitor is sotorasib or adagrasib.

[0146] Embodiment 76. In embodiment 76, there is provided a method of inhibiting TEAD1, 2, 3, and / or 4 in a subject or in a sample, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 106, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof; or a pharmaceutical composition according to embodiment 71.

[0147] Embodiment 77. In embodiment 77, there is provided the method of embodiment 76, wherein TEAD1 is selectively inhibited relative to TEAD2, 3, and 4.

[0148] Table 1 shows the structures of the compounds described in the examples of this disclosure. Table 1: TEAD inhibitor compounds TIFF2025532584000043.tif180147TIFF2025532584000044.tif234147TIFF20255325840 00045.tif224147TIFF2025532584000046.tif224147TIFF2025532584000047.tif224147 TIFF2025532584000048.tif207147TIFF2025532584000049.tif219147TIFF20255325840 00050.tif222147TIFF2025532584000051.tif225147TIFF2025532584000052.tif224147

[0149] In some or any embodiments, provided herein are: (a) compounds described herein, e.g., of Formula (I), (II), any embodiment herein, and any of Compounds 1-106, and pharmaceutically acceptable salts and compositions thereof; (b) compounds described herein, e.g., of any of Formula (I), (II), any embodiment herein, and compounds 1-106, and pharmaceutically acceptable salts and compositions thereof, for use in treating cancers and / or conditions modulated by TEAD1, 2, 3, and / or 4; (c) processes for the preparation of compounds described herein, e.g., of Formula (I), (II), any embodiment herein, and any of Compounds 1-106, as described in more detail elsewhere herein; (d) a pharmaceutical formulation comprising a compound described herein, e.g., any of Formulas (I), (II), any embodiment herein, and Compounds 1-106, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent; (e) A method for treating a condition associated with TEAD1, 2, 3, and / or 4 function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, a pharmaceutically acceptable salt thereof, or a composition, e.g., of any of Formulas (I), (II), any embodiment herein, and Compounds 1-106; (f) a method for treating cancer in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, a pharmaceutically acceptable salt thereof, or a composition, e.g., of any of Formulas (I), (II), any embodiment herein, and Compounds 1-106; (g) A pharmaceutical formulation comprising a compound described herein, e.g., any of Formula (I), (II), any embodiment herein, and Compounds 1-106, or a pharmaceutically acceptable salt thereof, together with one or more other active agents for treating cancers and / or conditions modulated by TEAD1, 2, 3, and / or 4, optionally in a pharmaceutically acceptable carrier or diluent; (h) a method for treating cancer in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, e.g., any of Formulas (I), (II), any embodiment herein, and compounds 1-106, a pharmaceutically acceptable salt, or a composition thereof, in combination and / or alternation with one or more agents for the treatment of cancers and / or conditions modulated by TEAD1, 2, 3, and / or 4; and (i) A method for treating a condition associated with TEAD1, 2, 3, and / or 4 function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, e.g., any of Formulas (I), (II), any embodiment herein, and compounds 1-106, a pharmaceutically acceptable salt thereof, or a composition, in combination and / or alternation with one or more agents for the treatment of cancer; (j) Use of any compound described herein, e.g., the use of any of Formulas (I), (II), any embodiment herein, and compounds 1-106, or the use of a composition comprising any compound described herein, e.g., the use of any of Formulas (I), (II), any embodiment herein, and compounds 1-106, for the treatment of a condition associated with the function of TEAD1, 2, 3, and / or 4 (e.g., cancer) described herein, optionally in combination and / or alternation with one or more agents for the treatment of cancer.

[0150] Isomers and Optically Active Compounds It will be recognized that the compounds provided herein have several chiral centers and can exist and be isolated as optically active and racemic forms.It is understood that any racemic, optically active, diastereoisomer, geometric isomer, tautomer, or other stereoisomer, mixture, or combination thereof of the compounds provided herein that have the useful properties described herein are within the scope of the present invention.How to prepare optically active forms (in some or any embodiments, by resolving racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) is well known in the art.

[0151] In some or any embodiments, methods for obtaining optically active materials (in some embodiments, compounds that are substantially pure, or that are "substantially free" of, or "in the substantial absence" of, unspecified isomers) are known in the art and include at least the following: i) Physical separation of crystals - a technique for manually separating macroscopic crystals of individual stereoisomers. This technique can be used when crystals of separate stereoisomers are present, i.e. the material is a conglomerate and the crystals are visually separate. ii) Simultaneous crystallization - a technique in which separate stereoisomers are crystallized separately from a solution of the racemate, possibly only if the latter are a conglomerate in the solid state. iii) Enzymatic resolution - a technique in which the racemate is partially or completely separated by the difference in the rate of reaction of the stereoisomers with an enzyme. iv) Enzymatic Asymmetric Synthesis - A synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain a stereomerically pure or stereomerically enriched synthetic precursor of a desired stereoisomer. v) Chemical asymmetric synthesis - a synthetic technique, feasible using chiral catalysts or chiral auxiliaries, in which a desired stereoisomer is synthesized from an achiral precursor under conditions that result in asymmetry (i.e., chirality) in the product. vi) Diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more distinct structural differences, after which the chiral auxiliary is removed to give the desired enantiomer. vii) First and second order asymmetric transformations - techniques in which the diastereomers derived from the racemate are equilibrated so that the diastereomer derived from the desired enantiomer predominates in solution, or the equilibrium is broken by preferential crystallization of the diastereomer derived from the desired enantiomer, ultimately converting essentially all of the material to the crystalline diastereomer derived from the desired enantiomer, followed by release of the desired enantiomer from the diastereomer. viii) Kinetic Resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to the heterogeneity of the reaction rates of stereoisomers with chiral non-racemic reagents or catalysts under kinetic conditions. ix) Stereospecific synthesis from non-racemic precursors - A synthetic technique in which the desired stereoisomer is obtained from non-chiral starting materials and the stereochemical integrity is not or only minimally compromised during the synthetic process. x) Chiral liquid chromatography - a technique in which stereoisomers of a racemate are separated in a liquid mobile phase by differential interaction with a stationary phase. The stationary phase may be made of a chiral material, and the mobile phase may contain an additional chiral material that induces the differential interaction. xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the stereoisomers are separated by their differential interaction with a column containing a stationary non-racemic chiral adsorbent phase in a gaseous mobile phase. xii) Chiral solvent extraction - a technique in which stereoisomers are separated by preferential dissolution of one stereoisomer in a particular chiral solvent. xiii) Transport across chiral membranes - a technique in which a racemate is contacted with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allows only one stereoisomer of the racemate to pass through.

[0152] In some or any embodiments, compositions of compounds are provided that contain a substantially pure specific stereoisomer (e.g., enantiomer, diastereomer) of the compound. In some or any embodiments, in the methods and compounds disclosed herein, the compound is substantially free of other stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers. In some or any embodiments, the composition contains at least 85%, 90%, 95%, 98%, 99%, or 100% by weight of a compound that is a specific compound, with the remainder containing other chemical species, geometric isomers, and / or stereoisomers thereof (e.g., enantiomers, diastereomers).

[0153] Isotopically enriched compounds Isotopically enriched compounds are also provided herein.

[0154] As used herein, the term "isotopic composition" refers to the amount of each isotope present in a given atom, unless otherwise specified, and "natural isotope composition" refers to the composition or abundance ratio of natural isotopes for a given atom.In this specification, atoms that contain natural isotope composition are also referred to as "non-enriched" atoms.Unless otherwise specified, atoms of compounds described herein are intended to represent any stable isotope of the atom.For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen in its natural isotope composition.

[0155] The term "isotopic enrichment" as used herein, unless otherwise specified, refers to the proportion of a certain amount of a specific isotope incorporated into a given atom in a molecule at the natural isotopic abundance of that atom.In some or any embodiment, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at a given position.Since the natural distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0156] As used herein, the term "isotopically enriched," unless otherwise specified, means that an atom has an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also mean that a compound contains at least one atom that has an isotopic composition other than the natural isotopic composition of that atom.

[0157] Isotopic enrichment (in some or any embodiments, deuteration) of drugs to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles has previously been demonstrated for several classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

[0158] In some or any embodiments, isotopic enrichment of a drug can be used to (1) reduce or eliminate undesirable metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of administrations required to achieve a desired effect, (4) decrease the dosage required to achieve a desired effect, (5) increase the formation of active metabolites, if any, and / or (6) decrease the production of harmful metabolites in specific tissues and / or create more effective and / or safer drugs for combination therapy, whether the combination therapy is intended or not.

[0159] In many cases, replacing an atom with one of its isotopes will change the reaction rate of chemical reactions.This phenomenon is known as kinetic isotope effect ("KIE").For example, if a C-H bond is broken during the rate-determining step (i.e., the step that shows the highest transition state energy) in a chemical reaction, replacing this hydrogen with deuterium will reduce the reaction rate and slow down the process.This phenomenon is known as deuterium kinetic isotope effect ("DKIE").See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

[0160] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond is broken and the rate of the same reaction in which hydrogen is replaced by deuterium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. That is, when hydrogen is replaced by deuterium, the reaction can be 50 times slower or more. High DKIE values ​​can be due, in part, to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling occurs because of the small mass of the hydrogen atom, allowing transition states involving protons to sometimes form without requiring activation energy. Deuterium, due to its greater mass, is statistically much less likely to undergo this phenomenon than hydrogen.

[0161] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to 3. Tritium occurs naturally in the environment at very low concentrations and is most commonly found as TO. Tritium decays slowly (half-life = 12.3 years) and emits low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the primary risk factor associated with this isotope, but large doses are required to pose significant health risks. The amount of tritium that must be consumed to reach harmful levels is less than that of deuterium. Substituting tritium ("T") for hydrogen results in a stronger bond than deuterium, resulting in more isotope effects. Similarly, other elements can be substituted for carbon. 13 C or 14 C, for sulfur 33 S, 34 S, or 36 S, for nitrogen 15 N and oxygen 17 O or 18 Substitution with isotopes including, but not limited to, O can result in similar kinetic isotope effects.

[0162] For example, DKIEs have been used to reduce the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can result in metabolic switching. The concept of metabolic switching proposes that xenogens, when captured by phase I enzymes, can temporarily bind and rebind in various conformations before chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets in many phase I enzymes and the random nature of many metabolic reactions. Metabolic switching can potentially produce different ratios of known and entirely new metabolites. This new metabolic profile can confer some or all of the toxicity.

[0163] In some embodiments, the compounds described herein may be used as radiopharmaceuticals, such as imaging agents. For example, the radiopharmaceutical is a positron emission tomography (PET) imaging agent. In such embodiments, the atom in the compound is replaced with a radionuclide (e.g., a positron-emitting isotope), thereby enabling the synthesis of a radiopharmaceutical that can function as an imaging agent. In some embodiments, the radionuclide that can be replaced in the compounds described herein includes: 18 F, 11 C. 13 N, 15 O. 76 Br, and 124 In some embodiments, the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms. In some embodiments, the compound is administered as an isotopic composition.

[0164] The animal body expresses various enzymes for the purpose of excreting foreign substances, such as therapeutic agents, from the circulatory system. In some or any embodiments, such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with the foreign substances and convert them into highly polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) bonds or carbon-carbon (CC) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic and pharmacodynamic properties, as well as acute and long-term toxicity profiles, compared to the parent compound. For many drugs, such oxidation is rapid. Therefore, these drugs often require multiple doses or high daily doses.

[0165] Thus, isotopic enrichment at specific positions in the compounds provided herein results in detectable KIEs that affect the pharmacokinetic, pharmacological, and / or toxicity profiles of the compounds provided herein compared to similar compounds with natural isotopic compositions.

[0166] General Scheme Scheme 1. Synthesis of Formula (I) TIFF2025532584000053.tif85128 Scheme 1 illustrates the synthesis of compounds of Formula (I) according to some aspects and embodiments of the present disclosure. For simplicity, only the E (trans) isomer is shown in Scheme 1, however, cis and / or trans isomers may occur and can be separated by common chromatographic methods. In certain aspects, mixtures of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) are produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to give the single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers). Compounds of formula (I) may also be prepared by other routes, some of which are described in the experimental section.

[0167] Scheme 2. General synthesis for some compounds of formula (I) TIFF2025532584000054.tif93128

[0168] Scheme 2 illustrates the synthesis of compounds of Formula (I) according to certain aspects and embodiments of the present disclosure. In certain aspects, mixtures of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) are produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers).

[0169] Scheme 3. General synthesis for some compounds of formula (I) TIFF2025532584000055.tif107128

[0170] Scheme 3 illustrates the synthesis of compounds of formula (I) according to some aspects and embodiments of the present disclosure. The aldehyde functionality in TIFF2025532584000056.tif26128 may alternatively be a cyclic ketone or lactone. For simplicity, only the E isomer is shown in Scheme 3, but one specific Z or E olefin isomer can be obtained for the double bond to which Ar is attached. In certain aspects, mixtures of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) are produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to give the single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) thereof.

[0171] Scheme 4. General synthesis for some compounds of formula (I) TIFF2025532584000057.tif74135

[0172] Scheme 4 illustrates the synthesis of compounds of Formula (I) according to some aspects and embodiments of the present disclosure. Under different conditions for reducing the alkyne functionality in the second step, one specific Z or E olefin isomer can be obtained (for simplicity, only the E isomer is shown in Scheme 4). In certain aspects, a mixture of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) is produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain the single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers).

[0173] Scheme 5. General synthesis for some compounds of formula (I) TIFF2025532584000058.tif75135

[0174] Scheme 5 illustrates the synthesis of compounds of Formula (I) according to some aspects and embodiments of the present disclosure. Under different conditions for reducing the alkyne functionality in the second step, one specific Z or E olefin isomer can be obtained (for simplicity, only the E isomer is shown in Scheme 5). In certain aspects, a mixture of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) is produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain the single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., positional isomers, cis and trans isomers, Z and E isomers).

[0175] Pharmaceutical Formulations and Methods of Treatment and Administration The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) therapeutic procedures or measures that cure, slow, alleviate the symptoms of, and / or halt the progression of a diagnosed pathological condition, disease, or disorder, and 2) preventative / prophylactic measures. Those in need of treatment may include individuals who already have a particular medical disease or disorder, as well as individuals who may eventually acquire the disorder (i.e., individuals in need of preventative measures).

[0176] "Treating" or "treatment" of any condition or disorder refers, in some or any embodiments, to improving the condition or disorder present in a subject, including prophylactically. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the condition or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the condition or disorder. In yet another embodiment, "treating" or "treatment" includes either reducing or eliminating the condition (e.g., cancer) or one or more parameters of the condition (e.g., cancer) (e.g., tumor size or tumor growth rate), or slowing the progression of the condition (e.g., cancer) or one or more parameters of the condition (e.g., cancer) (e.g., tumor size or tumor growth rate), or reducing the severity of the condition (e.g., cancer) or one or more parameters of the condition (e.g., cancer) (e.g., tumor size or tumor growth rate). In yet another embodiment, "treating" or "treatment" includes prophylactically administering a compound described herein. In some embodiments, "treating" or "treatment" of a disease includes (1) inhibiting the disease, i.e., preventing (i.e., stabilizing) or reducing the onset of the disease or its clinical symptoms, or (2) palliating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0177] The term "subject," as used herein, refers to any individual or patient on whom the subject method is performed. Generally, the subject is a human, and as will be understood by those skilled in the art, the subject may also be an animal.

[0178] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to the amount of a compound or composition that elicits the desired biological or medical response in a tissue, system, animal, individual, or human by administering the compound of interest. The biological or medical response can include one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder. Generally, the response is either an alleviation of symptoms or a desired biological outcome in a patient.

[0179] Also disclosed herein are pharmaceutical compositions comprising the compounds disclosed herein (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with a compound of the present disclosure and that does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0180] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, and self-emulsifying drug delivery systems (SEDDS), such as α-tocopherol, polyethylene glycol 1000 succinate, or other similar polymeric delivery matrices.

[0181] In pharmaceutical compositions containing only a compound described herein (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) as an active ingredient, methods of administering these compositions may further include administering an additional drug or therapy to a subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production; hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. In another embodiment, the therapy is anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production; hormones and antagonists, drugs that affect gastrointestinal function, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies may include any other drug or biologic agent found in any drug class. For example, other drug classes can include allergy / cold / ENT therapies, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antivirals, asthma / pulmonary therapies, cardiovascular therapies, dermatological therapies, endocrine / metabolic therapies, gastrointestinal therapies, cancer therapies, immunotherapy, neurotherapy, ophthalmological therapies, psychiatric therapies, or rheumatoid therapies. In another embodiment, the therapy is selected from anti-inflammatory agents, endocrine / metabolic therapies, gastrointestinal therapies, cancer therapies, immunotherapy, neurotherapy, and rheumatoid therapies. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0182] In another embodiment, the compounds disclosed herein (including those according to any of Formulas (I), (II), any embodiment herein, and compounds 1-106) are used in combination with another anti-cancer agent, such as one or more selected from an EGFR inhibitor, a MEK inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, an immune checkpoint inhibitor, and a chemotherapeutic agent for a neoplastic disease.

[0183] The compounds of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and compounds 1-106) may be used in conventional methods for controlling the diseases described herein, including, but not limited to, cancer. Such treatment methods, their dosage levels and requirements may be selected by one of ordinary skill in the art from available methods and techniques. For example, the compounds of the present disclosure may be combined with pharmaceutically acceptable adjuvants for administration to a patient suffering from cancer in a pharmaceutically acceptable manner and in an amount effective to treat the cancer.

[0184] Alternatively, compounds of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and compounds 1-106) may be used in compositions and methods for treating or protecting individuals over the long term from diseases described herein, including, but not limited to, cancer. The compounds may be used in such compositions alone or with other compounds of the present disclosure in a manner consistent with the conventional use of such compounds in pharmaceutical compositions. For example, compounds of the present disclosure may be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines and administered in prophylactically effective amounts to provide long term protection to individuals against diseases described herein, including, but not limited to, cancer.

[0185] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compounds (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides single unit dosage forms containing the described compounds, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" if a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" if a patient or individual simultaneously exhibits therapeutically relevant drug levels in specific target tissues or samples (e.g., in the brain, serum, etc.).

[0186] When a compound of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) is administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of a compound described herein (including those according to Formulas (I), (II), any embodiment herein, and Compounds 1-106) with another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0187] The compounds utilized in the compositions and methods of the present disclosure may be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include modifications that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0188] According to an embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat, or prevent any of the diseases described herein, including, but not limited to, cancer, in a subject.

[0189] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent, i.e., and various other pharmaceutically acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. The composition may also contain a pharmaceutically acceptable non-toxic carrier or diluent, defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration, depending on the desired formulation. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0190] In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents for use in treating a disease described herein, including, but not limited to, cancer. While it is possible to administer the described compounds alone, it is preferable to administer the described compounds (including those according to Formulas (I), (II), any embodiment herein, and Compounds 1-106) as pharmaceutical formulations (compositions) described herein. The described compounds (including those according to Formulas (I), (II), any embodiment herein, and Compounds 1-106), like other pharmaceuticals, may be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0191] As described in detail, the pharmaceutical compositions of the present disclosure may be specifically formulated for administration in solid or liquid form, including, for example, those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and tablets targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions, or sustained release formulations; topical application, e.g., as creams, ointments, or controlled release patches applied to the skin, lungs, or buccal cavity, or as sprays; vaginal, rectal, e.g., as pessaries, creams, or foams; sublingual; intraocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0192] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0193] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0194] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0195] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle-forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides, and a compound of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106). In certain embodiments, the formulations described above render the compounds described of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) orally bioavailable.

