YAP / TAZ-TEAD oncoprotein inhibitors

Abstract

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

Description

Technical Field

[0001] The present invention relates generally to cancer therapy, and more specifically to the synthesis of covalent inhibitors of YAP / TAZ-TEAD oncoprotein and their use for treating cancer. Background Art

[0002] TEA-domain transcription factors (TEAD proteins) are effectors of oncogenic YAP / TAZ signaling in cancers with dysregulated Hippo tumor suppressor pathway signaling. Interactions between Yes1-associated transcriptional regulator (YAP1, also known as YAP), WW domain-containing transcriptional regulator 1 (WWTR1, also known as TAZ), and YAP's transcriptional coactivator homolog, 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 through the MST1 / 2 and LATS1 / 2 kinases results in YAP / TAZ phosphorylation, cytoplasmic sequestration, and proteasomal degradation. Inactivation of Hippo signaling due to somatic mutations in NF2, MST, or LATS stabilizes YAP / TAZ and leads to 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 dysregulation. Furthermore, activation of YAP / TAZ signaling has been described as a mechanism of resistance to other targeted cancer therapies, such as EGFR and MEK inhibitors.

[0003] Therefore, inhibitors of TEAD1, 2, 3, and / or 4 have great potential for application in cancer therapy, both as monotherapy for cancers with dysregulated Hippo pathway signaling and as combination therapies with other targeted agents. Summary of the Invention

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

[0005] In a first aspect, there is provided a compound according to formula (I):

[0006]

[0007] or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0008] Bond b is a double bond or a triple bond;

[0009] R1 Selected from H, C 1-3 Alkyl, morpholin-4-yl and -CH2N(C 1-3 Alkyl)2;

[0010] When bond b is a triple bond, R 1a is not present; when bond b is a double bond, R 1a is H;

[0011] R 2 Selected from H, F, -OH, C 1-3 Alkyl, -OC 1-3 alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl;

[0012] R 3 Selected from H and C 1-3 alkyl; and

[0013] When bond b is a triple bond, R 8 is not present; when bond b is a double bond, R 8 Selected from H, F, CN and C 1-3 alkyl; and

[0014] i) where the key a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar are as follows:

[0015] Bond a is a double bond or a triple bond;

[0016] X 1 is absent or selected from O, CH(OH), CH(OCH3), CH2, CH2CH2, CH(CH3) and C(CH3)2, and R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN, and NHR 7 , and R 7 selected from H and C1-C3 alkyl; or X 1 and R 4 Together with the carbon to which they are attached, they form a C4-C6 cycloalkylene group;

[0017] X 2 For X 2a And X 2a is C;

[0018] When bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 Selected from H, F and C1-C3 alkyl;

[0019] When bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 Selected from H, F and C1-C3 alkyl;

[0020] A is absent or selected from O, CH2, CH2CH2, CH(OH), CH(OCH3), C(CH3)2 and CH(CH3); and

[0021] Ar is aryl or heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 R 9 group substitution; or

[0022] ii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0023] and

[0024] X 2 For X 2a And X 2a C; R 4 and R 6 Together they form -(CH2) m -; m is 0, 1 or 2; X 1 is absent or selected from CH2, CH2CH2, CH(CH3), O, CH2O and OCH2; R 5 is selected from H, F and C1-C3 alkyl; A is absent or selected from O, CH2, CH2CH2 and CH(CH3); and Ar is aryl or heteroaryl, each of which is optionally replaced by 1, 2, 3 or 4 R 9 group substitution; or

[0025] iii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0026] and

[0027] X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2b And X 2b N; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC1-3 Alkyl, CN, and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; R 5 Together with Ar and R 6 and A is absent; or

[0028] iv) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0029] and

[0030] X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2c And X 2c N or CR 6 , and R 6 is selected from H, F and C1-C3 alkyl; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN, and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; A is absent; and R 5 Together with Ar where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused arylene or fused heteroarylene ring, wherein Ar 1 The ring is optionally substituted with 1, 2, 3 or 4 R 9 group substitution; and

[0031] Each R 9 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, and CN; and

[0032] Provided that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)vinyl]-1-piperidinyl]-2-propen-1-one.