[0196] Methods of preparing formulations or compositions comprising the described compounds (including those according to any of Formula (I), (II), any embodiment herein, and Compounds 1-106) include the step of bringing into association a compound of the present disclosure (including those according to any of Formula (I), (II), any embodiment herein, and Compounds 1-106) with the carrier and, optionally, one or more accessory ingredients. In general, the formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and Compounds 1-106) with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0197] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Pharmacopeia Helvetica, or similar alcohols. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0198] In some cases, in order to prolong the effect of drugs, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of drug then depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in oil vehicle.

[0199] Injectable depot forms are made by forming microencapsule matrices of the described compounds (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0200] The pharmaceutical compositions of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.For oral tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For oral administration of aqueous suspensions, solutions, and propylene glycol, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners and / or flavorings and / or colorings can be added.

[0201] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) as an active ingredient. The compounds described herein (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) may also be administered as a bolus, electuary, or paste.

[0202] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, for example, glycerol; disintegrants, for example, hydroxybenzoates ... For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0203] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. When a solid carrier is used, the preparation may be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 to 400 mg. When a liquid carrier is used, the preparation may be in the form of a sterile injectable liquid such as a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. Where the composition is in capsule form, any routine encapsulation is suitable, for example using the above carriers in a hard gelatin capsule shell.

[0204] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can be optionally obtained or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Alternatively or additionally, they can be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They can also be formulated for rapid release, such as by lyophilization. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0205] Liquid dosage forms for oral administration of the compounds of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0206] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0207] Suspensions may contain, in addition to the active compound (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106), a suspending agent such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0208] The pharmaceutical compositions of the present disclosure may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol. Topical administration of the pharmaceutical compositions of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) include, but are not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0209] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0210] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0211] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0212] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0213] Such compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. In some embodiments, it may be desirable to include one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. Alternatively or additionally, it may be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. Furthermore, prolonged absorption of injectable pharmaceutical forms may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0214] In certain embodiments, the described compounds (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) or pharmaceutical preparations are administered orally. In other embodiments, the described compounds (including those according to Formulas (I), (II), any embodiment herein, and Compounds 1-106) or pharmaceutical preparations are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0215] When the compounds described herein (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) are administered to humans and animals as pharmaceuticals, they can be administered alone or in combination with a pharmaceutically acceptable carrier, for example, as a pharmaceutical composition containing 0.1% to 99.5% of the active ingredient. In some embodiments, 0.5% to 90% of the active ingredient can be used.

[0216] The preparations described herein may be administered orally, nasally, for example, by spray, parenterally, intravaginally, intracisternally, rectally, or topically (including buccal and sublingually), for example, by powder, ointment, or drops. They are, of course, administered in a form suitable for the relevant administration route. For example, they are administered in tablets or capsules, by injection, infusion, eye drops, ointments, suppositories, etc., by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppositories. Oral administration is preferred.

[0217] Regardless of the route of administration selected, the compounds described herein (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106), which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the disclosure, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0218] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.

[0219] The terms "administration of" and / or "administering" should be understood to mean providing a therapeutically effective amount of a pharmaceutical composition to a subject in need of treatment. The route of administration can be enteral, topical, or parenteral. Thus, routes of administration include, but are not limited to, intradermal, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal, oral, sublingual, buccal, rectal, intravaginal, nasal, ocular administration, as well as injection, inhalation, and spray.

[0220] The term "cancer" refers to a group of diseases characterized by abnormal and uncontrolled cell growth that begins at one site (primary site) with the potential to invade and spread to other sites (secondary sites, metastases), differentiating cancer (malignant tumors) from benign tumors. Nearly every organ can be affected, resulting in over 100 types of cancer that can affect humans. Cancer can arise from many causes, including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and / or alcohol use, obesity, poor diet, lack of physical activity, or any combination thereof.

[0221] Exemplary cancers listed by the National Cancer Institute include acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, cerebellum, pediatric; astrocytoma, brain, pediatric; bile duct cancer, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, brain astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma , pediatric;Brain tumor, medulloblastoma, pediatric;Brain tumor, supratentorial primitive neuroectodermal tumor, pediatric;Brain tumor, visual pathway and hypothalamic glioma, pediatric;Brain tumor, pediatric (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, pediatric;Breast cancer, male;Bronchial adenoma / carcinoid, pediatric;Carcinoid tumor, pediatric;Carcinoid tumor, gastrointestinal;Carcinoma, adrenal cortex;Carcinoma, pancreatic islet cell;Carcinoma of unknown primary;Central nervous system lymphoma, primary;Cerebellar astrocytoma, pediatric;Cerebral astrocytoma / malignant glioma, pediatric;Cervical cancer;Childhood cancer;Chronic lymphocytic leukemia;Chronic myeloid leukemia;Chronic myeloproliferative disorder;Tendon Clear cell sarcoma of the sheath;Colon cancer;Colorectal cancer;Children's;Cutaneous T-cell lymphoma;Endometrial cancer;Ependymoma, children;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, children;Ewing's sarcoma family of tumors;Extracranial germ cell tumors, children;Extragonadal germ cell tumors;Extrahepatic bile duct cancer;Eye cancer, intraocular melanoma;Eye cancer;Retinoblastoma;Gallbladder cancer;Stomach cancer;Stomach cancer, children;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, children;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumor;Glioma, children's brainstem;Glioma, children's visual pathway and hypothalamus;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) Pancreatic (hepatic) cancer, adult (primary); hepatocellular (liver) cancer, childhood (primary); Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma in pregnancy; Hypopharyngeal cancer; Hypothalamic and optic pathway glioma, childhood; Intraocular melanoma; Islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Laryngeal cancer, childhood; Leukemia, acute lymphoblastic, adult; Leukemia, acute lymphoblastic, childhood; Leukemia, acute myeloid, adult; Leukemia, acute myeloid, childhood; Leukemia, chronic lymphocytic; Leukemia, chronic myeloid; Leukemia, hairy cell; Lip and oral cavity cancer; Liver cancer, adult (primary);Liver cancer, childhood (primary); Lung cancer, non-small cell; Lung cancer, small cell; Lymphoblastic leukemia, adult acute; Lymphoblastic leukemia, childhood acute; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin, adult; Lymphoma, Hodgkin, childhood; Lymphoma, Hodgkin during pregnancy; Lymphoma, non-Hodgkin, adult; Lymphoma, non-Hodgkin, childhood; Lymphoma, non-Hodgkin during pregnancy; Lymphoma, primary central nervous system; Macroglobulinemia, Waldenstrom type;Male breast cancer;Malignant mesothelioma, adult;Malignant mesothelioma, pediatric;Malignant thymoma;Medulloblastoma, pediatric;Melanoma;Melanoma, intraocular;Merkel cell carcinoma;Mesothelioma, malignant;Metastatic squamous cell carcinoma of the neck of unknown primary;Multiple endocrine neoplasia syndrome, pediatric;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome;Myeloid leukemia, chronic;Myeloid leukemia, acute, pediatric;Myeloma, multiple;Myeloproliferative disorders, chronic;Nasal cavity and paranasal sinus cancer;Nasopharyngeal carcinoma; Nasopharyngeal cancer, children; neuroblastoma; non-Hodgkin's lymphoma, adults; non-Hodgkin's lymphoma, children; non-Hodgkin's lymphoma in pregnancy; non-small cell lung cancer; oral cavity cancer, children; oral cavity and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer, children; ovarian epithelial cancer; ovarian germ cell tumor; ovarian low malignant potential tumor; pancreatic cancer; pancreatic cancer, children, pancreatic islet cell cancer; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectoderm Cancers, pediatric;Pituitary tumors;Plasma cell neoplasms / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adult;Primary liver cancer, pediatric;Prostate cancer;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, pediatric;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, pediatric;Salivary gland cancer;Salivary gland cancer, pediatric;Sarcoma, Ewing's family of tumors;Sarcoma, Kaposi's;Sarcoma (osteosarcoma) Malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, pediatric;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, pediatric;Sézary syndrome;Skin cancer;Skin cancer, pediatric;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Small intestine cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, pediatric;Neck squamous cell carcinoma of unknown primary, metastatic;Gastric cancer;Gastric cancer, pediatric;These include supratentorial primitive neuroectodermal tumor, childhood; T-cell lymphoma, skin; testicular cancer; thymoma, childhood; thymoma, malignant; thyroid cancer; thyroid cancer, childhood; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumor, pregnancy; cancer of unknown primary site, childhood; unusual cancers of childhood; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; optic pathway and hypothalamic glioma, childhood; vulvar cancer; Waldenstrom macroglobulinemia; and Wilms' tumor.

[0222] In some aspects, cancers include lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, non-Hodgkin's lymphoma, leukemia, pancreatic cancer, kidney cancer, endometrial cancer, head and neck cancer, lip cancer, oral cavity cancer, thyroid cancer, brain cancer, ovarian cancer, melanoma, gallbladder cancer, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, and Kaposi's sarcoma.

[0223] The compounds of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) can be administered in combination with one or more additional therapeutic agents. Phrases such as "combination therapy," "in combination with," and the like refer to the simultaneous use of two or more drugs or treatments to increase response. The TEAD1, 2, 3, and / or 4 inhibitors of the present disclosure can be used in combination with other drugs or treatments used to treat cancer, for example. In various aspects, the compounds (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) are administered before, concurrently with, or after the administration of a chemotherapeutic agent.

[0224] The anti-cancer therapy that can be used in combination with compounds disclosed herein refers to any therapy or treatment that can be used to treat cancer.Anti-cancer therapy includes but is not limited to small molecule or large molecule therapy, surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy.In some or any embodiment, additional anti-cancer therapy is KRAS G12C and / or G12D inhibitor; in some embodiments, KRAS G12C and / or G12D inhibitor is sotorasib or adagrasib.

[0225] In some or any embodiments, the combination therapy may include, but is not limited to, one or more CDK4 / 6 inhibitors; one or more EGFR inhibitors; one or more RAF inhibitors; one or more MEK inhibitors; one or more Wnt signaling inhibitors, such as anti-β-catenin inhibitors, GSK3 inhibitors, JNK inhibitors, and CK1 inhibitors; one or more TGF-β signaling inhibitors, such as atezolizumab, durvalumab, and avelumab; one or more PD-1 / PD-L1 inhibitors; and / or a compound disclosed herein (including any of Compounds 1-106) administered in combination with radiation therapy.

[0226] Examples of chemotherapeutic or anticancer agents include actinomycin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, barbican, vinblastine, vincristine, vindesine, vinorelbine, panitumamab, erbitux (cetuximab), matuzumab, and IMC-IIF. 8, TheraCIM hR3, denosumab, Avastin (bevacizumab), Humira (adalimumab), Herceptin (trastuzumab), Remicade (infiliximab), rituximab, Synagis (palivizumab), Milotarg (gemtuzumab ozogamicin), Raptiva (efalizumab), Tysabri (natalizumab), Zenapax (dacliximab), NeutroSpec (technetium (99mTc) fanolesomab), tocilizumab, ProstaScint (indium-Ill-labeled capromab pendetide), Bexar (tositumomab), Zevalin (ibritumomab tiuxeta bound to yttrium-90) (IDEC-Y2B8)), Xolair (omalizumab), MabThera (rituximab), ReoPro (abciximab), MabCampath (alemtuzumab), Simulect (basiliximab), LeukoScan (sulesomab), CEA-scan (arcitumomab), Veluma (nofetumomab), Panorex (edrecolomab), alemtuzumab, CDP870, natalizumab gilotrif (afatinib), Lynparza (olaparib), Perjeta (pertuzumab), Otdivo (nivolumab), Bosulif (bosutinib), Cabometyx (cabozantinib), Ogibli (trastuzumab-dkst), Sutent (sunitinib malate), Adcetris (brentuximab vedotin), Alecensa (alectinib), Examples of immunotherapeutic agents include, but are not limited to, Calquence (acalabrutinib), Yescarta (ciloleucel), Verzenio (abemaciclib), Keytruda (pembrolizumab), Alicopa (copanlisib), Nerlynx (neratinib), Imfinzi (durvalumab), Darazalex (daratumumab), Tecentriq (atezolizumab), and Tarceva (erlotinib). Examples of immunotherapeutic agents include, but are not limited to, interleukins (IL-2, IL-7, IL-12), cytokines (interferon, G-CSF, imiquimod), chemokines (CCL3, CCL26, CXCL7), and immunomodulatory imide drugs (thalidomide and its analogs).

[0227] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, and / or a solvate thereof, in the treatment of any cancer indication in which YAP is localized in the nucleus of tumor cells, including, but not limited to, lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, and skin cancer.

[0228] In yet another embodiment, a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) or a pharmaceutical composition thereof can interfere with the interaction of YAP with TEAD1, 2, 3, and / or 4. In certain embodiments, a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) or a pharmaceutical composition thereof can prevent YAP from binding to TEAD1, 2, 3, and / or 4. In some embodiments, a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) or a pharmaceutical composition thereof can compete with YAP for binding to TEAD1, 2, 3, and / or 4. In some embodiments, a compound of the present disclosure (including those according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) or a pharmaceutical composition thereof can bind to TEAD1, 2, 3, and / or 4. In some embodiments, the disclosed compounds or pharmaceutical compositions thereof can bind to TEAD1. In some embodiments, the disclosed compounds or pharmaceutical compositions thereof can bind to TEAD1 selectively over that of other TEAD isoforms.

[0229] By "pharmaceutically acceptable" it is meant that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. For example, the carrier, diluent, or excipient, or compositions thereof, may be administered to a subject together with a TEAD1, 2, 3, and / or 4 inhibitor of the present disclosure (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) without causing undesired biological effects or interacting in an undesirable manner with the TEAD1, 2, 3, and / or 4 inhibitor of the pharmaceutical composition in which it is contained.

[0230] For treatment, the dosage of the agent is optionally in the range of about 0.0001 mg / kg to 100 mg / kg, about 0.01 mg / kg to 5 mg / kg, about 0.15 mg / kg to 3 mg / kg, 0.5 mg / kg to 2 mg / kg, and about 1 mg / kg to 2 mg / kg of the subject's body weight. In other embodiments, the dosage is in the range of about 100 mg / kg to 5 g / kg, about 500 mg / kg to 2 mg / kg, and about 750 mg / kg to 1.5 g / kg of the subject's body weight. For example, depending on the type and severity of the disease, about 1 μg / kg to 15 mg / kg (e.g., 0.1 to 20 mg / kg) of the agent is a candidate dose for administration to a patient, whether by one or more separate administrations or by continuous infusion, for example. Typical daily dosages range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration over several days or longer, depending on the condition, treatment is continued until the desired suppression of disease symptoms occurs. However, other administration regimens may be useful. The unit dose may be, for example, in the range of about 5 mg to 500 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. The progress of therapy is monitored by conventional techniques and assays.

[0231] In some embodiments, the agent is administered to a human patient in an effective amount (or dose) of less than about 1 μg / kg, e.g., about 0.35-0.75 μg / kg or about 0.40-0.60 μg / kg. In some embodiments, the dose of the agent is about 0.35 μg / kg, or about 0.40 μg / kg, or about 0.45 μg / kg, or about 0.50 μg / kg, or about 0.55 μg / kg, or about 0.60 μg / kg, or about 0.65 μg / kg, or about 0.70 μg / kg, or about 0.75 μg / kg, or about 0.80 μg / kg, or about 0.85 μg / kg, or about 0.90 μg / kg, or about 0.95 μg / kg, or about 1 μg / kg. In various embodiments, the absolute dose of the agent is about 2 μg / subject to 45 μg / subject, or about 5 to 40 μg / subject, or about 10 to 30 μg / subject, or about 15 to 25 μg / subject, hi some embodiments, the absolute dose of the agent is about 20 μg / subject, or about 30 μg / subject, or about 40 μg / subject.

[0232] In various embodiments, the dosage of the agent may be determined by the body weight of the human patient. For example, the absolute dose of the agent may be about 2 μg for a pediatric human patient weighing about 0 to 5 kg (e.g., about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg); or about 3 μg for a pediatric human patient weighing about 6 to 8 kg (e.g., about 6, or about 7, or about 8 kg); or about 5 μg for a pediatric human patient weighing about 9 to 13 kg (e.g., 9, or about 10, or about 11, or about 12, or about 13 kg); or about 8 μg for a pediatric human patient weighing about 14 to about 20 kg (e.g., about 14, or about 16, or about 18, or about 20 kg); or about 12 μg for a pediatric human patient weighing about 21 to about 30 kg (e.g., about 21, or about 23, or about 25, or about 27, or about 30 kg); or about 12 μg for a pediatric human patient weighing about 31 to about 33 kg (e.g., about 31, or about 32, or about 33 or about 20 μg for an adult human patient of about 34 to about 50 kg (e.g., about 34, or about 36, or about 38, or about 40, or about 42, or about 44, or about 46, or about 48, or about 50 kg); or about 30 μg for an adult human patient of about 51 to about 75 kg (e.g., about 51, or about 55, or about 60, or about 65, or about 70, or about 75 kg); or about 45 μg for an adult human patient of greater than about 114 kg (e.g., about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0233] In some embodiments, the agents according to the methods provided herein are administered subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. Administration of the agents described herein (including those according to any of Formulas (I), (II), any embodiment herein, and Compounds 1-106) can be, independently, 1-4 times daily, 1-4 times monthly, 1-6 times per year, or once every 2, 3, 4, or 5 years. Administration can be daily or for a period of 1, 2, 3, 6 months, 1, 2, 3 years, or even for the lifetime of the human patient. Dosages can be administered as a single dose or in multiple doses. In some embodiments, the agent is administered about 1-3 times (e.g., 1, or 2, or 3 times). [Example]

[0234] Synthesis Examples Below are presented examples that discuss the synthesis and characterization of TEAD1, 2, 3, and / or 4 inhibitors contemplated for the uses discussed. The following examples are provided to further illustrate aspects of the invention, but are not intended to limit the scope of the invention. While they are typical of those that may be used, other procedures, methods, or techniques known to those skilled in the art may alternatively be used.

[0235] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined.Specifically, but not by way of limitation, the following abbreviations may be used in the examples and throughout the specification: aq. (aqueous); calcd. (calculated); avg. (average); ESI (electrospray ionization); HPLC (high pressure liquid chromatography); g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimole); h, hr, or hrs (hours); min (minute); MS (mass spectrometry); ppm (parts per million); rt or rt (room temperature); sat. (saturated); TLC (thin layer chromatography); ACN (acetonitrile); BOC (t-butyloxycarbonyl); DCM (dichloromethane); DIEA (diisopropylethylamine); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); dppf (1,1′-bis(diphenylphosphino)ferrocene); EA (ethyl acetate); Hex (hexane), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); IPA (isopropyl acetate); MeOH (methanol); MsCl (mesyl chloride); MTBE (methyl tert-butyl ether); PE (petroleum ether); TEA (triethylamine); HATU (hexafluorophosphate azabenzotriazole tetramethyluronium); HOBT (hydroxybenzotriazole), Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride), DMF (dimethylformamide), TBAF (tetra-n-butylammonium fluoride), LiHMDS (lithium bis(trimethylsilyl)amide), HMPA (hexamethylphosphoramide), AcOH (acetic acid), TMSOTf (trimethylsilyl trifluoromethanesulfonate), mCPBA (meta-chloroperoxybenzoic acid), DIBALH (diisobutylaluminum hydride), LDA (lithium diisopropylamide), TFA (trifluoroacetic acid); and THF (tetrahydrofuran).