[0033] In a second aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present application (including a compound according to formula (I), (II), any embodiment herein, and any one of compounds 1-106) or a stereoisomer thereof and / or a pharmaceutically acceptable salt and / or solvate, and a pharmaceutically acceptable carrier.

[0034] In a third aspect, a method for treating a disease or condition regulated by TEAD1, 2, 3 and / or 4 is provided, the method comprising administering a therapeutically or prophylactically effective amount of a compound disclosed herein (including formula (I), (II), a compound of any embodiment, and any one of compounds 1-106) to an individual in need thereof, or administering a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound disclosed herein (including formula (I), (II), a compound of any embodiment, and any one of compounds 1-106) and a pharmaceutically acceptable carrier. In some or any embodiments, the method is a method in which TEAD1 is selectively inhibited relative to TEAD2, 3, and 4. In some or any embodiments, the disease or condition is selected from cancer, fibrotic disease, neurofibromatosis type 2, and polycystic kidney disease.

[0035] In a fourth aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (including compounds according to Formula (I), (II), any embodiment herein, and any one of Compounds 1-106) or a stereoisomer and / or a 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 a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0036] In a fifth aspect, provided herein is a compound useful as an intermediate in the preparation of compounds disclosed herein.

[0037] In a sixth aspect, provided herein is a method for preparing a compound of formula (I) according to any one of the general schemes or synthetic examples.

[0038] In another aspect, the present disclosure provides a method of inhibiting TEAD1, 2, 3 and / or 4 in a subject or sample, the method comprising administering a compound of formula (I) (including any one of the compounds according to formula (I), (II), any embodiment herein, and compounds 1-106), or a stereoisomer thereof and / or a pharmaceutically acceptable salt and / or a solvate thereof. In certain embodiments, the compound is at least one of the compounds shown in Table 1, or a stereoisomer thereof, and / or a pharmaceutically acceptable salt, and / or a solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is a schematic diagram of how compounds of the present disclosure function as covalent TEAD1 inhibitors.

[0040] FIG. 2 is a graph illustrating the percentage change in body weight of mice over time after treatment according to Example 5.

[0041] FIG3 is a graph illustrating the percentage change in tumor volume over time in mice after treatment according to Example 5. DETAILED DESCRIPTION

[0042] 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; in some embodiments, they selectively inhibit the activity of TEAD1 relative to other TEAD isoforms, showing potential in cancer treatment; and in some embodiments, showing potential in the treatment of certain types of cancer. TEAD1 belongs to the TEAD family, which regulates cell growth and proliferation through the TEAD1 / YAP / TAZ complex. TEAD1 regulates the stemness and invasiveness of glioblastoma by regulating EGFR and AQP4 expression via the TEAD-EGFR / AQP4 pathway. In addition, through the Hippo-YAP / TAZ-TEAD pathway, YAP / TAZ-TEAD activation induces the transcription of cell cycle-promoting genes; TEAD1 regulates the expression of cytoskeleton remodeling genes; TEAD1 increases the expression of other transcription factors such as Myc and SP1; the YAP / TAZ-TEAD1 axis regulates cell apoptosis; blocking the abnormal activity of TEAD1 downregulates the expression of genes such as MYC, KRAS, BRAF, NF2, LKB1 and PD-L1. Therefore, inhibitor compounds that inhibit the activity of TEAD1, 2, 3, and / or 4 (in some embodiments, selectively targeting TEAD1) have the potential to treat cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).

[0043] It is to be understood that the aspects and embodiments disclosed herein are not limited to the specific compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0044] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, it will be understood that modifications and variations are encompassed within the spirit and scope of the present disclosure.Preferred methods and materials are now described.

[0045] 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.

[0046] definition

[0047] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents 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, which will become apparent to those skilled in the art upon reading this disclosure.

[0048] If there are multiple definitions of a term herein, the definition in this section will prevail unless otherwise specified. Unless otherwise specified, when a term is defined as substituted, the groups listed in the substituent list are themselves unsubstituted. For example, a substituted alkyl group may be substituted with, for example, a cycloalkyl group, and unless otherwise specified, the cycloalkyl group may not be further substituted.

[0049] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, 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.

[0050] The term "about" is understood by those of ordinary skill in the art. Regardless of whether the term "about" is explicitly used, each amount given herein refers to the actual given value, and it is also intended to refer to the approximate amount of the given value that can be reasonably inferred based on the ordinary skill in the art. References to "about" values ​​or parameters herein include (and describe) variations for the value or parameter itself. For example, a description of "about X" includes a description of "X." As used herein, and unless otherwise specified, when the terms "about" and "approximately" are used in conjunction with the temperature, dose, amount, or weight percentage of a composition or dosage form, it refers to a dose, amount, or weight percentage that a person of ordinary skill in the art believes can provide a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. Specifically, the terms "about" and "approximately" when used in this context encompass doses, amounts, or weight percentages within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dose, amount, or weight percentage.

[0051] As used herein, "acyl" refers to a -C(O)R group, where R is alkyl or cycloalkyl, as defined herein.

[0052] "Alkyl" refers to a linear or branched monovalent saturated hydrocarbon, wherein the alkyl group has 1 to 12 carbon atoms, and in some embodiments has 1 to 10 carbon atoms, in some embodiments has 1 to 6 carbon atoms, in some embodiments has 1 to 3 carbon atoms, or in some embodiments has 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. "Lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms. "C0" alkyl (such as the "C0" alkyl in "C0-C6-alkyl") is a covalent bond. "C6 alkyl" refers to, for example, n-hexyl, isohexyl, etc. In some embodiments, an alkyl group is C 1-3 Alkyl or C 1-4 alkyl.

[0053] "Alkylcarbonyl" refers to a -C(O)R group, where R is alkyl, as defined herein. In some embodiments, acyl is acetyl. Lower alkylcarbonyl is an alkylcarbonyl group where alkyl is C1-C6 alkyl.

[0054] "Alkylcarbonyloxy" means a -OC(O)R group where R is alkyl, as defined herein.

[0055] "Alkylsulfonyl" refers to a -S(O)2R group where R is alkyl, as defined herein.

[0056] "C1-C6 alkylthio" refers to a -SR group where R is alkyl, as defined herein.

[0057] "Alkoxy" refers to a -OR group, where R is an alkyl group, 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 cyclohexyloxy. In some embodiments, the alkoxy group is methoxy. "Lower alkoxy" refers to a -OR group, where R is an alkyl group having from one to six carbon atoms.

[0058] "C1-C6 alkoxycarbonyl" refers to a -C(O)R group where R is C1-C6 alkoxy, as defined herein.

[0059] "Haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogens (e.g., one, two, three, four, or five halogen atoms). Representative examples include 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl. "Lower haloalkyl" refers to an alkyl group having from one to six carbon atoms. In some embodiments, haloalkyl is trifluoromethyl. "Lower perhaloalkyl" refers to an alkyl group in which each hydrogen is replaced with a halogen.

[0060] "C1-C6 haloalkylthio" refers to a -SR group where R is a C1-C6 haloalkyl as defined herein.

[0061] "Haloalkenyl" refers to an alkenyl group as defined herein substituted with one or more halogens (e.g., one, two, three, four, or five halogen atoms). "Lower haloalkenyl" means that the alkenyl group has two to six carbon atoms.

[0062] "Haloalkynyl" refers to an alkynyl group, as defined herein, substituted with one or more halogens (e.g., one, two, three, four, or five halogen atoms). "Lower haloalkynyl" means that the alkynyl group has two to six carbon atoms.

[0063] "Haloalkoxy" refers to a -OR group where R is a haloalkyl group, as defined herein. "Lower perhaloalkoxy" refers to an alkyl group where each hydrogen is replaced by a halogen.