[0236] In all of the following examples, standard workup and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are in °C (degrees Celsius). Unless otherwise noted, all reactions are conducted at room temperature. The synthetic methods presented herein are intended to illustrate applicable chemical reactions through the use of specific examples and are not indicative of the scope of the present disclosure.

[0237] Example 1: Synthesis of 1-{3-[(2Z)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000059.tif20128

[0238] Synthetic Route: TIFF2025532584000060.tif56141

[0239] Synthesis of tert-butyl 3-{3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl}azetidine-1-carboxylate

[0240] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (250 mg, 1.255 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with potassium tert-butoxide (176 mg, 1.568 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h, then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified on a silica gel column eluted with EA / PE (0-20%) to give tert-butyl 3-{3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl}azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 15 H 19 F3N2O3, 332.13 m / z, found, 277.00 [M+H-56] + .

[0241] Synthesis of 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate

[0242] tert-Butyl 3-{3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl}azetidine-1-carboxylate (270 mg, 0.812 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate as a light brown oil (300 mg, crude). MS (ESI) mass calculation for C 10 H 11 F3N2O, 232.08 m / z, found, 233.05 [M+H] + .

[0243] Synthesis of 1-{3-[(2Z)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one

[0244] 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate (300 mg, 0.866 mmol), a stir bar, EtN (438 mg, 4.328 mmol), and DCM (8 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (118 mg, 1.304 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to obtain a mixture, which was purified by Chiral HPLC (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 20 min; wavelength: 220 / 254 nm; RT1 (min): 14.806; sample solvent: Further separation by EtOH-HPLC (injection volume: 0.4 mL; run number: 9) gave 1-{3-[(2Z)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one as a white solid (, MS (ESI) mass calculation for C). 13 H 13 F3N2O2, 286.09 m / z, found, 287.05 [M+H] + , TIFF2025532584000061.tif27148

[0245] Example 2: Synthesis of 1-{3-[(2E)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000062.tif16128

[0246] Synthetic Route: TIFF2025532584000063.tif22128

[0247] Synthesis of 1-{3-[(2E)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one

[0248] 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate (300 mg, 0.866 mmol), a stir bar, EtN (438 mg, 4.328 mmol), and DCM (8 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (118 mg, 1.304 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to obtain a mixture, which was purified by Chiral HPLC (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 20 min; wavelength: 220 / 254 nm; RT2 (min): 16.998; sample solvent: Further separation by EtOH--HPLC; injection volume: 0.4 mL; run number: 9) gave 1-{3-[(2E)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl]azetidin-1-yl}prop-2-en-1-one as a white solid (MS (ESI) mass calcd. for C 13 H 13 F3N2O2, 286.09 m / z, found, 287.10 [M+H] + , TIFF2025532584000064.tif35148

[0249] Example 3: Synthesis of 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000065.tif27128

[0250] Synthetic Route: TIFF2025532584000066.tif57128

[0251] Synthesis of [3-methoxy-4-(trifluoromethyl)phenyl]methanol 3-Methoxy-4-(trifluoromethyl)benzoic acid (3 g, 13.627 mmol), a stir bar, and BH3 in THF (40 mL) were added to a microwave vial (40 mL × 2). The resulting mixture was stirred at rt overnight, then poured into ice water and extracted with DCM (50 mL × 3). The combined layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give [3-methoxy-4-(trifluoromethyl)phenyl]methanol (2.02 g, crude) as a white solid.

[0252] Synthesis of [3-methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate

[0253] [3-Methoxy-4-(trifluoromethyl)phenyl]methanol (1 g, 4.851 mmol), a stir bar, DCM (15 mL), and triethylamine (2.42 g, 23.915 mmol) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated dropwise with MsCl (850 mg, 7.421 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h, diluted with water (10 mL), and extracted with DCM (10 mL × 3). The combined layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give [3-methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate (1 g, crude) as a yellow oil.

[0254] Synthesis of diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate

[0255] [3-Methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate (1 g, 3.518 mmol), a stir bar, and P(OEt) (15 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at 110 °C overnight, cooled to room temperature, and concentrated under vacuum. The residue was purified by reverse-phase chromatography (0% to 62% ACN / 10 mM NHHCO in water) to give diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate as a green oil. MS (ESI) mass calculation for C13H18F3O4P, 326.09 m / z, found, 327.05 [M+H]. + .

[0256] Synthesis of tert-butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

[0257] Diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate (620 mg, 1.900 mmol), a stir bar, THF (10 mL), and tert-butyl 3-formylazetidine-1-carboxylate (430 mg, 2.322 mmol) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with potassium tert-butoxide (323 mg, 2.878 mmol) in several portions at 0 °C. The resulting mixture was stirred at rt for 6 h, then diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 17% EA in PE) to give tert-butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate as a green oil. MS (ESI) mass calculation for C18 H 22 F3NO3, 357.16 m / z, found, 302.00 [M-56+H] + .

[0258] Synthesis of 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine hydrochloride

[0259] tert-Butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate (380 mg, 1.063 mmol), a stir bar, and 1,4-dioxane (3 mL) were added to a 25 mL round-bottom flask, stirred until homogeneous, and treated dropwise with 4 M HCl in 1,4-dioxane (4.00 mL) at rt. The resulting mixture was stirred at rt for 2 h and then concentrated in vacuo to give 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine hydrochloride (320 mg, crude) as a white solid. MS (ESI) mass calculation for C 13 H 14 F3NO, 257.10 m / z, found, 258.00 [M+H] + .

[0260] Synthesis of 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0261] 3-[(E)-2-[3-Methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidine (150 mg, 0.583 mmol), a stir bar, triethylamine (294 mg, 2.905 mmol), and DCM (3 mL) were added to a 25 mL round-bottom flask and stirred until homogeneous. The mixture was then treated dropwise with a solution of acryloyl chloride (52.5 mg, 0.593 mmol) in DCM (0.5 mL) at 0 °C. The reaction mixture was stirred at rt for 1 h, then diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 38% B to 68% B, 68% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one (18.7 mg) as a yellow oil. MS (ESI) mass calculation for C 16 H 16 F3NO2, 311.11 m / z, found, 312.05 [M+H] + ; TIFF2025532584000067.tif34151

[0262] Example 4: Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000068.tif24128

[0263] Synthetic Route: TIFF2025532584000069.tif84128

[0264] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate 4-(Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (0.5 g, 1.945 mmol), a stir bar, and P(OEt) (5 mL) were added to a 20 mL vial. The resulting mixture was stirred at 100 °C overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM NHHCO (30%-60%) to give diethyl [3-(trifluoromethyl)phenyl]methylphosphonate as a pale yellow oil (0.575 g, 94.07%). MS (ESI) mass calculation for C 12 H 15 F4O3P, 314.2 m / z, found, 315.2 [M+H] + .

[0265] Synthesis of tert-butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

[0266] Diethyl [2-fluoro-4-(trifluoromethyl)phenyl]methylphosphonate (575 mg, 1.830 mmol), tert-butyl 3-formylazetidine-1-carboxylate (406 mg, 2.192 mmol), a stir bar, and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (308 mg, 2.745 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL), and extracted with EA (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography (0-80% EtOAc / pet ether) to give tert-butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calcd. for C17H19F4NO2, 345.1 m / z, found, 290.05 [M+H-56]+.

[0267] Synthesis of (E)-3-(3-fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0268] tert-Butyl 3-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethyl}azetidine-1-carboxylate (200 mg, 0.579 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask and then treated with TFA (2 mL). The resulting mixture was stirred at rt for 1 h and then concentrated in vacuo to give the crude product, (E)-3-(3-fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate, as a yellow solid (280 mg). MS (ESI), calcd. for C12H11F4N, m / z 245.1, found 246.05 [M+H]+.

[0269] Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0270] (E)-3-(3-Fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (280 mg, 0.779 mmol), triethylamine (410 mg, 4.052 mmol), a stir bar, and DCM (8 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (110 mg, 1.215 mmol) at 0° C. The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL) and extracted with DCM (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was further purified by PREP-Chiral-HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 63% B, 63% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one as a white solid. MS (ESI) mass calculation for C 15 H 13 F4NO, 299.10 m / z, found, 300.10[M+H] + . TIFF2025532584000070.tif37144

[0271] Example 5: Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000071.tif22128

[0272] Synthetic Route: TIFF2025532584000072.tif67144

[0273] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate

[0274] 1-(Bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (500 mg, 1.945 mmol), a stir bar, and P(OEt) (5 mL) were added to a 40 mL vial. The resulting mixture was stirred at 100 °C overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM NHHCO (30%-60%) to give diethyl [3-(trifluoromethyl)phenyl]methylphosphonate as a pale yellow oil. MS (ESI) mass calculation for C 12 H 15 F4O3P, 314.2 m / z, found, 315.2 [M+H] + .

[0275] Synthesis of tert-butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

[0276] Diethyl [2-fluoro-4-(trifluoromethyl)phenyl]methylphosphonate (537 mg, 1.709 mmol), tert-butyl 3-formylazetidine-1-carboxylate (380 mg, 2.052 mmol), a stir bar, and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (287 mg, 2.558 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL), and extracted with EA (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography (0-80% EtOAc / petroleum ether) to give tert-butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 17 H 19 F4NO2, 345.1m / z, found, 289.95 [M+H-56] + .

[0277] Synthesis of (E)-3-(2-fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0278] tert-Butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate (200 mg, 0.579 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask and then treated with TFA (2 mL). The resulting mixture was stirred at rt for 1 h and then concentrated in vacuo to give the crude product, (E)-3-(2-fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate, as a yellow solid (250 mg). MS (ESI), calcd. for C 12 H 11 F4N, 245.1 m / z, found 246.45 [M+H]+ .

[0279] Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0280] (E)-3-(2-Fluoro-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (264 mg, 0.735 mmol), a stir bar, triethylamine (387 mg, 3.824 mmol), and DCM (8 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (104 mg, 1.149 mmol) at 0° C. The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL), and extracted with DCM (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was further purified by PREP-Chiral-HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 66% B, 66% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one as an off-white solid (71.5 mg). MS (ESI) mass calculation for C 15 H 13 F4NO, 299.10 m / z, found, 300.10[M+H] + . TIFF2025532584000073.tif28149

[0281] Example 6: Synthesis of 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]piperidin-1-yl}prop-2-en-1-one TIFF2025532584000074.tif24128

[0282] Synthetic Route: TIFF2025532584000075.tif65128

[0283] Synthesis of tert-butyl 4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]piperidine-1-carboxylate

[0284] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (300 mg, 1.013 mmol), a stir bar, tert-butyl 4-formylpiperidine-1-carboxylate (259 mg, 1.214 mmol), and THF (8 mL) were added to an oven-dried 50 mL round-bottom flask and stirred until homogenous. The reaction mixture was then cooled to 0 °C, and potassium tert-butoxide (170 mg, 1.515 mmol) was added. The reaction mixture was stirred at rt for 2 h, quenched with water, and extracted with EA (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 0-50%) to give tert-butyl 4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]piperidine-1-carboxylate as a pale yellow solid. MS (ESI) mass calculation for C 19 H 24 F3NO2, 355.2 m / z, found, 300.05 [M+H-56] + .

[0285] Synthesis of (E)-4-(4-(trifluoromethyl)styryl)piperidine 2,2,2-trifluoroacetate

[0286] tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (270 mg, 0.760 mmol), a stir bar, and DCM (10 mL) were added to an oven-dried, nitrogen-purged 50 mL round-bottom flask and stirred until homogeneous, after which trifluoroacetic acid (2 mL) was added. The resulting mixture was stirred at rt for 2 h and then concentrated in vacuo to give (E)-4-(4-(trifluoromethyl)styryl)piperidine 2,2,2-trifluoroacetate (330 mg, crude) as a pale yellow semisolid. MS (ESI) mass calculation for C 14 H 16 F3N, 255.1 m / z, found, 256.05 [M+H] + .

[0287] Synthesis of 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]piperidin-1-yl}prop-2-en-1-one

[0288] (E)-4-(4-(trifluoromethyl)styryl)piperidine 2,2,2-trifluoroacetate (330 mg, 0.894 mmol), a stir bar, DCM (6 mL), and EtN (452 ​​mg, 4.467 mmol) were added to an oven-dried 50 mL round-bottom flask and stirred at 0 °C until homogeneous. The mixture was then treated with a solution of acryloyl chloride (121 mg, 1.337 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h, then quenched with water and extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography with ACN / 10 mM NH4HCO3 (5-60%) to give 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]piperidin-1-yl}prop-2-en-1-one as a yellow solid. MS (ESI) mass calculation for C 17 H 18 F3NO, 309.15 m / z, found, 310.15 [M+H]+ ; TIFF2025532584000076.tif27145

[0289] Example 7: Synthesis of (E)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000077.tif18128

[0290] Synthetic Route: TIFF2025532584000078.tif89145

[0291] Synthesis of tert-butyl 3-fluoro-3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

[0292] 4-[4-(trifluoromethyl)phenoxy]benzoic acid (1 g, 3.543 mmol), 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (2 g, 9.124 mmol), N,O-dimethylhydroxylamine hydrochloride (1.8 g, 18.454 mmol), a stir bar, and ACN (20 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with HOBt (2.5 g, 18.501 mmol), EDCI (3 g, 15.649 mmol), and N-methylmorpholine (6.3 mL, 11.864 mmol) in several portions at rt. The resulting mixture was stirred overnight at 25 °C and then diluted with water. The resulting mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column (0% to 50% EA in PE) to give tert-butyl 3-fluoro-3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (750 mg, 31.34%) as a white oil. TIFF2025532584000079.tif20144

[0293] Synthesis of tert-butyl 3-fluoro-3-formylazetidine-1-carboxylate

[0294] tert-Butyl 3-fluoro-3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (750 mg, 2.860 mmol), THF (2 mL, 24.686 mmol), and a stir bar were added to a 20 mL vial and stirred until homogenous, then treated dropwise with DIBAL-H (4 mL, 19.716 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 2 h, then quenched with water, filtered, and washed with DCM (20 mL). The resulting mixture was extracted with DCM (5 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 3-fluoro-3-formylazetidine-1-carboxylate (700 mg, 120.46%) as a yellow oil.

[0295] Synthesis of tert-butyl 3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0296] tert-Butyl 3-fluoro-3-formylazetidine-1-carboxylate (700 mg, 3.445 mmol), diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (112 mg, 0.390 mmol), a stir bar, and THF (7 mL) were added to a 20 mL vial and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (482 mg, 4.295 mmol) in several portions at rt. The resulting mixture was stirred at 25 °C overnight and then quenched with water. The resulting mixture was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 40% EA in PE) to give tert-butyl 3-fluoro-3-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl}azetidine-1-carboxylate (280 mg, 24.17%) as a white solid. MS (ESI) mass calculation for C 14 H 16 F4N2O3, 336.00 m / z, found, 322.05 [M+H+CH3CN] + .

[0297] Synthesis of 3-(2-(3-fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0298] tert-Butyl 3-fluoro-3-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl}azetidine-1-carboxylate (280 mg, 0.833 mmol), DCM (2.5 mL), and a stir bar were added to an 8 mL vial, stirred until homogeneous, and then treated dropwise with TFA (0.5 mL, 6.732 mmol) at rt. The resulting mixture was stirred at 25 °C for 2 h and concentrated in vacuo to give 3-(2-(3-fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (400 mg, 203.42% crude) as a yellow oil. MS (ESI) calcd. for C9H8F4N2O, 236.00 m / z, found 237.00 [M+H] + .

[0299] Synthesis of (E)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0300] 3-(2-(3-Fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (378 mg, 1.386 mmol), TEA (808 mg, 7.985 mmol), a stir bar, and DCM (4 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with acryloyl chloride (216 mg, 2.386 mmol) at rt. The resulting mixture was stirred at 25 °C overnight and then quenched with water. The resulting mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting mixture was then purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B, 67% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-{3-fluoro-3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one (53.5 mg) as a white solid. MS (ESI) calcd. for C 12 H 10 F4N2O2, 290.07 m / z, found 290.95 [M+H] + ; TIFF2025532584000080.tif27145

[0301] Example 8: Synthesis of (Z)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000081.tif22128

[0302] Synthetic Route: TIFF2025532584000082.tif44128

[0303] Synthesis of (Z)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0304] 3-(2-(3-Fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (378 mg, 1.386 mmol), TEA (808 mg, 7.985 mmol), a stir bar, and DCM (4 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with acryloyl chloride (216 mg, 2.386 mmol) at rt. The resulting mixture was stirred at 25 °C overnight and then quenched with water. The resulting mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting mixture was then purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B, 67% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-{3-fluoro-3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one (4.9 mg, 1.22%) as a yellow oil. MS (ESI) calcd. for C 12 H 10 F4N2O2, 290.07 m / z, found 291.00 [M+H] + ; TIFF2025532584000083.tif27145

[0305] Example 9: Synthesis of 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one TIFF2025532584000084.tif21128

[0306] Synthetic Route:

[0307] TIFF2025532584000085.tif30151

[0308] (SFC separation continues)

[0309] Synthesis of tert-butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate

[0310] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (300 mg, 1.013 mmol), a stir bar, tert-butyl 3-formylpyrrolidine-1-carboxylate (242 mg, 1.215 mmol), and THF (8 mL) were added to an oven-dried 50 mL round-bottom flask and stirred until homogeneous. The reaction mixture was then cooled to 0 °C, and potassium tert-butoxide (170 mg, 1.515 mmol) was added. The reaction mixture was stirred at rt for 2 h, quenched with water, and extracted with EA (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 0-30%) to give tert-butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 18 H 22 F3NO2, 341.2 m / z, found, 286.00 [M+H-56] + .

[0311] Synthesis of (E)-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0312] tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (150 mg, 0.439 mmol), a stir bar, and DCM (10 mL) were added to an oven-dried, nitrogen-purged 50 mL round-bottom flask and stirred until homogeneous, after which trifluoroacetic acid (2 mL) was added. The resulting mixture was stirred at rt for 2 h and then concentrated in vacuo to give (E)-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate as a light brown semisolid. MS (ESI) mass calculation for C 13 H 14 F3N, 241.1 m / z, found, 242.05 [M+H] + .

[0313] Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one

[0314] (E)-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (154 mg, 0.433 mmol), a stir bar, DCM (6 mL), and EtN (219 mg, 2.164 mmol) were added to an oven-dried, nitrogen-purged 50 mL round-bottom flask. The resulting mixture was stirred until homogeneous. The reactor was then cooled to 0 °C, and a solution of acryloyl chloride (59 mg, 0.652 mmol) in DCM (2 mL) was added. The resulting mixture was stirred at rt for 2 h, quenched with water, and extracted with DCM (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (ACN / 10 mM NH4HCO3 water, 5% to 55%) to give 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one as a pale yellow solid. MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + ; TIFF2025532584000086.tif20144

[0315] Synthesis of 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one

[0316] The racemic product was further separated by SFC (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 21 min; wavelength: 220 / 254 nm; RT (min): 14.491 (first isomer); sample solvent: EtOH-HPLC; injection volume: 0.4 mL; number of runs: 2) to give one stereoisomer assigned as (S) (first eluting isomer), 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one, as a white solid (4.7 mg). MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.15 [M+H] + ). TIFF2025532584000087.tif20144

[0317] Example 10: Synthesis of 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one TIFF2025532584000088.tif21128

[0318] Synthesis of 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one

[0319] The racemic product was separated by SFC (column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 21 min; wavelength: 220 / 254 nm; RT2 (min): 18.48 (second isomer); sample solvent: EtOH-HPLC; injection volume: 0.4 mL; number of runs: 2) to give one stereoisomer assigned as R (second eluting isomer), 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one, as a white solid (3.8 mg). MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + ). TIFF2025532584000089.tif20145

[0320] Example 11: Synthesis of 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000090.tif15128

[0321] Synthetic Route: TIFF2025532584000091.tif45137

[0322] Synthesis of (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate

[0323] (5-(trifluoromethyl)pyridin-2-yl)methanol (1.0 g, 5.646 mmol), a stir bar, EtN (1.14 g, 11.292 mmol), and DCM (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with MsCl (0.78 g, 6.810 mmol). The mixture was stirred at rt for 1 h, then quenched with water (50 mL) and extracted with DCM (100 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified on a silica gel column eluting with EA / PE (0–50%) to give (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate as a pale yellow solid. MS (ESI) mass calcd. for C8H8F3NO3S, 255.02 m / z, found, 255.90 [M+H] + .

[0324] Synthesis of diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate

[0325] A solution of (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (0.98 g, 3.840 mmol) in toluene (10 mL) and triethyl phosphite (3 mL) was heated at 110 °C and stirred overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM aqueous NHHCO (5%-60%) to give diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate as a light brown liquid. MS (ESI) mass calculation for C 11 H 15 F3NO3P, 297.07 m / z, found, 298.00 [M+H] + .

[0326] Synthesis of tert-butyl 3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate

[0327] Diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate (470 mg, 1.581 mmol), tert-butyl 3-formylazetidine-1-carboxylate (360 mg, 1.944 mmol), a stir bar, and THF (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (266 mg, 2.370 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h, then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified on a silica gel column eluting with EA / PE (0-50%) to give tert-butyl 3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 16 H 19 F3N2O2, 328.14 m / z, found, 273.15 [M+H-56] + .

[0328] Synthesis of 2-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)pyridine 2,2,2-trifluoroacetate

[0329] tert-Butyl 3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate (410 mg, 1.249 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 2-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)pyridine 2,2,2-trifluoroacetate as a light brown oil (600 mg, crude). MS (ESI) mass calculation for C 11 H 11F3N2, 228.09 m / z, found, 229.10 [M+H] + .

[0330] Synthesis of 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0331] 2-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)pyridine 2,2,2-trifluoroacetate (600 mg, 1.753 mmol), a stir bar, EtN (888 mg, 8.775 mmol), and DCM (13 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (206 mg, 2.276 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm; RT1 (min): 6; Run number: 0) to give 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one as a pale orange solid (121.1 mg). MS (ESI) mass calculation for C 14 H 13 F3N2O, 282.10 m / z, found, 283.00 [M+H] + , TIFF2025532584000092.tif27146

[0332] Example 12: Synthesis of 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000093.tif22128

[0333] Synthetic Route: TIFF2025532584000094.tif65145

[0334] Synthesis of methyl [2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl methanesulfonate

[0335] [2-(trifluoromethyl)-1,3-thiazol-5-yl]methanol (1.0 g, 5.460 mmol), a stir bar, EtN (1.10 g, 10.865 mmol), and DCM (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with MsCl (0.74 g, 6.443 mmol). The mixture was stirred at rt for 1 h, then quenched with water (50 mL) and extracted with DCM (100 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified on a silica gel column eluting with EA / PE (0–50%) to give [2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl methanesulfonate as a pale yellow oil. MS (ESI) mass calcd. for C6H6F3NO3S2, 260.97 m / z, found, 261.95 [M+H] + .

[0336] Synthesis of diethyl [2-(trifluoromethyl)-1,3-thiazol-5-yl]methylphosphonate

[0337] A solution of [2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl methanesulfonate (0.75 g, 2.871 mmol) in toluene (10 mL) and triethyl phosphite (3 mL) was heated at 110 °C and stirred overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM aqueous NHHCO (5%-60%) to give diethyl [2-(trifluoromethyl)-1,3-thiazol-5-yl]methylphosphonate as a light brown liquid. MS (ESI) mass calculations for CH 13 F3NO3PS, 303.03 m / z, found, 304.00 [M+H] + .

[0338] Synthesis of tert-butyl 3-{2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl}azetidine-1-carboxylate

[0339] Diethyl [2-(trifluoromethyl)-1,3-thiazol-5-yl]methylphosphonate (400 mg, 1.319 mmol), tert-butyl 3-formylazetidine-1-carboxylate (293 mg, 1.582 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with potassium tert-butoxide (222 mg, 1.978 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h, then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified on a silica gel column eluted with EA / PE (0-50%) to give tert-butyl 3-{2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl}azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 14 H 17 F3N2O2S, 334.36 m / z, found, 278.95 [M+H-56] +.

[0340] Synthesis of 5-[2-(azetidin-3-yl)ethenyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate

[0341] tert-Butyl 3-{2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl}azetidine-1-carboxylate (300 mg, 0.897 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 5-[2-(azetidin-3-yl)ethenyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate as a light brown oil (400 mg, crude). MS (ESI) mass calculation for C9H9F3N2S, 234.04 m / z, found, 235.00 [M+H] + .

[0342] Synthesis of 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0343] 5-[2-(Azetidin-3-yl)ethenyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate (400 mg, 1.149 mmol), a stir bar, EtN (596 mg, 5.890 mmol), and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated dropwise with a solution of acryloyl chloride (156 mg, 1.724 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B, 55% B in 7 min; wavelength: 254 nm; RT1 (min): 6.10) to give a mixture, which was purified by Achiral SFC (column: YMC-Actus SIL, 3 × 25 cm, 5 μm; mobile phase A: CO 2, Further separation by HPLC (Mobile Phase B: IPA (0.5% 2M NH3-MeOH); Flow Rate: 50 mL / min; Gradient: Isocratic 13% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wavelength: 254 nm; RT1 (min): 5.43; Sample Solvent: MeOH; Injection Volume: 1 mL; Run Number: 13) gave 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one as a colorless oil (27.8 mg). MS (ESI) mass calculation for C 12 H 11 F3N2OS, 288.05 m / z, found, 289.05 [M+H] + , TIFF2025532584000095.tif27140

[0344] Example 13: Synthesis of 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000096.tif17128

[0345] Synthetic Route: TIFF2025532584000097.tif39128

[0346] Synthesis of 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0347] 5-[2-(Azetidin-3-yl)ethenyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate (400 mg, 1.149 mmol), a stir bar, EtN (596 mg, 5.890 mmol), and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated dropwise with a solution of acryloyl chloride (156 mg, 1.724 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B, 55% B in 7 min; wavelength: 254 nm; RT1 (min): 6.10) to give a mixture, which was purified by Achiral SFC (column: YMC-Actus SIL, 3 × 25 cm, 5 μm; mobile phase A: CO 2,Further separation by HPLC (Mobile Phase B: IPA (0.5% 2M NH3-MeOH); Flow Rate: 50 mL / min; Gradient: Isocratic 13% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wavelength: 254 nm; RT2 (min): 6.37; Sample Solvent: MeOH; Injection Volume: 1 mL; Run Number: 13) afforded 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one as a white solid (85.0 mg). MS (ESI) mass calculation for C 12 H 11 F3N2OS, 288.05 m / z, found, 289.05 [M+H] + , TIFF2025532584000098.tif27145

[0348] Example 14: Synthesis of 1-(3-(3-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000099.tif14128

[0349] Synthetic Route: TIFF2025532584000100.tif54150

[0350] Synthesis of diethyl (3-(trifluoromethyl)benzyl)phosphonate

[0351] A mixture of 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.0 g, 4.183 mmol) and triethyl phosphite (10 mL) was heated at 110 °C and stirred overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM aqueous NHHCO (5%-60%) to give diethyl (3-(trifluoromethyl)benzyl)phosphonate as a light brown liquid. MS (ESI) mass calculation for C 12 H 16F3O3P, 296.08 m / z, found, 397.00 [M+H] + .

[0352] Synthesis of tert-butyl 3-(3-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0353] Diethyl (3-(trifluoromethyl)benzyl)phosphonate (500 mg, 1.688 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (285 mg, 2.540 mmol). The mixture was stirred at rt for 20 min, after which tert-butyl 3-formylazetidine-1-carboxylate (375 mg, 2.025 mmol) was added. The reaction mixture was stirred at rt for 2 h, then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified on a silica gel column eluted with EA / PE (0-20%) to give tert-butyl 3-(3-(trifluoromethyl)styryl)azetidine-1-carboxylate as a pale yellow oil. MS (ESI) mass calculation for C 17 H 20 F3NO2, 327.14 m / z, found, 272.00 [M+H-56] + .

[0354] Synthesis of 3-(3-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0355] tert-Butyl 3-(3-(trifluoromethyl)styryl)azetidine-1-carboxylate (120 mg, 0.367 mmol), a stir bar, and DCM (5 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 3-(3-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate as a light brown oil (130 mg, crude). MS (ESI) mass calculation for C 12 H 12 F3N, 227.09 m / z, found, 228.10 [M+H] + .

[0356] Synthesis of 1-(3-(3-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one

[0357] 3-(3-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (130 mg, 0.381 mmol), a stir bar, EtN (193 mg, 1.907 mmol), and DCM (5 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (52 mg, 0.575 mmol) in DCM (1 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 42% B to 72% B, 72% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to give 1-(3-(3-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one as a pale yellow oil (32.5 mg). MS (ESI) mass calculation for C 15 H 14 F3NO, 281.10 m / z, found, 282.15 [M+H] + ; TIFF2025532584000101.tif27145

[0358] Example 15: Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000102.tif14128

[0359] Synthetic Route: TIFF2025532584000103.tif95134

[0360] Synthesis of diethyl [4-(trifluoromethyl)phenyl]methylphosphonate

[0361] A mixture of 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.0 g, 4.183 mmol) and triethyl phosphite (10 mL) was heated at 110 °C and stirred overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM aqueous NHHCO (5%-60%) to give diethyl [4-(trifluoromethyl)phenyl]methylphosphonate as a light brown liquid. MS (ESI) mass calculation for C 12 H 16 F3O3P, 296.08 m / z, found, 397.00 [M+H] + .

[0362] Synthesis of tert-butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

[0363] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (500 mg, 1.688 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (285 mg, 2.540 mmol). The mixture was stirred at rt for 20 min, after which tert-butyl 3-formylazetidine-1-carboxylate (375 mg, 2.025 mmol) was added. The reaction mixture was stirred at rt for 2 h, then diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified on a silica gel column eluting with EA / PE (0–20%) to give tert-butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate as a pale yellow semisolid. MS (ESI) mass calculation for C 17 H 20 F3NO2, 327.14 m / z, found, 272.05 [M+H-56]+ .

[0364] Synthesis of 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine 2,2,2-trifluoroacetate

[0365] tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate (300 mg, 0.916 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo to give 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine 2,2,2-trifluoroacetate as a light brown oil (340 mg, crude). MS (ESI) mass calculation for C 12 H 12 F3N, 227.09 m / z, found, 228.10 [M+H] + .

[0366] Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0367] 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidine 2,2,2-trifluoroacetate (340 mg, 0.996 mmol), a stir bar, EtN (505 mg, 4.990 mmol), and DCM (7 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (135 mg, 1.492 mmol) in DCM (1 mL). The mixture was stirred at rt for 1 h, then quenched with water (30 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 42% B to 72% B, 72% B in 7 min; wavelength: 254 nm) to give 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one as a pale yellow solid (69.5 mg). MS (ESI) mass calculation for C 15 H 14 F3NO, 281.10 m / z, found, 282.00 [M+H] + ; TIFF2025532584000104.tif35147

[0368] Example 16: Synthesis of 1-(3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000105.tif23128

[0369] Synthetic Route: TIFF2025532584000106.tif60145

[0370] 3-((diethoxy(methylene)- λ 5 Synthesis of (-phosphanyl)methyl)-5-(trifluoromethyl)isoxazole (5-(trifluoromethyl)isoxazol-3-yl)methyl methanesulfonate (800 mg, 3.263 mmol), a stir bar, and P(OEt) (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous. The resulting mixture was stirred at 110 °C overnight. The reaction mixture was then subjected to reverse-phase chromatography on C18 (ACN / H2O (0.05% NH4HCO3) = 5-50%) to obtain 3-(diethoxy(methylene)-λ 5 (-phosphanyl)methyl-5-(trifluoromethyl)isoxazole was obtained as a pale yellow oil (735 g, 78.44%). MS (ESI) calculation for CH 13 F3NO4P, 287.05 m / z, found 288.05 [M+H] + .

[0371] Synthesis of tert-butyl 3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0372] 3-((diethoxy(methylene)- λ 5(-phosphanyl)methyl)-5-(trifluoromethyl)isoxazole (300 mg, 1.052 mmol), a stir bar, tert-butyl 3-formyl-3-methylazetidine-1-carboxylate (314 mg, 1.576 mmol), and THF (6 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (177 mg, 1.577 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The resulting residue was then subjected to silica gel chromatography (20-50% EA / PE) to give tert-butyl 3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate as a white solid (283 mg, 80.96%, MS (ESI) calcd. for C 15 H 19 F3N2O3, 332.13 m / z, found 276.95 [M+H-56] + ).

[0373] Synthesis of 3-(2-(3-methylazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0374] tert-Butyl 3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (283 mg, 0.852 mmol), a stir bar, and DCM (9 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 3-(2-(3-methylazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a red oil (402 mg, crude, MS (ESI) mass calcd. for C). 10 H 11F3N2O, 232.08 m / z, found, 233.10 [M+H] + ).

[0375] Synthesis of 1-(3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0376] 3-(2-(3-Methylazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (402 mg, 1.161 mmol), a stir bar, TEA (588 mg, 5.811 mmol), and DCM (8 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (210 mg, 2.320 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 75% B, 75% B in 7 min; wavelength: 254 nm) to give 1-(3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one as a pale yellow solid (62.2 mg). MS (ESI) mass calculation for C 13 H 13 F3N2O2, 286.09 m / z, found, 287.00 [M+H] + . TIFF2025532584000107.tif28149

[0377] Example 17: Synthesis of 1-(3-methoxy-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000108.tif23128

[0378] Synthetic Route: TIFF2025532584000109.tif73145

[0379] Synthesis of tert-butyl 3-formyl-3-methoxyazetidine-1-carboxylate To a solution of (COCl) (1.1 g, 8.657 mmol) in DCM (5 mL) was added dropwise a solution of DMSO (1.3 g, 16.651 mmol) in DCM (4 mL) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate (0.9 g, 4.142 mmol) in DCM (5 mL) was added dropwise, and stirring was continued for 30 min. To the mixture was added EtN (3.4 g, 33.592 mmol) in DCM (4 mL), and the resulting mixture was stirred at −70° C. for 10 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-formyl-3-methoxyazetidine-1-carboxylate as a dark yellow oil (787 mg, 88.26%, MS (ESI) calcd. for C 10 H 17 NO4, 215.11 m / z, found 177.95 [M+H-56+18] + ).

[0380] Synthesis of tert-butyl 3-methoxy-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0381] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (400 mg, 1.350 mmol), a stir bar, tert-butyl 3-formyl-3-methoxyazetidine-1-carboxylate (349 mg, 1.621 mmol), and THF (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (227 mg, 2.023 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The resulting residue was then subjected to silica gel chromatography (0-30% EA / PE) to give tert-butyl 3-methoxy-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate as a pale yellow oil (449 mg, 93.04%, MS (ESI) calcd. for C 18 H 22 F3NO3, 357.16 m / z, found 302.10 [M+H-56] + ).

[0382] Synthesis of 3-methoxy-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0383] tert-Butyl 3-methoxy-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate (200 mg, 0.560 mmol), a stir bar, and DCM (6 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 3-methoxy-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate as a colorless oil (239 mg crude). MS (ESI) mass calculation for C 13 H 14 F3NO, 257.10 m / z, found, 258.15 [M+H] + ).

[0384] Synthesis of 1-(3-methoxy-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one

[0385] 3-Methoxy-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (239 mg, 0.644 mmol), a stir bar, TEA (326 mg, 3.222 mmol), and DCM (5 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (117 mg, 1.293 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B, 65% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-(3-methoxy-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one as an off-white solid (79.5 mg). MS (ESI) mass calculation for C 16 H 16 F3NO2, 311.11 m / z, found, 312.05 [M+H] + , TIFF2025532584000110.tif29145

[0386] Example 18: Synthesis of 1-(3-methyl-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000111.tif21128

[0387] Synthetic Route: TIFF2025532584000112.tif73147

[0388] Synthesis of tert-butyl 3-formyl-3-methylazetidine-1-carboxylate

[0389] To a solution of (COCl) (1.0 g, 10.243 mmol) in DCM (5 mL) was added dropwise a solution of DMSO (1.6 g, 20.479 mmol) in DCM (5 mL) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate (1.0 g, 4.969 mmol) in DCM (5 mL) was added dropwise, and stirring was continued for 30 min. To the mixture was added EtN (4.0 g, 39.528 mmol) in DCM (5 mL), and the resulting mixture was stirred at −70° C. for 10 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-formyl-3-methylazetidine-1-carboxylate as a dark yellow oil (972 mg, 98.18%). MS (ESI) calcd. for C 10 H 17 NO3, 199.12 m / z, found 218.05 [M+H+18] + .

[0390] Synthesis of tert-butyl 3-methyl-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0391] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (500 mg, 1.688 mmol), a stir bar, tert-butyl 3-formyl-3-methylazetidine-1-carboxylate (404 mg, 2.028 mmol), and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (284 mg, 2.531 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The resulting residue was then subjected to silica gel chromatography (0-30% EA / PE) to give tert-butyl 3-methyl-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate as a colorless oil (412 mg, 71.50%). MS (ESI) calcd. for C 18 H 22 F3NO2, 341.16 m / z, found 286.00 [M+H-56] + .

[0392] Synthesis of 3-methyl-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0393] tert-Butyl 3-methyl-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate (200 mg, 0.586 mmol), a stir bar, and DCM (6 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 3-methyl-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate as a pale yellow oil (423 mg, crude). MS (ESI) mass calculation for C 13 H 14 F3N, 241.11 m / z, found, 242.10 [M+H] + .