[0064] "Cycloalkyl" refers to a monocyclic or bicyclic monovalent hydrocarbon radical having three to fourteen carbon ring atoms. Cycloalkyl groups are saturated or partially saturated, but cannot contain aromatic rings. Cycloalkyl groups include fused, bridged, and spiro ring systems. In some embodiments, cycloalkyl groups have from 3 to 12, 3 to 10, 3 to 8, 4 to 6, or 3, 4, 5, 6, or 7 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include, but are not limited to, bicyclo[4.4.0]decyl, bicyclo[2.2.1]heptyl, spiro[2.2]pentyl, and the like.

[0065] "Cycloalkylene" refers to a divalent cycloalkyl group, as defined herein. Examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropyldiyl, cyclobutyldiyl, cyclopentyldiyl, and cyclohexyldiyl. Examples of bicyclic cycloalkylene groups include, but are not limited to, bicyclo[4.4.0]decanediyl, bicyclo[2.2.1]heptanediyl, spiro[2.2]pentanediyl, and the like. In some embodiments, the cycloalkylene group is a C4-C6 cycloalkylene group.

[0066] "Alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms and one or more double bonds between two carbon atoms. In some embodiments, the alkenyl group has from 2 to about 10 carbon atoms, in some embodiments 2 to 8 carbon atoms, in some embodiments from 2 to about 6 carbon atoms, or in some embodiments 2, 3, or 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, etc. "Lower alkenyl" refers to an alkenyl group having two to six carbon atoms.

[0067] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more triple bonds between two carbon atoms and having from 2 to 12 carbon atoms, in some embodiments from 2 to 10 carbon atoms, in some embodiments from 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(CH3). "Lower alkynyl" refers to an alkynyl group having from two to six carbon atoms.

[0068] "Aryl" refers to a monovalent six to fourteen membered mono- or bicyclic carbon ring, wherein the monocyclic ring is aromatic and at least one of the bicyclic rings is aromatic. In some embodiments, the aryl group contains 6 to 10 carbon ring atoms. Representative examples include phenyl, naphthyl, and indanyl. In some embodiments, the aryl group is phenyl.

[0069] "Heteroaryl" refers to a monovalent group comprising a monocyclic, fused bicyclic, or fused tricyclic ring of 5 to 14 ring atoms containing one or more heteroatoms (e.g., one, two, three, or four ring heteroatoms) independently selected from N, -N(R x )-, O, S and S(O) n -(n is 0, 1 or 2) and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be substituted 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 as permitted by the valence rules. In particular, when the point of attachment is on nitrogen, R xis absent. Heteroaryl includes, but is not limited to, isoxazolyl, oxazolyl, oxadiazolyl, pyridinyl, 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, etc.), isoindolyl, indolinyl, isoindolyl, phthalimido, pyrazolopyridinyl, benzofuranyl, benzimidazolyl, benzodihydro-1H-indolyl, Oxol-4-yl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, etc.), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiophenyl. In some embodiments, the heteroaryl group is a 5-membered or 6-membered heteroaryl group. In some embodiments, the heteroaryl group 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.

[0070] "Fused arylene" means a divalent monocyclic aromatic ring, as defined herein, fused to a second ring, consisting of Ar 1 Partially stated: In some embodiments, Ar 1 The fused arylene group is (Benzo).

[0071] "Fused heteroarylene" refers to a bivalent monocyclic heteroaryl ring, as defined herein, fused to a second ring and consisting of Ar 1 Partially stated: In some embodiments, Ar 1 The fused heteroarylene is

[0072] "Heterocycloalkyl" refers to a saturated monovalent monocyclic radical having 3 to 9 ring atoms or a saturated monovalent fused bicyclic radical having 5 to 12 ring atoms, wherein one or more heteroatoms (e.g., one, two, three or four ring heteroatoms) are independently selected from -O-, -S(O) ... n -(n is 0, 1 or 2), -N=, -N(R y )-(where R yis hydrogen, alkyl, hydroxy, alkoxy, acyl or alkylsulfonyl), and the remaining ring atoms are carbon. One or two ring carbon atoms may be substituted by -C(O)-, -C(S)- or -C(=NH)- groups. Fused bicyclic groups include bridged ring systems. Unless otherwise specified, the point of attachment of a group may be on any atom of any ring within the group, as long as the valence rules permit. In particular, when the point of attachment is on a nitrogen atom, R y More specifically, the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepine 1-Hydroxy-1-pyrrolidyl, ...

[0073] Halogen groups include F, Cl, Br, and I; nitro refers to -NO2; and cyano refers to -CN.

[0074] "Amino" refers to -NH2.

[0075] "Lower carbamate" refers to -O(C=O)NR a R b , where R a and R b are independently hydrogen, C1-C6 alkyl, aryl or heterocyclic.

[0076] The term "substituted heteroaryl" refers to a heteroaryl group as defined herein substituted by one or more (1, 2, 3 or 4) substituents independently selected from the group consisting of 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 haloalkoxy, oxo alkyl), -C(O)NH, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), cyano, halogen, hydroxy, amino, lower alkylamino, -NHC(O)R (wherein R is C1-C6 alkyl), nitro, C1-C6 alkylthio, C1-C6 haloalkylthio, SH and lower carbamate.

[0077] Unless otherwise specified, as used herein, term " protecting group " refers to the group that is added to oxygen, nitrogen or phosphorus atom to prevent it from further reaction or for other purposes. Known multiple oxygen and nitrogen protecting groups of those skilled in the art of organic synthesis (see, for example, Greene et al., " protecting group in organic synthesis ", John Wiley and Sons press, 4th edition, those described in 2006, incorporated herein by reference). In some or any embodiments, " nitrogen protecting group " is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl ,-C (O) OCH2CCl3(Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylmethylene, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfonyl (tosyl). In some or any embodiments, oxygen protecting group (for example, for X 1 ) is methoxymethyl (MOM), ethoxyethyl, methoxyethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, methyl, tert-butyl, allyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, dimethoxytrityl, trityl, methoxytrityl, p-methoxybenzyl or methylthiomethyl.

[0078] "Stereoisomers" refers to compounds with the same molecular formula and sequence of bonded atoms (configuration) but different three-dimensional orientations of their atoms in space. Stereoisomers include enantiomers, diastereomers, geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) and atropisomers. Enantiomers are a pair of molecules with exactly the same connectivity that exist in two forms that are mirror images of each other but cannot be superimposed on each other. Diastereomers are unequal stereoisomers that have different configurations 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 with the same molecular formula but different orientations of their functional groups in three-dimensional space. Cis-trans stereoisomers contain double bonds that do not rotate, or they may contain ring structures in which rotation of the bonds is restricted or prevented. Cis means that the functional groups (substituents) are located on the same side of a plane, while trans means that they are located on opposite (lateral) sides. Atropisomers are stereoisomers that arise due to hindered rotation about a single bond, where the steric tension barrier to rotation is high enough to allow separation of conformers. In some or any embodiments, stereoisomers are geometric isomers. In some or any embodiments, stereoisomers are enantiomers. In some or any embodiments, stereoisomers are enantiomers and geometric isomers.

[0079] The term "substantially free" or "substantially absent" of stereoisomers (e.g., geometric isomers), with respect to a composition, refers to a composition that comprises at least 85 or 90% by weight (in some or any embodiments, 95%, 98%, 99%, or 100% by weight) of a specified stereoisomer (e.g., geometric isomer) of a compound in the composition. In some or any embodiments, in the methods and compounds provided herein, the compound is substantially free of stereoisomers (e.g., geometric isomers) of a specified compound.

[0080] 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 a particular compound, with the remainder comprising other chemical species or stereoisomers (e.g., geometric isomers) thereof.