[0394] Synthesis of 1-(3-methyl-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one

[0395] 3-Methyl-3-(4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (423 mg, 1.191 mmol), a stir bar, TEA (602 mg, 5.949 mmol), and DCM (8 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (216 mg, 2.386 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 64% B, 64% B in 7 min; Wavelength: 254 nm; RT (min): 5.72) to give 1-(3-methyl-3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one as a pale yellow oil (38.6 mg). MS (ESI) mass calculation for C 16 H 16 F3NO, 295.12 m / z, found, 296.05 [M+H] + , TIFF2025532584000113.tif29144

[0396] Example 19: Synthesis of 1-(3-(2-methoxy-4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000114.tif14128

[0397] Synthetic Route: TIFF2025532584000115.tif84150

[0398] Synthesis of diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate

[0399] A mixture of 1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene (500 mg, 1.858 mmol) and P(OEt) (5 mL) was heated at 110 °C and stirred overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography with CHCN / 10 mM aqueous NHHCO (5%-60%) to give diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate as a white solid (408 mg, 67.30%). MS (ESI) calcd. for C 13 H 18 F3O4P, 326.09 m / z, found 327.10 [M+H] + .

[0400] Synthesis of tert-butyl 3-(2-methoxy-4-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0401] Diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate (408 mg, 1.251 mmol), a stir bar, tert-butyl 3-formylazetidine-1-carboxylate (278 mg, 1.501 mmol), and THF (7 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with t-BuOK (211 mg, 1.880 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (20 mL) and extracted with EA (3 × 30 mL). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The resulting residue was then subjected to silica gel chromatography (30%-40% EA / PE) to afford tert-butyl 3-(2-methoxy-4-(trifluoromethyl)styryl)azetidine-1-carboxylate as a colorless oil (231 mg). MS (ESI) calculation for C 18 H 22 F3NO3, 357.15 m / z, found 302.10 [M+H-56] + .

[0402] Synthesis of 3-(2-methoxy-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate

[0403] tert-Butyl 3-(2-methoxy-4-(trifluoromethyl)styryl)azetidine-1-carboxylate (231 mg, 0.646 mmol), a stir bar, and DCM (5 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 3-(2-methoxy-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate as a red oil (281 mg, crude). MS (ESI) mass calculation for C 13 H 14 F3NO, 257.10 m / z, found, 258.15 [M+H] + .

[0404] Synthesis of 1-(3-(2-methoxy-4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one

[0405] 3-(2-Methoxy-4-(trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (281 mg, 0.757 mmol), a stir bar, TEA (383 mg, 3.785 mmol), and DCM (5 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (137 mg, 1.514 mmol). The resulting mixture was stirred at room temperature for 1 h, then quenched with water (10 mL) and extracted with DCM (10 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 36% B to 66% B, 66% B in 7 min; wavelength: 254 nm) to give 1-(3-(2-methoxy-4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one as a white solid (100.2 mg). MS (ESI) mass calculation for C 16 H 16 F3NO2, 311.11 m / z, found, 312.15 [M+H] + , TIFF2025532584000116.tif28145

[0406] Example 20: Synthesis of 1-(6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one TIFF2025532584000117.tif14128

[0407] Synthetic Route: TIFF2025532584000118.tif50128

[0408] Synthesis of tert-butyl 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane-2-carboxylate

[0409] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (330 mg, 1.114 mmol), a stir bar, tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (301 mg, 1.336 mmol), and THF (12 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (188 mg, 1.675 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (20 mL), extracted with EA (3 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo. The residue was purified on a silica gel column eluted with EA / PE (10%-30%) to give tert-butyl 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane-2-carboxylate as a pale yellow oil (287 mg). MS (ESI) mass calculation for C 20 H 24 F3NO2, 367.18 m / z, found, 312.00 [M+H-56] + .

[0410] Synthesis of 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate

[0411] tert-Butyl 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane-2-carboxylate (287 mg, 0.781 mmol), a stir bar, and DCM (8 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate as a red solid (284 mg). MS (ESI) mass calculation for C 15 H 16 F3N, 267.12 m / z, found, 268.05 [M+H] + .

[0412] Synthesis of 1-(6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0413] 6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (284 mg, 0.745 mmol), a stir bar, EtN (377 mg, 3.726 mmol), and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (135 mg, 1.492 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 75% B, 75% B in 7 min; wavelength: 254 nm) to give 1-(6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one as a white solid (65.9 mg). MS (ESI) mass calculation for C 18 H 18 F3NO, 321.13 m / z, found, 322.05 [M+H] + , TIFF2025532584000119.tif27145

[0414] Example 21: Synthesis of (E)-1-(3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000120.tif21128

[0415] Synthetic Route: TIFF2025532584000121.tif45150

[0416] Synthesis of diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate

[0417] To a stirred solution of [5-(trifluoromethyl)-1,2-oxazol-3-yl]methyl methanesulfonate (1 g, 4.079 mmol, 1 equiv) in toluene was added P(OEt)3 (2.03 g, 12.237 mmol, 3 equiv). The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 50% in 10 min; detector, UV 254 nm. This afforded diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (600 mg, 51.22%) as a pale yellow oil.

[0418] Synthesis of tert-butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidine-1-carboxylate

[0419] To a stirred solution of diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (600 mg, 2.089 mmol, 1 equiv) in THF at −60° C. was added LiHMDS (524.41 mg, 3.133 mmol, 1.5 equiv) dropwise. The mixture was stirred at −60° C. for 1 min. Next, a solution of tert-butyl 3-formylazetidine-1-carboxylate (464.39 mg, 2.507 mmol, 1.2 equiv) in THF was added dropwise, and stirring was continued at −60° C. for 15 min; the reaction mixture was then warmed to rt overnight. The reaction was quenched at rt by the addition of sat. NH4Cl (aq.) (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated NaCl (aq.) (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm. This afforded tert-butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidine-1-carboxylate (200 mg, 30.07%) as a pale yellow oil.

[0420] Synthesis of 1-{3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0421] To a stirred solution of tert-butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidine-1-carboxylate (100 mg, 0.314 mmol, 1 equiv) in DCM was added TFA (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The crude product was used directly in the next step without further purification.

[0422] To a stirred solution of 3-[(E)-2-(azetidin-3-yl)ethenyl]-5-(trifluoromethyl)-1,2-oxazole (100 mg, 0.458 mmol, 1 equiv) in DCM, TEA (139.14 mg, 1.374 mmol, 3 equiv) was added, and the mixture was stirred for 10 min. Next, acryloyl chloride (62.23 mg, 0.687 mmol, 1.5 equiv) was added dropwise to the solution at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by prep-HPLC under the following conditions (column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient from 10% to 50% in 10 min; detector: UV 254 nm) to give 1-{3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one (15.3 mg) as an off-white solid. LC-MS: (ES, m / z): [M+1]=273.0. TIFF2025532584000122.tif20140

[0423] Example 22: Synthesis of 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one TIFF2025532584000123.tif15128

[0424] Synthetic Route: TIFF2025532584000124.tif55139

[0425] Synthesis of tert-butyl 6-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0426] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (285 mg, 1.265 mmol), a stir bar, and THF (10 mL) were added to a 40 mL vial and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (176 mg, 1.568 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL), and extracted with EA (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to silica gel chromatography (0-30% EtOAc / PE) to give tert-butyl 6-[-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil. MS (ESI) mass calculation. For C 17 H 21 F3N2O3, 358.15 m / z, found, 304.15 [M-56+H] + .

[0427] Synthesis of 3-(2-(2-azaspiro[3.3]heptan-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0428] tert-Butyl 6-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl}-2-azaspiro[3.3]heptane-2-carboxylate (370 mg, 1.032 mmol), a stir bar, and DCM (5 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The resulting mixture was stirred at rt for 1 h and then concentrated under vacuum to give 3-(2-(2-azaspiro[3.3]heptan-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a white solid (580 mg). MS (ESI) mass calculation for C 14 H 14 F6N2O3, 258.24 m / z, found, 259.00 [M+H] + .

[0429] Synthesis of 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one

[0430] 3-(2-(2-Azaspiro[3.3]heptan-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (580 mg, 2.246 mmol), triethylamine (0.79 g, 7.807 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.41 g, 4.492 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL) and extracted with DCM (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product, which was purified by PREP-Chiral-HPLC (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.1% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 10 min; Wavelength: 220 / 254 nm; RT2 (min): 7.102; Sample solvent: EtOH-HPLC; Injection volume: 0.3 The resulting mixture was purified with 1 mL of 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one as a white solid. MS (ESI) mass calculation for C 15 H 15 F3N2O2, 312.11m / z, found, 313.10 [M+H] + . TIFF2025532584000125.tif27145

[0431] Example 23: Synthesis of 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one TIFF2025532584000126.tif20128

[0432] Synthetic Route: TIFF2025532584000127.tif29128

[0433] Synthesis of 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one

[0434] 3-(2-(2-Azaspiro[3.3]heptan-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (580 mg, 2.246 mmol), triethylamine (0.79 g, 7.807 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.41 g, 4.492 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL) and extracted with DCM (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product, which was purified by PREP-Chiral-HPLC (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: Hex (0.1% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 10 min; Wavelength: 220 / 254 nm; RT1 (min): 6.862; Sample solvent: EtOH-HPLC; Injection volume: 0.3 The resulting mixture was purified with 1 mL of 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one as a pale yellow solid (4.8 mg). MS (ESI) mass calculation for C 15 H 15 F3N2O2, 312.11m / z, found, 313.10 [M+H] + . TIFF2025532584000128.tif20148

[0435] Example 24: Synthesis of 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one TIFF2025532584000129.tif14128

[0436] Synthetic Route: TIFF2025532584000130.tif43128

[0437] Synthesis of tert-butyl 7-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0438] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate (330 mg, 1.303 mmol), a stir bar, and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (181 mg, 1.613 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to silica gel chromatography (0-30% EtOAc / PE) to give tert-butyl 7-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2-azaspiro[3.5]nonane-2-carboxylate as a colorless oil. MS (ESI) mass calculation for C 19 H 25 F3N2O3, 386.18 m / z, found, 331.15 [M-56+H] + .

[0439] Synthesis of 3-(2-(2-azaspiro[3.5]nonan-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0440] tert-Butyl 7-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl}-2-azaspiro[3.5]nonane-2-carboxylate (360 mg, 0.932 mmol), a stir bar, and DCM (5 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The resulting mixture was stirred at rt for 1 h and then concentrated under vacuum to give 3-(2-(2-azaspiro[3.5]nonan-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a white solid (520 mg). MS (ESI) mass calculation for C 14 H 14 F6N2O3, 258.24 m / z, found, 259.00 [M+H] + .

[0441] Synthesis of 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one

[0442] 3-(2-(2-Azaspiro[3.5]nonan-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (520 mg, 1.353 mmol), triethylamine (685 mg, 6.769 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (245 mg, 2.707 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL) and extracted with DCM (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by Prep-HPLC (column: XBridge Prep OBD C 18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.1% NH₃H₂O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm) to obtain 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one as a white solid (76.5 mg). MS (ESI) mass calculation for C 17 H 19 F3N2O2, 340.14 m / z, found, 341.15 [M+H] + . TIFF2025532584000131.tif27146

[0443] Example 25: Synthesis of 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one TIFF2025532584000132.tif27128

[0444] Synthetic Route: TIFF2025532584000133.tif31128

[0445] Synthesis of 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one

[0446] 3-(2-(2-Azaspiro[3.5]nonan-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (520 mg, 1.353 mmol), triethylamine (685 mg, 6.769 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (245 mg, 2.707 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL) and extracted with DCM (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by Prep-HPLC (column: XBridge Prep OBD C 18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.1% NH₃H₂O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm) to obtain 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl}prop-2-en-1-one as a pale yellow solid (40.8 mg). MS (ESI) mass calculation for C 17 H 19 F3N2O2, 340.14 m / z, found, 341.15 [M+H] + . TIFF2025532584000134.tif29141

[0447] Example 26: Synthesis of 1-{3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000135.tif24128

[0448] Synthetic Route: TIFF2025532584000136.tif36142

[0449] Synthesis of 3-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0450] tert-Butyl 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (300 mg, 0.943 mmol), a stir bar, and DCM (5 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 3-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a crude yellow oil (290 mg). MS (ESI), calcd. for C9H9F3N2O, 218.07 m / z, found 219.10 [M+H] + .

[0451] Synthesis of 1-{3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one

[0452] 3-(2-(Azetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (300 mg, 0.949 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with triethylamine (480 mg, 4.743 mmol), which was subsequently cooled to 0 °C (ice / water) and acryloyl chloride (172 mg, 1.90 mmol) was added. The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL) and extracted with DCM (50 mL × 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was further purified by Prep-HPLC (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 25% B to 25% B in 13 min; Wavelength: 220 / 254 nm; RT1(min): 9.204; Sample solvent: EtOH-HPLC; Injection volume: 0.5 mL) to give 1-{3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethenyl]azetidin-1-yl}prop-2-en-1-one as a yellow solid (6.9%). mg). MS (ESI) mass calculation for C 12 H 11 F3N2O2, 272.08 m / z, found, 273.10 [M+H] + . TIFF2025532584000137.tif20146

[0453] Example 27: (S * Synthesis of ,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000138.tif29128

[0454] Synthetic Route: TIFF2025532584000139.tif28128

[0455] (S * Synthesis of ,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0456] 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-3-ol hydrochloride (550 mg, 1.873 mmol), triethylamine (758 mg, 7.492 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (203 mg, 2.248 mmol) in DCM (2 mL) at rt. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 57% B, 57% B in 7 min; wavelength: 254 nm; RT1 (min): 5.75) and Prep-Chiral-HPLC (column: Lux 5um Cellulose-2, 2.12 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 29 min; wavelength: 220 / 254 nm; RT2 (min): 5.75). 26.631; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) and purified as a single stereoisomer (absolute stereochemistry randomly assigned as S) (S *,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one (59.8 mg) was obtained as a white solid. MS (ESI) mass calculation for C 16 H 16 F3NO2, 311.11, found, 312.15 [M+H] + ; TIFF2025532584000140.tif27145

[0457] Example 28: (R * Synthesis of ,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000141.tif29128

[0458] Synthetic Route: TIFF2025532584000142.tif55142

[0459] Synthesis of tert-butyl 3-hydroxy-3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate

[0460] To a solution of 1-ethynyl-4-(trifluoromethyl)benzene (3.03 g, 17.817 mmol) in THF (35 mL) was added butyllithium (7.77 mL, 19.436 mmol) at −78° C. under nitrogen. After stirring for 30 min, tert-butyl 3-oxopyrrolidine-1-carboxylate (3 g, 16.197 mmol) in THF (15 mL) was added at −78° C. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with NH4Cl and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (EA / PE = 0-30%) to give tert-butyl 3-hydroxy-3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidine-1-carboxylate (3.4 g, 59.07%) as an off-white solid. MS (ESI) mass calculation for C 18 H 20 F3NO3, 355.15, found, 300.15 [M-56+H] + .

[0461] Synthesis of tert-butyl (E)-3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0462] To a solution of tert-butyl 3-hydroxy-3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidine-1-carboxylate (3.2 g, 9.00 mmol) in THF (60 mL) was added Red-Al (4 mL, 70%) at -78 °C. The resulting mixture was warmed to rt and stirred for 2 h. EA and sat. aq. sodium potassium tartrate (Rochelle's salt) were added, and the mixture was stirred vigorously for 2 h. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (EA / PE = 0-40%) to give tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (2.8 g, 87.01%) as a white solid. MS (ESI) mass calculation for C 18 H 22 F3NO3, 357.16, found, 283.95 [M-56-18+H] + .

[0463] Synthesis of (E)-3-(4-(trifluoromethyl)styryl)pyrrolidin-3-ol hydrochloride

[0464] To a solution of tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (700 mg, 1.959 mmol) in 1,4-dioxane (15 mL) was added HCl (7 mL, 4 M in dioxane). The resulting mixture was stirred at rt for 1.5 h. The resulting mixture was concentrated. The resulting residue was purified by reverse-phase chromatography on C18 (ACN / HO (0.05% TFA) = 5-30%) to give 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-3-ol hydrochloride (600 mg, crude) as a yellow solid. MS (ESI) mass calculation for C 13 H 15 ClF3NO: 293.08, found: 257.95 [M-HCl+H]+ .

[0465] (R * Synthesis of ,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0466] 3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-3-ol hydrochloride (550 mg, 1.873 mmol), triethylamine (758 mg, 7.492 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (203 mg, 2.248 mmol) in DCM (2 mL) at rt. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 57% B, 57% B in 7 min; wavelength: 254 nm; RT1 (min): 5.75) and Prep-Chiral-HPLC (column: Lux 5um Cellulose-2, 2.12 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 29 min; wavelength: 220 / 254 nm; RT1 (min): 5.75). 22.356; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) and purified as a single stereoisomer (absolute stereochemistry randomly assigned as R) (R *,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one (62.8 mg) was obtained as a white solid. MS (ESI) mass calculation for C 16 H 16 F3NO2, 311.11, found, 312.15 [M+H] + ; TIFF2025532584000143.tif27145

[0467] Example 29: 1-[(3S * Synthesis of )-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one TIFF2025532584000144.tif28128

[0468] Synthetic Route: TIFF2025532584000145.tif53145

[0469] Synthesis of tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate

[0470] (COCl)2 (1.063 g, 8.375 mmol), a stir bar, and DCM (10 mL) were added to an oven-dried, nitrogen-purged 100 mL round-bottom flask and stirred until homogenous. The mixture was then treated with a solution of DMSO (1.306 g, 16.716 mmol) in DCM (3 mL) at −70 °C under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate (900 mg, 4.180 mmol) in DCM (5 mL) was added dropwise, and stirring was continued for 30 min. Et3N (3.382 g, 33.421 mmol) was added to the mixture, and the resulting mixture was stirred at −70 °C for 30 min, then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM (300 mL × 2). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate as a pale yellow oil (1 g, crude). MS (ESI) calcd. for C 11 H 19 NO3, 213.10 m / z, found 158.15 [M+H-56] + .

[0471] Synthesis of tert-butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate

[0472] tert-Butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (1 g, 4.689 mmol), a stir bar, diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (926 mg, 3.126 mmol), and THF (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0 °C and treated with potassium 2-methylpropan-2-olate (701 mg, 6.247 mmol). The resulting mixture was stirred at rt for 2 h, then quenched with water and extracted with EA (100 mL × 2). The combined organic layer was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 0-30%) to give tert-butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate as a pale yellow oil (958 mg, 86.23%). MS (ESI) calculation for C 19 H 24 F3NO2, 355.18 m / z, found 300.05 [M+H-56] + .

[0473] Synthesis of (E)-3-methyl-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0474] tert-Butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (958 mg, 2.696 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0 °C and treated dropwise with TFA (3 mL). The resulting mixture was stirred at rt for 2 h and then concentrated in vacuo to give (E)-3-methyl-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate as a yellow oil (1.26 g, crude, MS (ESI) calcd. for C). 14 H16 F3N, 255.12 m / z, found 256.05 [M+H] + ).