[0081] As used herein, and unless otherwise specified, the term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0082] Pharmaceutically acceptable salts of the compounds described herein (including compounds according to formula (I), (II), any embodiment herein, and any of compounds 1-106) include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, 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, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. In other cases, the compounds may contain one or more acidic functional groups and, therefore, are capable of forming 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 reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with 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, and the like.

[0083] Compound

[0084] Aspects and embodiments described herein include the compounds described and 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 compounds described are provided as pharmaceutically acceptable salts, and / or stereoisomers, and / or tautomers, and / or mixtures or any combination thereof. In some embodiments, the compounds described are provided as pharmaceutically acceptable salts, and / or stereoisomers, and / or tautomers. In some embodiments, the compounds described are provided as pharmaceutically acceptable salts.

[0085] Certain polycyclic structures provided herein carry one or more floating substituents. Unless otherwise indicated or the context clearly indicates otherwise, substituents may be present on any atom of the polycyclic ring as long as it is chemically feasible and the valence rules permit. For example, in the structure: In, R 9 Substituents may be on either the benzo portion of the bicyclic or the furyl portion of the bicyclic.

[0086] Embodiment A: In some or any embodiments, the compound of formula (I) is wherein for Compounds;

[0087] Bond b is a double bond or a triple bond;

[0088] R 1 H or C 1-3 alkyl (in some embodiments, methyl);

[0089] When bond b is a triple bond, R 1a is not present; when bond b is a double bond, R 1a is H;

[0090] R 2 Selected from H, C 1-2 Alkyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), and 5-membered heteroaryl (in some embodiments, pyrazolyl);

[0091] R 3 is H or methyl; and

[0092] When bond b is a triple bond, R 8 is not present; when bond b is a double bond, R 8 selected from H and F; and

[0093] i) where the key a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar are as follows:

[0094] Bond a is a double bond or a triple bond;

[0095] X 1 is absent, CH2, CH(OH) or C(CH3)2, and R 4 is selected from H, methyl, F, -OH, methoxy and CN; or X 1 and R 4 Together with the carbon to which they are attached, they form a C4-C6 cycloalkylene group;

[0096] X 2 For X 2a And X 2a is C;

[0097] When bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 is H;

[0098] When bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 is H;

[0099] A is absent or selected from CH2, CH(OH), CH(OCH3) and C(CH3)2; and

[0100] Ar is phenyl, oxazolyl, thiazolyl or pyridyl, each of which is optionally substituted with 1 or 2 R 9 group substitution; or

[0101] ii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0102] and

[0103] X 2 For X 2a And X 2a C; R 4 and R 6 Together they form -(CH2) m -; m is 0, 1 or 2; X 1 is absent or selected from CH2, O, CH2O and OCH2; R 5 is H; A is absent; and Ar is phenyl, which is optionally replaced by 1 R 9 Group substitution; provided that when X 1 When is absent, m is 1 or 2; or

[0104] iii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0105] and

[0106] X 1 Does not exist; X 2 For X 2b And X 2b N; R 4 H; R 5 Together with Ar and R 6 and A is absent; or

[0107] iv) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0108] and

[0109] X 1 Does not exist; X 2 For X 2c And X 2c CR 6 , and R 6 H; R 4 is H; A is absent; and R 5 Together with Ar where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused phenylene group, which is optionally substituted by 1 R 9 Replacement; and

[0110] Each R 9 are independently selected from ethynyl, F, -CF3 and methoxy; and

[0111] Provided that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)vinyl]-1-piperidinyl]-2-propen-1-one.

[0112] Embodiment B: In some or any embodiments, the compound of formula (I) is wherein for Compounds;

[0113] Bond b is a double bond or a triple bond;

[0114] R 1 is H;

[0115] When bond b is a triple bond, R 1a is not present; when bond b is a double bond, R 1a is H;

[0116] R 2 Selected from H, C 1-2 Alkyl, methoxy, and 5-membered heteroaryl (in some embodiments, pyrazolyl);

[0117] R 3 is H or methyl; and

[0118] When bond b is a triple bond, R 8 is not present; when bond b is a double bond, R 8 selected from H and F; and