[0475] 1-[(3S * Synthesis of )-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one

[0476] (E)-3-Methyl-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.26 g, 3.412 mmol), a stir bar, and DCM (10 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0 °C, and EtN (1.724 g, 17.037 mmol) was added over 2 min, followed by the dropwise addition of a solution of acryloyl chloride (615 mg, 6.795 mmol) in DCM (10 mL) over 5 min. The resulting mixture was stirred at rt for 2 h, quenched with water, and extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC (column: XBridge Prep Phenyl OBD column, 19 × 100 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 67% B, 67% B in 7 min; wavelength: 254 nm) to give the racemic product. The racemic product was further separated by SFC (Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 7% B to 7% B in 18 min; Wavelength: 220 / 254 nm; RT1(min): 12.588; Sample solvent: EtOH-HPLC; Injection volume: 0.3 mL) to give 1-[(3S)] (a single stereoisomer, absolute stereochemistry randomly assigned as S).* )-3-Methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one was obtained as a colorless oil (119.4 mg). MS (ESI) mass calculation for C 17 H 18 F3NO, 309.10 m / z, found, 310.15 [M+H] + ; TIFF2025532584000146.tif27146

[0477] Example 30: 1-[(3R * Synthesis of )-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one TIFF2025532584000147.tif29128

[0478] Synthetic Route: TIFF2025532584000148.tif30142

[0479] 1-[(3R * Synthesis of )-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one

[0480] (E)-3-Methyl-3-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.26 g, 3.412 mmol), a stir bar, and DCM (10 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0 °C, and EtN (1.724 g, 17.037 mmol) was added over 2 min, followed by the dropwise addition of a solution of acryloyl chloride (615 mg, 6.795 mmol) in DCM (10 mL) over 5 min. The resulting mixture was stirred at rt for 2 h, quenched with water, and extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC (column: XBridge Prep Phenyl OBD column, 19 × 100 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 67% B, 67% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to give the racemic product. The racemic product was further separated by SFC (Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 7% B to 7% B in 18 min; Wavelength: 220 / 254 nm; RT2 (min): 15.997; Sample solvent: EtOH-HPLC; Injection volume: 0.3 mL) to give a single stereoisomer (absolute stereochemistry randomly assigned as R), 1-[(3R * )-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one) was obtained as a colorless oil (128.6 mg). MS (ESI) mass calculation for C 17 H 18 F3NO, 309.10 m / z, found, 310.15 [M+H] + ; TIFF2025532584000149.tif27146

[0481] Example 31: Synthesis of 1-{3-ethyl-4-[(Z)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one TIFF2025532584000150.tif27128

[0482] Synthetic Route: TIFF2025532584000151.tif94144

[0483] Synthesis of 1-tert-butyl 3-ethyl (3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate

[0484] Ethyl (3R,4R)-1-benzyl-4-ethylpyrrolidine-3-carboxylate (2.5 g, 9.565 mmol), a stir bar, and MeOH (40 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with ammonium formate (1.81 g, 28.705 mmol) and Pd / C (0.25 g). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (10 mL). Triethylamine (4.84 g, 47.829 mmol) and ethyl (3R,4R)-1-benzyl-4-ethylpyrrolidine-3-carboxylate (6.26 g, 28.683 mmol) were added to the filtrate. The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was subjected to silica gel chromatography (0-40% EA / PE) to give 1-tert-butyl 3-ethyl (3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate as a colorless oil. MS (ESI) mass calculation for C 14 H 25 NO4, 271.18 m / z, found 216.15 [M+H-56] + .

[0485] Synthesis of tert-butyl (3R,4R)-3-ethyl-4-(hydroxymethyl)pyrrolidine-1-carboxylate

[0486] 1-tert-Butyl 3-ethyl (3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate (2.5 g, 9.213 mmol), a stir bar, and THF (40 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with 1 M LiAlH (11 mL, 11.000 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, then warmed to rt and treated with water (0.9 g) and NaSO. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (0-70% EA / PE) to give tert-butyl (3R,4R)-3-ethyl-4-(hydroxymethyl)pyrrolidine-1-carboxylate as a colorless oil. MS (ESI) mass calculation for C 12 H 23 NO3, 229.17 m / z, found 174.05 [M+H-56] + .

[0487] Synthesis of tert-butyl (3R,4R)-3-ethyl-4-formylpyrrolidine-1-carboxylate

[0488] (COCl) (990 mg, 7.800 mmol), a stir bar, and DCM (15 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. This was then cooled to −78 °C (dry ice / EtOH) under N and DMSO (1.23 g, 15.743 mmol) was added dropwise. The resulting mixture was stirred at −78 °C (dry ice / EtOH) under N for 0.5 h and then treated dropwise with a solution of tert-butyl (3R,4R)-3-ethyl-4-(hydroxymethyl)pyrrolidine-1-carboxylate (900 mg, 3.925 mmol) in DCM (3 mL). The resulting mixture was stirred at −78 °C (dry ice / EtOH) under N for 0.5 h and then treated dropwise with a solution of triethylamine (3.18 g, 31.426 mmol) in DCM (2 mL). The resulting mixture was stirred at -78 °C (dry ice / EtOH) under N for 10 min, then warmed to room temperature and continued stirring for 2 h. The resulting mixture was quenched with water (150 mL) and extracted with DCM (200 mL x 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give tert-butyl (3R,4R)-3-ethyl-4-formylpyrrolidine-1-carboxylate as a yellow oil. MS (ESI), calcd. for C 12 H 21 NO3, 227.15 m / z, found 172.05 [M+H-56] + .

[0489] Synthesis of tert-butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidine-1-carboxylate

[0490] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (775 mg, 2.616 mmol), tert-butyl (3R,4R)-3-ethyl-4-formylpyrrolidine-1-carboxylate (890 mg, 3.915 mmol), a stir bar, and THF (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (587 mg, 5.231 mmol). The resulting mixture was stirred at room temperature for 1 h, then diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was subjected to silica gel chromatography (0–25% EA / PE) to afford tert-butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) mass calculation for C 20 H 26 F3NO2, 369.19 m / z, found 314.05 [M+H-56] + .

[0491] Synthesis of 3-ethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0492] tert-Butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidine-1-carboxylate (870 mg, 2.355 mmol), a stir bar, and DCM (15 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (5 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give 3-ethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, crude) as a yellow solid. MS (ESI) mass calculation for C 17 H 19 F6NO, 269.14 m / z, found, 270.05 [M+H] + .

[0493] Synthesis of 1-{3-ethyl-4-[(Z)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one

[0494] 3-Ethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, 3.496 mmol), a stir bar, DIEA (2.7 g, 20.890 mmol), and DCM (28 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (0.38 g, 4.198 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h and then purified by PREP_HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.25) to give the crude product. The crude product was further purified by PREP_CHIRAL_HPLC (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 7% B to 7% B in 11 min; Wavelength: 220 / 254 nm; RT1 (min): 7.539; Sample solvent: EtOH-HPLC; Injection volume: 0.5 mL) to give 1-{3-ethyl-4-[(Z)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one as an off-white solid. MS (ESI) mass calculation for C 18 H 20 F3NO, 323.15 m / z, found, 324.10 [M+H]+. TIFF2025532584000152.tif35144

[0495] Example 32: Synthesis of 1-{3-ethyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one TIFF2025532584000153.tif26128

[0496] Synthetic Route: TIFF2025532584000154.tif27128

[0497] Synthesis of 1-{3-ethyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one

[0498] 3-Ethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, 3.496 mmol), a stir bar, DIEA (2.7 g, 20.890 mmol), and DCM (28 mL) were added to a 100 mL round-bottom flask, stirred until homogeneous, and then treated dropwise with a solution of acryloyl chloride (0.38 g, 4.198 mmol) in DCM (2 mL). The mixture was stirred at rt for 1 h and then purified by PREP_HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.25) to give the crude product. The crude product was further purified by PREP_CHIRAL_HPLC (Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 7% B to 7% B in 11 min; Wavelength: 220 / 254 nm; RT2 (min): 8.812; Sample solvent: EtOH-HPLC; Injection volume: 0.5 mL) to give 1-{3-ethyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one as a white solid. MS (ESI) mass calculation for C 18 H 20 F3NO, 323.15 m / z, found, 324.10 [M+H] + . TIFF2025532584000155.tif35145

[0499] Example 33: (S * Synthesis of )-1-(3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000156.tif24128

[0500] Synthetic Route: TIFF2025532584000157.tif97135

[0501] Synthesis of tert-butyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate

[0502] 1-(tert-Butoxycarbonyl)-4,4-dimethylpyrrolidine-3-carboxylic acid (1 g, 4.110 mmol), a stir bar, and THF (7 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with borane in THF (1 M, 8.2 mL, 8.200 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was then quenched with MeOH (15 mL), stirred for an additional 0.5 h, and then concentrated in vacuo. The residue was purified by silica gel chromatography (0–5% DCM / MeOH) to afford tert-butyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate as a colorless oil (853 mg, 90.50%). MS (ESI) calcd. for C 12 H 23 NO3, 229.17 m / z, found 174.10 [M+H-56] + .

[0503] Synthesis of tert-butyl 4-formyl-3,3-dimethylpyrrolidine-1-carboxylate

[0504] To a solution of (COCl) (941 mg, 7.414 mmol) in DCM (4 mL) was added dropwise a solution of DMSO (1158 mg, 14.821 mmol) in DCM (4 mL) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate (850 mg, 3.707 mmol) in DCM (4 mL) was added dropwise, and stirring was continued for 30 min. To the mixture was added EtN (3000 mg, 29.646 mmol) in DCM (4 mL), and the resulting mixture was stirred at −70° C. for 10 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 4-formyl-3,3-dimethylpyrrolidine-1-carboxylate (825 mg, 97.92%). MS (ESI) calcd. for C 12 H 21 NO3, 227.15 m / z, found 172.05 [M+H-56] + .

[0505] Synthesis of tert-butyl 3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0506] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (800 mg, 2.701 mmol), tert-butyl 4-formyl-3,3-dimethylpyrrolidine-1-carboxylate (737 mg, 3.242 mmol), a stir bar, and THF (16 mg) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (455 mg, 4.055 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with EA (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc / PE) to give tert-butyl 3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate as a pale yellow oil (842 mg, 84.39%). MS (ESI) calcd. for C 20 H 26 F3NO2, 369.19 m / z, found 314.10 [M+H-56] + .

[0507] Synthesis of 3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0508] tert-Butyl 3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate (840 mg, 2.274 mmol), a stir bar, and DCM (9 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated in vacuo to give 3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate as a dark yellow oil (1.3 g, crude). MS (ESI) mass calculation for C 15 H 18F3N, 296.14 m / z, found, 270.05 [M+H] + .

[0509] (S * Synthesis of )-1-(3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0510] 3,3-Dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (1.3 g, 3.391 mmol), TEA (1.7 g, 16.800 mmol), a stir bar, and DCM (20 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.6 g, 6.629 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (5%–50% ACN / 10 mM NH4HCO3 in water) to give the crude product, which was further purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B–70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give a single stereoisomer (absolute stereochemistry randomly assigned as S) (S * )-1-(3,3-dimethyl-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one was obtained as a colorless oil (83.3 mg, 7.55%). MS (ESI) calculation for C 18 H 20 F3NO, 323.15 m / z, found 324.10 [M+H] + . TIFF2025532584000158.tif27146

[0511] Example 34: Synthesis of 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile TIFF2025532584000159.tif16128

[0512] Synthetic Route: TIFF2025532584000160.tif70138

[0513] Synthesis of tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate

[0514] To a solution of diisopropylamine (8.3 g, 82.024 mmol) in THF (20 mL) was added n-butyllithium in hexane (2.5 M, 33 mL, 82.500 mmol) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-cyanoazetidine-1-carboxylate (5.0 g, 27.439 mmol) in THF (40 mL) was added and stirring was continued for 1 h. To the above mixture was added 1,2,3-benzotriazol-1-ylmethanol (8.2 g, 54.977 mmol). The resulting mixture was stirred at −70° C. for an additional 2 h. The reaction mixture was then quenched with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (5% to 50% ACN / 0.05% TFA in water) to give tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate as a white solid (2.0 g, 34.34%). MS (ESI) calculation for C 10 H 16 N2O3, 212.12 m / z, found 157.05 [M+H-56] + .

[0515] Synthesis of tert-butyl 3-cyano-3-formylazetidine-1-carboxylate

[0516] To a solution of (COCl)2 (1.2 g, 9.455 mmol) in DCM (5 mL) was added dropwise a solution of DMSO (1.5 g, 19.199 mmol) in DCM (5 mL) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (1 g, 4.711 mmol) in DCM (5 mL) was added dropwise, and stirring was continued for 30 min. To the mixture was added TEA (3.8 g, 37.552 mmol) in DCM (5 mL), and the resulting mixture was stirred at −70° C. for 10 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-cyano-3-formylazetidine-1-carboxylate as a dark yellow viscous oil (1 g, crude). MS (ESI) calcd. for C 10 H 14 N2O3, 210.10 m / z, found 173.00 [M+H-56+18] + .

[0517] Synthesis of tert-butyl 3-cyano-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0518] Diethyl ((5-(trifluoromethyl)isoxazol-3-yl)methyl)phosphonate (300 mg, 1.045 mmol), tert-butyl 3-cyano-3-formylazetidine-1-carboxylate (439 mg, 2.088 mmol), a stir bar, and THF (6 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (352 mg, 3.137 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc / PE) to give tert-butyl 3-cyano-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate as a yellow solid (147 mg, 40.99%). MS (ESI) calcd. for C 15 H 16 F3N3O3, 343.11 m / z, found 288.00 [M+H-56] + .

[0519] Synthesis of 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate

[0520] tert-Butyl 3-cyano-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (147 mg, 0.428 mmol), a stir bar, and DCM (2 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate as a dark yellow oil (200 mg, crude). MS (ESI) mass calculation for C10 H8F3N3O, 243.06 m / z, found 244.05 [M+H] + .

[0521] Synthesis of 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile

[0522] 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate (200 mg, 0.560 mmol), TEA (283 mg, 2.797 mmol), a stir bar, and DCM (4 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (101 mg, 1.116 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 65% B, 65% B in 10 min; wavelength: 254 nm; RT (min): 8.22) to give 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile as a white solid (25.2 mg). MS (ESI) mass calculation for C 13 H 10 F3N3O2, 297.07 m / z, found, 298.00 [M+H] + , TIFF2025532584000161.tif35144

[0523] Example 35: Synthesis of (E)-1-(3-methoxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000162.tif25128

[0524] Synthetic Route: TIFF2025532584000163.tif53128

[0525] Synthesis of tert-butyl (E)-3-methoxy-3-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0526] To a solution of tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (700 mg, 1.959 mmol) in DMF (10 mL) was added NaH (94 mg, 2.351 mmol, 60%) at 0 °C under nitrogen. After stirring for 30 min, methyl iodide (334 mg, 2.351 mmol) was added. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with HO and extracted with EA. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (EA / PE = 0-25%) to afford tert-butyl 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (670 mg, 92.10%) as a colorless oil. MS (ESI) calculation for C 19 H 24 F3NO3: 371.17, found: 743.25 [2M+H] + .

[0527] Synthesis of (E)-3-methoxy-3-(4-(trifluoromethyl)styryl)pyrrolidine hydrochloride

[0528] To a solution of tert-butyl 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (630 mg, 1.696 mmol) in 1,4-dioxane (5 mL) was added HCl (10 mL, 4 M in 1,4-dioxane). The resulting mixture was stirred at rt for 2 h. The resulting mixture was concentrated to give 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (560 mg, crude) as a brown oil. MS (ESI) mass calcd. for C 14 H 17 ClF3NO, 307.10, found, 272.15 [M-HCl+H] + .

[0529] Synthesis of (E)-1-(3-methoxy-3-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0530] To a solution of 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (560 mg, 1.820 mmol) in DCM (8 mL) at rt was added triethylamine (736 mg, 7.280 mmol) and acryloyl chloride (165 mg, 1.820 mmol) in DCM (2 mL). The resulting mixture was stirred at rt for 2 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B in 10 min; wavelength: 254 nm; RT1 (min): 8.89) to give 1-{3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl}prop-2-en-1-one (22.0 mg) as a yellow semisolid. MS (ESI) mass calculation for C 17 H 18 F3NO2, 325.13, found, 326.05 [M+H] + ; TIFF2025532584000164.tif27144

[0531] Example 36: Example 37 Synthesis of 1-(3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000165.tif21128

[0532] Synthetic Route: TIFF2025532584000166.tif89138

[0533] Synthesis of 1-tert-butyl 3-ethyl 4-methoxypyrrolidine-1,3-dicarboxylate 1-tert-Butyl 3-ethyl 4-hydroxypyrrolidine-1,3-dicarboxylate (1 g, 3.857 mmol), MeI (2.7 g, 19.022 mmol), a stir bar, and DCM (20 mL) were added to a 40 mL vial, stirred until homogeneous, and then treated with AgO (2.7 g, 11.651 mmol). The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere, then filtered and washed with DCM (mL). The filtrate was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20–50% EtOAc / PE) to give 1-tert-butyl 3-ethyl 4-methoxypyrrolidine-1,3-dicarboxylate as a colorless oil (430 mg, 40.79%). MS (ESI) calcd. for C 13 H 23 NO5, 273.16 m / z, found 218.15 [M+H-56] + .

[0534] Synthesis of tert-butyl 3-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate

[0535] 1-tert-Butyl 3-ethyl 4-methoxypyrrolidine-1,3-dicarboxylate (430 mg, 1.573 mmol), a stir bar, and THF (4 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with LiAlH4 in THF (1 M, 1.9 mL, 1.900 mmol) at 0 °C. The reaction was warmed to rt and stirred under a nitrogen atmosphere for 2 h. It was then quenched with water (142 mg, 7.865 mmol) and anhydrous Na2SO4 and stirred for 20 min. The mixture was filtered, washed with EA (10 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (50–100% EtOAc / PE) to give tert-butyl 3-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate as a pale yellow oil (340 mg, 93.44%). MS (ESI) calcd. for C11 H 21 NO4, 231.15 m / z, found 176.10 [M+H-56] + .

[0536] Synthesis of tert-butyl 3-formyl-4-methoxypyrrolidine-1-carboxylate

[0537] To a solution of (COCl)2 (373 mg, 2.939 mmol) in DCM (2 mL) was added dropwise a solution of DMSO (459 mg, 5.875 mmol) in DCM (1 mL) at −70° C. under a nitrogen atmosphere. After stirring for 30 min, tert-butyl 3-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate (340 mg, 1.470 mmol) in DCM (2 mL) was added dropwise, and stirring was continued for 30 min. To the mixture was added TEA (1190 mg, 11.760 mmol) in DCM (1 mL), and the resulting mixture was stirred at −70° C. for 10 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water and extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 3-formyl-4-methoxypyrrolidine-1-carboxylate as a dark yellow oil (320 mg, 94.95%). MS (ESI) calculation for C 11 H 19 NO4, 229.13 m / z, found 174.20 [M+H-56] + .

[0538] Synthesis of tert-butyl 3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0539] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (320 mg, 1.080 mmol), tert-butyl 3-formyl-4-methoxypyrrolidine-1-carboxylate (297 mg, 1.295 mmol), a stir bar, and THF (6 mg) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (182 mg, 1.622 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-25% EtOAc / PE) to give tert-butyl 3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate as a colorless oil (180 mg, 41.02%). MS (ESI) calcd. for C 19 H 24 F3NO3, 371.17 m / z, found 316.10 [M+H-56] + .

[0540] Synthesis of 3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0541] tert-Butyl 3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate (180 mg, 0.485 mmol), a stir bar, and DCM (3 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated in vacuo. The residue was purified by reverse-phase chromatography (5% to 50% ACN / 0.05% TFA in water) to give 3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate as a black solid (174 mg, crude). MS (ESI) mass calculation for C 14 H16 F3NO, 271.12 m / z, found, 272.15 [M+H] + .

[0542] Synthesis of 1-(3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0543] 3-Methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (147 mg, 0.382 mmol), TEA (193 mg, 1.907 mmol), a stir bar, and DCM (2 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (69 mg, 0.762 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 65% B, 65% B in 7 min; wavelength: 254 nm; RT1 (min): 5.25) to give 1-(3-methoxy-4-(4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one as a pale yellow oil (15.1 mg). MS (ESI) mass calculation for C 17 H 18 F3NO2, 325.13 m / z, found, 326.05 [M+H] + , TIFF2025532584000167.tif35145

[0544] Example 37: Synthesis of 1-acryloyl-3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile TIFF2025532584000168.tif22128

[0545] Synthetic Route: TIFF2025532584000169.tif46141

[0546] Synthesis of tert-butyl 3-cyano-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0547] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (650 mg, 2.194 mmol), tert-butyl 3-cyano-3-formylazetidine-1-carboxylate (554 mg, 2.635 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with t-BuOK (369 mg, 3.288 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-25% EtOAc / PE) to give tert-butyl 3-cyano-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate as a white solid (157 g, 20.31%). MS (ESI) calcd. for C 18 H 19 F3N2O2, 352.14 m / z, found 297.05 [M+H] + .

[0548] Synthesis of 3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate

[0549] tert-Butyl 3-cyano-3-(4-(trifluoromethyl)styryl)azetidine-1-carboxylate (150 mg, 0.426 mmol), a stir bar, and DCM (3 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated in vacuo to give 3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate as a pale yellow oil (214 mg, crude). MS (ESI) mass calculation for C 13 H 11 F3N2, 252.09 m / z, found,253.00 [M+H] + .

[0550] Synthesis of 1-acryloyl-3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile

[0551] 3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile (214 mg, 0.604 mmol), TEA (306 mg, 3.024 mmol), a stir bar, and DCM (4 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (109 mg, 1.204 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B in 10 min; wavelength: 254 nm; RT1 (min): 8.25) to give 1-acryloyl-3-(4-(trifluoromethyl)styryl)azetidine-3-carbonitrile as a white solid (39.6 mg). MS (ESI) mass calculation for C 16 H 13 F3N2O, 306.10 m / z, found, 307.05 [M+H] + , TIFF2025532584000170.tif27145

[0552] Example 38: Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000171.tif26128

[0553] Synthetic Route: TIFF2025532584000172.tif47142

[0554] Synthesis of tert-butyl 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate

[0555] 1-Iodo-4-(trifluoromethyl)benzene (650 mg, 2.390 mmol), a stir bar, TEA (10 mL), and tert-butyl 3-ethynylpyrrolidine-1-carboxylate (466 mg, 2.387 mmol) were added to an oven-dried, nitrogen-purged 25 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with CuI (91 mg, 0.478 mmol) and Pd(PPh)Cl (335 mg, 0.477 mmol) in several portions at rt. The resulting mixture was stirred at 80 °C under a N atmosphere for 15 h and cooled to room temperature. It was then quenched with water and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 20% EA in PE) to give tert-butyl 3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidine-1-carboxylate (640 mg, 78.92%) as a yellow solid. MS (ESI) mass calculation for C 18 H 20 F3NO2, 339.00 m / z, found 325.15 [M-56+CH3CN] + .

[0556] Synthesis of 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate

[0557] tert-Butyl 3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidine-1-carboxylate (640 mg, 1.886 mmol), a stir bar, DCM (6 mL), and TFA (2 mL, 26.926 mmol) were added to an 8 mL vial and stirred until homogeneous. The resulting mixture was stirred at 25 °C for 1 h and then concentrated in vacuo to give 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (600 mg, crude) as a yellow oil. MS (ESI) mass calculation for C 13H 12 F3N, 239.00 m / z, found 240.15 [M+H] + .

[0558] Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0559] 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (500 mg, 2.090 mmol), a stir bar, DCM (5 mL), and TEA (1056 mg, 10.436 mmol) were added to an 8 mL vial and stirred until homogeneous, then treated dropwise with acryloyl chloride (282 mg, 3.116 mmol) at rt. The resulting mixture was stirred at 0 °C for 3 h and then quenched with water. The resulting mixture was extracted with DCM (5 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC (column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50% B to 65% B, 65% B in 9 min; wavelength: 254 nm; RT1 (min): 8.23) to give 1-(3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidin-1-yl)prop-2-en-1-one (209.1 mg), which was purified by Prep-Chiral-HPLC (column: CHIRALPAK IA-3, 4.6 × 50 mm, 3 μm; mobile phase A: Hex(0.1% DEA):EtOH=80:20; flow rate: 1 mL / min; Further purification by elution with a gradient of 0% B to 0% B; injection volume: 5 μL mL) gave 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one (209.1 mg) as a white solid. MS (ESI) calcd. for C 16 H 14F3NO, 293.00 m / z, found 294.00 [M+H] + ; TIFF2025532584000173.tif27144

[0560] Example 39: 1-((3S * ,4S * Synthesis of )-3-methyl-4-((E)-4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000174.tif24128

[0561] Synthetic Route: TIFF2025532584000175.tif28133

[0562] 1-((3S * ,4S * Synthesis of )-3-methyl-4-((E)-4-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0563] To a solution of 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (400 mg, 1.371 mmol) in DCM (4 mL) was added triethylamine (694 mg, 6.855 mmol) and acryloyl chloride (149 mg, 1.645 mmol) in DCM (1 mL) at 0 °C. The resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 70% B, 70% B in 7 min; wavelength: 254 nm) and Prep-Chiral-HPLC (column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 18 mL / min; gradient: 30% B to 30% B in 13 min; wavelength: 220 / 254 nm; RT2 (min): 10.438). The compound was purified by HPLC (sample solvent: EtOH; injection volume: 0.5 mL) to give 1-[(3S,S)-(3S)] (single stereoisomer, absolute stereochemistry randomly assigned as S,S). * ,4S * )-3-Methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one (55.5 mg) was obtained as a white solid. MS (ESI) mass calculation for C 17 H 18 F3NO, 309.13, found, 310.05 [M+H] + ; TIFF2025532584000176.tif27145

[0564] Example 40: 1-[(3R * ,4R* Synthesis of )-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one TIFF2025532584000177.tif24128

[0565] Synthetic Route: TIFF2025532584000178.tif50150

[0566] Synthesis of tert-butyl 3-formyl-4-methylpyrrolidine-1-carboxylate

[0567] To a solution of oxalyl chloride (1.05 g, 8.284 mmol) in DCM (10 mL) was added DMSO (1.29 g, 16.568 mmol) in DCM (3 mL) at −70° C. After stirring for 30 min, tert-butoxy[3-(hydroxymethyl)-4-methylpyrrolidin-1-yl]methanol (900 mg, 4.142 mmol) in DCM (4 mL) was added at −70° C. After stirring for 1 h, triethylamine (3.35 g, 33.136 mmol) in DCM (3 mL) was added. The resulting mixture was stirred at −70° C. for 10 min and warmed to rt for 2 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give tert-butyl 3-formyl-4-methylpyrrolidine-1-carboxylate (850 mg, crude) as a yellow oil. MS (ESI) mass calculation for C 11 H 19 NO3, 213.14, found, 158.00 [M-56+H] + .

[0568] Synthesis of tert-butyl (E)-3-methyl-4-(4-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0569] To a solution of tert-butyl 3-formyl-4-methylpyrrolidine-1-carboxylate (850 mg, 3.985 mmol) and diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (1.42 g, 4.782 mmol) in THF (20 mL) was added t-BuOK (670 mg, 5.978 mmol) at 0 °C. After stirring for 10 min, the resulting mixture was warmed to rt for 1 h. The reaction was quenched with HO and extracted with EA. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (EA / PE = 0-15%) to give tert-butyl 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (1.04 g, 73.42%) as a yellow oil. MS (ESI) mass calculation for C 19 H 24 F3NO2, 355.18, found, 300.05 [M-56+H] + .

[0570] Synthesis of (E)-3-methyl-4-(4-(trifluoromethyl)styryl)pyrrolidine hydrochloride

[0571] To a solution of tert-butyl 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (1 g, 2.814 mmol) in MeOH (5 mL) was added HCl (10 mL, 4 M in 1,4-dioxane). The resulting mixture was stirred at rt for 1 h. The resulting mixture was concentrated to give 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (800 mg, crude). MS (ESI) mass calculation for C 14 H 17 ClF3N, 291.10, found, 256.10 [M-HCl+H] + .

[0572] 1-[(3R * ,4R* Synthesis of )-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one

[0573] To a solution of 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (400 mg, 1.371 mmol) in DCM (4 mL) was added triethylamine (694 mg, 6.855 mmol) and acryloyl chloride (149 mg, 1.645 mmol) in DCM (1 mL) at 0 °C. The resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 70% B, 70% B in 7 min; wavelength: 254 nm) and Prep-Chiral-HPLC (column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 18 mL / min; gradient: 30% B to 30% B in 13 min; wavelength: 220 / 254 nm; RT1 (min): 9.179; The compound was purified by HPLC (sample solvent: EtOH; injection volume: 0.5 mL) to give 1-[(3R * ,4R * )-3-Methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one (54.8 mg) was obtained as a white solid. MS (ESI) mass calculation for C 17 H 18 F3NO, 309.13, found, 310.05 [M+H] + ; TIFF2025532584000179.tif27145

[0574] Example 41: (S * Synthesis of ,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000180.tif22128 Synthetic Route: TIFF2025532584000181.tif62136

[0575] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate

[0576] 1-(Bromomethyl)-3-(trifluoromethyl)benzene (1 g, 4.183 mmol), a stir bar, and triethyl phosphite (10 mL) were added to a 40 mL vial. The reaction mixture was stirred at 100 °C overnight, then cooled to rt and concentrated in vacuo. The residue was purified by reverse column chromatography (5% to 70% CH3CN / 10 mM NH4HCO3 in water) to give diethyl [3-(trifluoromethyl)phenyl]methylphosphonate as a pale yellow oil. MS (ESI) mass calculation for C 12 H 16 F3O3P, 296.08 m / z, found, 297.10 [M+H] + .

[0577] Synthesis of tert-butyl 3-(3-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate

[0578] Diethyl [3-(trifluoromethyl)phenyl]methylphosphonate (400 mg, 1.350 mmol), a stir bar, tert-butyl 3-formylazetidine-1-carboxylate (300 mg, 1.506 mmol), and THF (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with t-BuOK (228 mg, 2.032 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h and then quenched with water (30 mL). The resulting mixture was extracted twice with EA (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-30% EA / PE) to give tert-butyl 3-(3-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) mass calculation for C 17 H 20 F3NO2, 327.14 m / z, found, 328.14 [M+H] + .

[0579] Synthesis of 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate

[0580] tert-Butyl 3-(3-(trifluoromethyl)styryl)pyrrolidine-1-carboxylate (500 mg, 1.527 mmol), a stir bar, and DCM (10 mL) were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with TFA (2 mL). The resulting mixture was stirred at rt for 1 h and then concentrated in vacuo to give 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate as a yellow oil (600 mg, crude). MS (ESI), calcd. for C 13 H 14 F3N, 241.1 m / z, found 242.05 [M+H] + .

[0581] (S *Synthesis of ,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0582] 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol), and a stir bar were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one as a yellow oil (180 mg).180 mg of the racemic product was purified by Chiral HPLC (column: CHIRALPAK AS-H, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 9.056; and a second purification run (column: CHIRALPAK IF, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 11.5 min; wavelength: 220 / 254 nm). nm; RT1(min): 8.514; Sample solvent: EtOH--HPLC; Injection volume: 0.5 mL; Number of runs: 6) Sample solvent: EtOH--HPLC; Injection volume: 0.4 mL) and purified as a single stereoisomer (absolute stereochemistry randomly assigned as S) (S). * ,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one was obtained as a pale yellow oil (3.2 mg). MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + . TIFF2025532584000182.tif27144

[0583] Example 42: (R * Synthesis of ,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000183.tif22128

[0584] Synthetic Route: TIFF2025532584000184.tif21128

[0585] (R* Synthesis of ,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0586] 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol), and a stir bar were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was further purified by (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one as a yellow oil (180 mg). 180 mg of the racemic product was further purified by Chiral HPLC (column: CHIRALPAK AS-H, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 min; wavelength: 220 / 254 nm; 12.48; sample solvent: EtOH-HPLC; injection volume: 0.4 mL) and purified as a single stereoisomer (with absolute stereochemistry randomly assigned as R) (R *,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one was obtained as a pale yellow oil (8.2 mg). MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + , TIFF2025532584000185.tif27145

[0587] Example 43: (R * Synthesis of ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000186.tif14128

[0588] Synthetic Route: TIFF2025532584000187.tif18128

[0589] (R * Synthesis of ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0590] 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol), and a stir bar were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one as a yellow oil (180 mg). 180 mg of the racemic product was further purified by Chiral HPLC (Column: CHIRALPAK AS-H, 2 × 25 cm, 5 μm; Mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 16 min; Wavelength: 220 / 254 nm; RT3 (min): 15.095; Sample solvent: EtOH-HPLC; Injection volume: 0.4 mL) to give a single stereoisomer (absolute configuration randomly assigned as R) (R * ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one was obtained as a pale yellow oil. MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + , TIFF2025532584000188.tif27145

[0591] Example 44: (S * Synthesis of ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one TIFF2025532584000189.tif16128

[0592] Synthetic Route: TIFF2025532584000190.tif18128

[0593] (S * Synthesis of ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one

[0594] 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol), and a stir bar were added to a 50 mL round-bottom flask, stirred until homogeneous, and then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with water (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-1-yl]prop-2-en-1-one as a yellow oil (180 mg).180 mg of the racemic product was purified by Chiral HPLC (column: CHIRALPAK AS-H, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 9.056; sample solvent: EtOH-HPLC; injection volume: 0.4 mL), and then a second purification run (column: CHIRALPAK IF, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 15% B to 10% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 9.056; sample solvent: EtOH-HPLC; injection volume: 0.4 mL). Further purification by HPLC (B ~ 15% B in 11.5 min; wavelength: 220 / 254 nm; RT (min): 10.22; sample solvent: EtOH; injection volume: 0.5 m) afforded the single stereoisomer (absolute configuration randomly assigned as S) (S). * ,E)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one was obtained as a pale yellow oil. MS (ESI) mass calculation for C 16 H 16 F3NO, 295.10 m / z, found, 296.10 [M+H] + . TIFF2025532584000191.tif27146

[0595] Example 45: Synthesis of (E)-1-(3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one TIFF2025532584000192.tif27128

[0596] Synthetic Route: TIFF2025532584000193.tif88142

[0597] Synthesis of (3-bromo-4-(trifluoromethyl)phenyl)methanol

[0598] 3-Bromo-4-(trifluoromethyl)benzoic acid (4 g, 14.869 mmol), a stir bar, and BH3 in THF (40 mL) were added to a 100 mL round-bottom flask and stirred at rt until homogeneous. The resulting mixture was stirred at 25 °C for 2 h and then quenched with water. The resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–50% EA in PE) to give [3-bromo-4-(trifluoromethyl)phenyl]methanol (3 g, 79.11%) as a white solid. MS (ESI) mass calcd. for C8H6BrF3O, 253.00 m / z, found 252.90 [MH] - .

[0599] Synthesis of (4-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)phenyl)methanol

[0600] [3-Bromo-4-(trifluoromethyl)phenyl]methanol (3 g, 11.763 mmol), trimethylsilylacetylene (4.62 g, 47.037 mmol), a stir bar, and TEA (30 mL) were added to an oven-dried, nitrogen-purged 100 mL vial, stirred until homogeneous, and then treated with Pd(PPh)Cl (1.65 g, 2.351 mmol) and CuI (0.9 g, 4.726 mmol) in several portions at rt. The resulting mixture was stirred under a N atmosphere at 80 °C for 48 h, cooled to RT, diluted with water, and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 60% EA in PE) to give the crude product, which was further purified by reverse-phase chromatography (0% to 100% ACN / 0.1% FA in water) to give [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methanol (1.1 g, 34.34%) as a white solid. MS (ESI) mass calculation for C 13 H 15 F3OSi, 272.00 m / z, found 271.00 [MH] - .

[0601] Synthesis of 4-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzyl methanesulfonate

[0602] [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methanol (500 mg, 1.836 mmol), DCM (5 mL), a stir bar, and TEA (500 mg, 4.941 mmol) were added to a 20 mL vial and stirred until homogeneous. Then, at 0 °C, methanesulfonyl chloride (316 mg, 2.759 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 1.5 h and then quenched with water. The resulting mixture was extracted with DCM (5 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methyl methanesulfonate (700 mg, crude) as a yellow oil, which was detected by TLC.

[0603] Synthesis of diethyl (4-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzyl)phosphonate

[0604] [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methyl methanesulfonate (700 mg, 1.998 mmol), a stir bar, and triethyl phosphite (7 mL) were added to a 20 mL vial and stirred until homogeneous. The resulting mixture was stirred at 110 °C for 3 h, then concentrated in vacuo and purified by reverse-phase chromatography (0% to 70% ACN / 10 mM NH4HCO3 in water) to give diethyl [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methylphosphonate (440 mg, 56.13%) as a yellow oil. MS (ESI) mass calculation for C 17 H 24 F3O3PSi, 392.00 m / z, found 393.05 [MH] - .

[0605] Synthesis of tert-butyl (E)-3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidine-1-carboxylate

[0606] Diethyl [4-(trifluoromethyl)-3-[2-(trimethylsilyl)ethynyl]phenyl]methylphosphonate (440 mg, 1.121 mmol), a stir bar, THF (5 mL), and tert-butyl 3-formylazetidine-1-carboxylate (206 mg, 1.112 mmol) were added to a 20 mL vial and stirred until homogeneous. The mixture was then treated with potassium tert-butoxide (188 mg, 1.675 mmol) in several portions at rt. The resulting mixture was stirred at 25 °C for 12 h, then quenched with water and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 20% EA in PE) to give tert-butyl 3-[(E)-2-[3-ethynyl-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate (285 mg, 72.34%) as a yellow oil. MS (ESI) mass calculation for C 19 H 20 F3NO2, 351.00 m / z, found 296.05[M-Boc+H] + .

[0607] Synthesis of (E)-3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidine hydrochloride

[0608] tert-Butyl 3-[(E)-2-[3-ethynyl-4-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate (285 mg, 0.811 mmol), a stir bar, dioxane (1.5 mL), and 4 M HCl in dioxane (1.5 mL) were added to an 8 mL vial and stirred until homogeneous. The resulting mixture was stirred at 25 °C for 2 h and concentrated in vacuo to give 3-[(E)-2-[3-ethynyl-4-(trifluoromethyl)phenyl]ethenyl]azetidine hydrochloride (250 mg, 107.13%) as a yellow oil. MS (ESI) mass calculation for C 14 H13 ClF3N, 251.00 m / z, found 252.05 [MH] - .

[0609] Synthesis of (E)-1-(3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1-one

[0610] (E)-3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidine hydrochloride (240 mg, 0.955 mmol), prop-2-enoyl prop-2-enoate (181 mg, 1.435 mmol), a stir bar, and DCM (3 mL) were added to an 8 mL vial, stirred until homogeneous, and then treated with TEA (483 mg, 4.773 mmol) in several portions at rt. The resulting mixture was stirred at 25 °C for 2 h, then quenched with water and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was separated by prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 65% B, 65% B in 7 min; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-[(E)-2-[3-ethynyl-4-(trifluoromethyl)phenyl]ethenyl]azetidin-1-yl}prop-2-en-1-one (25.6 mg) as a yellow oil. MS (ESI) mass calculation for C 17 H 14 F3NO, 305.00 m / z, found 306.15[M+H] + ; TIFF2025532584000194.tif35146

[0611] Example 46: Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-en-2-yl)prop-2-en-1-one TIFF2025532584000195.tif9128

[0612] Synthetic Route: TIFF2025532584000196.tif48146

[0613] Synthesis of tert-butyl 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-ene-2-carboxylate

[0614] To a solution of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate (110 mg, 0.315 mmol) in dioxane (1.5 mL) and HO (0.3 mL) was added 1-bromo-4-(trifluoromethyl)benzene (156 mg, 0.693 mmol), potassium carbonate (132 mg, 0.945 mmol), and Pd(dppf)Cl (23 mg, 0.032 mmol). The resulting mixture was kept under nitrogen and stirred at 100 °C overnight. The resulting mixture was quenched with HO and extracted with EA. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (EA / PE = 0-15%) to give tert-butyl 7-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.5]non-6-ene-2-carboxylate (107 mg, 92.47%). MS (ESI) mass calculation for C 20 H 24 F3NO2, 367.18 m / z, found, 312.05 [M-56+H] + .

[0615] Synthesis of 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-ene 2,2,2-trifluoroacetate To a solution of tert-butyl 7-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.5]non-6-ene-2-carboxylate (30 mg, 0.082 mmol) in DCM (1 mL) was added TFA (0.2 mL). The resulting mixture was stirred at rt overnight. The resulting mixture was concentrated to give 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-ene 2,2,2-trifluoroacetate (29 mg, 97.22%) as a brown oil. MS (ESI) mass calculation for C 17 H 17 F6NO, 365.12, found, 268.10 [M-TFA+H]+.

[0616] Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-en-2-yl)prop-2-en-1-one

[0617] To a solution of 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6-ene 2,2,2-trifluoroacetate (29 mg, 0.079 mmol) in DCM (0.5 mL) at rt was added triethylamine (48 mg, 0.474 mmol) and acryloyl chloride (8 mg, 0.095 mmol) in DCM (0.5 mL). The resulting mixture was stirred at rt for 2 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC (column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50% B to 80% B, 80% B in 7 min; wavelength: 254 nm; RT1 (min): 5) to give 1-{7-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.5]non-6-en-2-yl}prop-2-en-1-one (3.0 mg, 11.73%) as an off-white solid. MS (ESI) mass calculation for C 18 H 18 F3NO, 321.13, found, 322.15 [M+H] + ; TIFF2025532584000197.tif27145

[0618] Example 47: Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-5-en-2-yl)prop-2-en-1-one TIFF2025532584000198.tif18128

[0619] Synthetic Route: TIFF2025532584000199.tif56134

[0620] Synthesis of tert-butyl 6-hydroxy-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate

[0621] To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.658 mmol) in THF (16 mL) was added bromo[4-(trifluoromethyl)phenyl]magnesium (11 mL, 6.658 mmol) at −10 °C under a nitrogen atmosphere. The resulting mixture was stirred at −10 °C for 1 h. The reaction was quenched with NH₄Cl solution and extracted with EA. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by reverse-phase chromatography on C18 (MeCN / HO (10 Mm NH₄HCO₃) = 5–65%) to give tert-butyl 6-hydroxy-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate as a yellow oil (1.0 g, 43.11%). MS (ESI) mass calculation for C 19 H 24 F3NO3, 371.17, found, 316.10 [M-56+H] + .

[0622] Synthesis of 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octene 2,2,2-trifluoroacetate

[0623] tert-Butyl 6-hydroxy-6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]octane-2-carboxylate (500 mg, 1.35 mmol), a stir bar, DCM (10 mL), and TFA (0.5 mL) were added to a 50 mL flask. The resulting mixture was stirred at rt for 1 h. The resulting mixture was concentrated to give a mixture of 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-5-ene trifluoroacetate and 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-6-ene trifluoroacetate (160 mg, 0.455 mmol). MS (ESI) mass calculation for C 16 H 15 F6NO2, 367.10 m / z, found, 254.00 [M-TFA+H] + .

[0624] Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-5-en-2-yl)prop-2-en-1-one

[0625] To a mixture of 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-5-ene trifluoroacetate and 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-6-ene trifluoroacetate (160 mg, 0.455 mmol) in DCM (4 mL) was added triethylamine (276 mg, 2.730 mmol) and acryloyl chloride (49 mg, 0.546 mmol) in DCM (1 mL) at rt. The resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC (column: Viridis BEH Prep 2-EP OBD column, 30 × 150 mm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: THF-HPLC; flow rate: 30 mL / min; gradient: 5% B to 60% B, 60% B in 6 min; wavelength: 254 nm; RT (min): 5.15) to give 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-5-en-2-yl)prop-2-en-1-one (4.8 mg) as a white solid. MS (ESI) mass calculation for C 17 H 16 F3NO, 307.12 m / z, found, 308.05 [M+H] + ; TIFF2025532584000200.tif29142

[0626] Example 48: Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-6-en-2-yl)prop-2-en-1-one TIFF2025532584000201.tif19128

[0627] Synthetic Route: TIFF2025532584000202.tif39138

[0628] Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-6-en-2-yl)prop-2-en-1-one

[0629] To a mixture of 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-5-ene trifluoroacetate and 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-6-ene trifluoroacetate (160 mg, 0.455 mmol) in DCM (4 mL) was added triethylamine (276 mg, 2.730 mmol) and acryloyl chloride (49 mg, 0.546 mmol) in DCM (1 mL) at rt. The resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with HO and extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated. The resulting residue was purified by prep-HPLC (column: Viridis BEH Prep 2-EP OBD column, 30 × 150 mm, 5 μm; mobile phase A: Hex-HPLC, mobile phase B: THF-HPLC; flow rate: 30 mL / min; gradient: 5% B to 60% B, 60% B in 6 min; wavelength: 254 nm; RT (min): 5.44) to give 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-5-en-2-yl)prop-2-en-1-one (4.9 mg) as a white solid. MS (ESI) mass calculation for C 17 H 16 F3NO, 307.12 m / z, found, 308.10 [M+H] + ; TIFF2025532584000203.tif29146

[0630] Example 49: Synthesis of 1-{3-[6-(trifluoromethyl)-1-benzofuran-2-yl]azetidin-1-yl}prop-2-en-1-one TIFF2025532584000204.tif16128

[0631] Synthetic Route: TIFF2025532584000205.tif73139

[0632] Synthesis of 2-(2,2-dibromoethenyl)-5-(trifluoromethyl)phenol

[0633] 2-Hydroxy-4-(trifluoromethyl)benzaldehyde (2 g, 10.520 mmol), a stir bar, carbon tetrabromide (10.47 g, 31.572 mmol), and DCM (30 mL) were added to an oven-dried, nitrogen-purged 250 mL round-bottom flask. The reaction mixture was stirred at 0 °C for 20 min and then treated with a solution of triphenylphosphine (8.28 g, 31.560 mmol) in DCM (10 mL) over 5 min. The resulting mixture was stirred for 1 h, after which the temperature was allowed to rise to room tem...

Claims

1. Compounds of formula (I): or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, During the ceremony: Bond b is a double or triple bond; R 1 is H, C 1～3 Alkyl, morpholin-4-yl, and -CH 2 N(C 1～3 alkyl) 2 selected from the group consisting of: If bond b is a triple bond, R 1a is absent; if bond b is a double bond, R 1a is H; R 2 are H, F, -OH, C 1～3 Alkyl, -OC 1～3 selected from the group consisting of alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl; R 3 H and C 1～3 alkyl; and If bond b is a triple bond, R 8 is absent; if bond b is a double bond, R 8 are H, F, CN, and C 1～3 alkyl; and i) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: Bond a is a double or triple bond; X 1 is absent or is O, CH(OH), CH(OCH 3 ), CH 2 , C.H. 2 CH 2 , CH(CH 3 ), and C(CH 3 ) 2 and R 4 is H, C 1 ~C 4 Alkyl, cyclopropyl, F, Cl, -OH, -OC 1～3 Alkyl, CN, and NHR 7 and R 7 H and C 1 ~C 3 alkyl; or X 1 and R 4 C together with the carbon to which they are attached 4 ~C 6 forming a cycloalkylene; X 2 is X 2a and X 2a is C; If bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 H, F, and C 1 ~C 3 is selected from the group consisting of alkyl, If bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 H, F, and C 1 ~C 3 selected from the group consisting of alkyl; A is absent or O, CH 2 , C.H. 2 CH 2 , CH(OH), CH(OCH 3 ), C(CH 3 ) 2 and CH(CH 3 and Ar is aryl or heteroaryl, each of which may contain 1, 2, 3, or 4 R 9 or optionally substituted with a group; ii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together and X 2 is X 2a and X 2a is C; R 4 and R 6 Together - (CH 2 ) m -; m is 0, 1, or 2; X 1 is not present or CH 2 , C.H. 2 CH 2 , CH(CH 3 ), O, CH 2 O, and OCH 2 R 5 H, F, and C 1 ~C 3 alkyl; A is absent or selected from the group consisting of O, CH 2 , C.H. 2 CH 2 , and CH(CH 3 and Ar is aryl or heteroaryl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 9 or optionally substituted with a group; iii) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together and X 1 is absent or O, CH 2 , C.H. 2 CH 2 , and CH(CH 3 ) selected from the group consisting of; X 2 is X 2b and X 2b is N; R 4 is H, C 1 ~C 4 Alkyl, cyclopropyl, F, Cl, -OH, -OC 1～3 Alkyl, CN, and NHR 7 and R 7 H and C 1 ~C 3 alkyl; R 5 and Ar together and R 6 and A is absent; or iv) In the formula, bonds a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together and X 1 is absent or O, CH 2 , C.H. 2 CH 2 , and CH(CH 3 ) selected from the group consisting of; X 2 is X 2c and X 2c is N or CR 6 and R 6 H, F, and C 1 ~C 3 alkyl; R 4 is H, C 1 ~C 4 Alkyl, cyclopropyl, F, Cl, -OH, -OC 1～3 Alkyl, CN, and NHR 7 and R 7 H and C 1 ~C 3 alkyl; A is absent; and R 5 and Ar together where X 3 are O, NH, N(C 1 ~C 3 alkyl), and Ar 1 is a fused arylene or fused heteroarylene ring, where Ar 1 The ring may contain 1, 2, 3, or 4 R 9 optionally substituted with a group; Here, each R 9 independently, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 selected from the group consisting of alkoxy, and CN; With the proviso that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)ethenyl]-1-piperidinyl]-2-propen-1-one, A compound of formula (I) or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

2. Bond b is a double bond, and R 1a is H, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

3. Bond b is a triple bond, and R 1a and R 8 2. The compound of claim 1, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein:

4. R 1 is H, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

5. R 1 4. The compound of any one of claims 1 to 3, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is Me.

6. R 1 is selected from the group consisting of H and Me, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

7. R 2 is H, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

8. R 2 7. The compound of any one of claims 1 to 6, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

9. R 2 C 1～3 7. The compound of any one of claims 1 to 6, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is alkyl.

10. R 2 7. The compound of any one of claims 1 to 6, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is H, methyl, or ethyl.

11. R 2 Ga-OC 1～3 7. The compound of any one of claims 1 to 6, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein R is alkyl.

12. R 2 12. The compound of any one of claims 1 to 6 and 11, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is -OMe.

13. R 2 7. The compound of any one of claims 1 to 6, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is -NH-heteroaryl or -NH-(substituted heteroaryl).

14. R 2 is unsubstituted heteroaryl (in some embodiments, pyrazolyl) or substituted heteroaryl (in some embodiments, pyrazolyl), or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

15. R 2 is H, methyl, ethyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), or unsubstituted heteroaryl (in some embodiments, pyrazolyl), or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof.

16. R 3 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

17. R 3 16. The compound of any one of claims 1 to 15, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is methyl or ethyl.

18. Bond b is a double bond, and R 8 18. The compound of any one of claims 1, 2, and 4-17, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

19. Bond b is a double bond, and R 8 18. The compound of any one of claims 1, 2, and 4-17, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

20. bond a, x 1 , X 2 , R 4 , R 5 , R 6 20. The compound of any one of claims 1 to 19, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein, A, and Ar are according to i).

21. X 1 does not exist or CH 2 , CH(OH), or C(CH 3 ) 2 21. The compound of claim 20, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein:

22. X 1 22. The compound of claim 20 or 21, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is absent.

23. X 1 is CH 2 22. The compound of claim 20 or 21, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, wherein:

24. The following formula:

2. The compound of claim 1, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, according to

25. R 4 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

26. R 4 C 1 ~C 4 25. The compound of any one of claims 20 to 24, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, which is alkyl(methyl).

27. R 4 25. The compound of any one of claims 20 to 24, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

28. R 4 25. The compound of any one of claims 20 to 24, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is -OH.

29. R 4 25. The compound of any one of claims 20 to 24, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is -OMe.

30. R 4 25. The compound of any one of claims 20 to 24, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is CN.

31. X 1 and R 4 However, together with the carbon to which they are attached, C 4 ~C 6 21. The compound of claim 20, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, which forms a cycloalkylene.

32. X 1 and R 4 However, together with the carbon to which they are attached, C 4 Cycloalkylene or C 6 32. The compound of claim 20 or 31, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, which forms a cycloalkylene.

33. 33. The compound of any one of claims 20 to 32, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is a double bond.

34. R 5 and R 6 and R are each H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

35. 35. The compound of any one of claims 20 to 34, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is cis.

36. 35. The compound of any one of claims 20 to 34, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein bond a is trans.

37. Bond a is a triple bond and R 5 and R 6 33. The compound of any one of claims 20 to 32, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

38. bond a, x 1 , X 2 , R 4 , R 5 , R 6 20. The compound of any one of claims 1 to 19, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein, A, and Ar are according to ii).

39. 39. The compound of claim 38, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein m is 1.

40. 39. The compound of claim 38, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein m is 2.

41. X 1 41. The compound of any one of claims 38 to 40, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is absent.

42. m is 0 and X 1 39. The compound of claim 38, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is other than absent.

43. X 1 But CH 2 , C.H. 2 CH 2 , CH(CH 3 ), O, CH 2 O, or OCH 2 43. The compound of any one of claims 38 to 40 and 42, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

44. R 5 is H, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

45. 45. The compound of any one of claims 20 to 44, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein A is absent.

46. A is CH 2 , CH(OH), CH(OCH 3 ), and C(CH 3 ) 2 38. The compound of any one of claims 20 to 37, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, selected from the group consisting of:

47. Ar can be 1, 2, 3, or 4 R 9 and phenyl optionally substituted with one R group (in some embodiments, the phenyl is 9 47. The compound of any one of claims 20 to 46, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

48. Ar can be 1, 2, 3, or 4 R 9 and heteroaryl (preferably oxazolyl, imidazolyl, or pyridinyl) optionally substituted with a group (in some embodiments, the heteroaryl is substituted with one R 9 47. The compound of any one of claims 20 to 46, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

49. bond a, x 1 , X 2 , R 4 , R 5 , R 6 20. The compound of any one of claims 1 to 19, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein, A, and Ar are according to iii).

50. X 1 does not exist and R 4 50. The compound of claim 49, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

51. bond a, x 1 , X 2 , R 4 , R 5 , R 6 20. The compound of any one of claims 1 to 19, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein, A, and Ar are according to iv).

52. X 2 52. The compound of claim 51, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is CH.

53. X 1 does not exist and R 4 53. The compound of any one of claims 51-52, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

54. X 3 54. The compound of any one of claims 51 to 53, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein is O, NH, N(Me).

55. Ar 1 but 1, 2, 3, or 4 R 9 55. The compound of any one of claims 51 to 54, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, which is benzo or pyrido, optionally substituted by a group.

56. Each R 9 independently, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkynyl, Halo, C 1 ~C 6 Haloalkyl, and C 1 ~C 6 alkoxy; or each R 9 are independently methyl, ethynyl, F, CF 3 56. The compound of any one of claims 1 to 55, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, selected from the group consisting of:

57. 1 or 2 R 9 are present and independently selected, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof.

58. 1 R 9 CF 3 58. The compound of any one of claims 1 to 57, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

59. is 59. The compound of any one of claims 1 to 58, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, wherein

60. 2. The compound of claim 1, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof, selected from the compounds in Table 1.

61. The compound of claim 1, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, selected from the group consisting of:

62. 62. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims 1 to 61, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof, and a pharmaceutically acceptable carrier.

63. 63. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of any one of claims 1-61, or a stereoisomer, and / or pharmaceutically acceptable salt, and / or solvate thereof; or a pharmaceutical composition of claim 62.

64. The cancers include bladder cancer, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), glioblastoma, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia, non-Hodgkin's lymphoma, prostate cancer, rectal cancer, malignant melanoma, gastrointestinal / gastrointestinal tract cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye cancer, rectal cancer, colorectal cancer, cervical cancer, oral cancer, benign and malignant tumors, stomach cancer 64. The method of claim 63, wherein the cancer is selected from the group consisting of: uterine cancer, testicular cancer, renal cancer, throat cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, oral cavity / pharyngeal cancer, esophageal cancer, laryngeal cancer, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

65. 64. The method of claim 63, wherein the cancer is selected from the group consisting of glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).

66. The method comprises: one or more additional anticancer therapies; or one or more KRAS G12C and / or G12D inhibitors; one or more CDK4 / 6 inhibitors; one or more EGFR inhibitors; one or more RAF inhibitors; one or more MEK inhibitors; one or more Wnt signaling inhibitors, such as anti-β-catenin inhibitors, GSK3 inhibitors, JNK inhibitors, and CK1 inhibitors; one or more TGF-β signaling inhibitors, such as atezolizumab, durvalumab, and avelumab; one or more PD-1 / PD-L1 inhibitors; and / or radiation therapy. or the one or more additional therapies comprises a KRAS G12C and / or G12D inhibitor; or 66. The method of any one of claims 63-65, wherein said one or more KRAS G12C and / or G12D inhibitors is sotorasib or adagrasib.

67. 63. A method for inhibiting TEAD1, 2, 3, and / or 4 in a subject or sample, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-61, or a stereoisomer, and / or a pharmaceutically acceptable salt, and / or solvate thereof; or a pharmaceutical composition of claim 62.

68. 68. The method of claim 67, wherein TEAD1 is selectively inhibited compared to TEAD2, 3, and 4.

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