[0119] i) where the key a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar are as follows:

[0120] Bond a is a double bond or a triple bond;

[0121] X 1 is absent or is CH2, and R 4 is selected from H, methyl, F, -OH, methoxy and CN; or X 1 and R 4 Together with the carbon to which they are attached, they form a C4-C6 cycloalkylene group;

[0122] X 2 For X 2a And X 2a is C;

[0123] When bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 is H;

[0124] When bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 is H;

[0125] A is absent; and

[0126] Ar is phenyl, oxazolyl, thiazolyl or pyridyl, each of which is optionally substituted with 1 or 2 R 9 group substitution; or

[0127] ii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0128] and

[0129] X 2 For X 2a And X 2a C; R 4 and R 6 Together they form -(CH2) m -; m is 1 or 2; X 1 is absent or selected from CH2; R 5 is selected from H; A is absent; and Ar is phenyl, which is optionally replaced by 1 R 9 group substitution; or

[0130] iii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0131] and

[0132] X 1 Does not exist; X 2 For X 2b And X 2b N; R 4 Selected from H; R 5 Together with Ar and R 6 and A is absent; or

[0133] iv) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0134] and

[0135] X 1 Does not exist; X 2 For X 2c And X 2c CR 6 , and R 6 Selected from H; R 4 is H; A is absent; and R5 Together with Ar where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused phenylene group, which is optionally substituted by 1 R 9 Replacement; and

[0136] Each R 9 are independently selected from ethynyl, F, -CF3 and methoxy; and

[0137] Provided that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)vinyl]-1-piperidinyl]-2-propen-1-one.

[0138] Embodiment 1: Provided is a compound of formula (I) as provided in the first aspect, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof. In some or any embodiments, the compound of formula (I) is according to embodiment A or B.

[0139] Embodiment 1A: Provided is a compound of formula (I), or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof,

[0140] in:

[0141] Bond b is a double bond or a triple bond;

[0142] R 1 Selected from H, C 1-3 Alkyl, morpholin-4-yl and -CH2N(C 1-3 Alkyl)2;

[0143] When bond b is a triple bond, R 1a is not present; when bond b is a double bond, R 1a is H;

[0144] R 2 Selected from H, F, -OH, C 1-3 Alkyl, -OC 1-3 alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl;

[0145] R 3 Selected from H and C 1-3 alkyl; and

[0146] When bond b is a triple bond, R 8 is not present; when bond b is a double bond, R 8 Selected from H, F, CN and C 1-3 alkyl; and

[0147] i) where the key a, X 1 、X2 、R 4 、R 5 、R 6 , A and Ar are as follows:

[0148] Bond a is a double bond or a triple bond;

[0149] X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3), and R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN, and NHR 7 , and R 7 selected from H and C1-C3 alkyl; or X 1 and R 4 Together with the carbon to which they are attached, they form a C4-C6 cycloalkylene group;

[0150] X 2 For X 2a And X 2a is C;

[0151] When bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 Selected from H, F and C1-C3 alkyl;

[0152] When bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 Selected from H, F and C1-C3 alkyl;

[0153] A is absent or selected from O, CH2, CH2CH2 and CH(CH3); and

[0154] Ar is aryl or heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R 9 group substitution; or

[0155] ii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0156] and

[0157] X 2 For X 2a And X 2a C; R 4 and R 6 Together they form -(CH2) m -; m is 1 or 2; X1 is absent or selected from CH2, CH2CH2 and CH(CH3); R 5 is selected from H, F and C1-C3 alkyl; A is absent or selected from O, CH2, CH2CH2 and CH(CH3); and Ar is aryl or heteroaryl, which is optionally replaced by 1, 2, 3 or 4 R 9 group substitution; or

[0158] iii) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0159] and

[0160] X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2b And X 2b N; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN, and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; R 5 Together with Ar and R 6 and A is absent; or

[0161] iv) wherein the bonds a and X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar together form:

[0162] and

[0163] X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2c And X 2c N or CR 6 , and R 6 is selected from H, F and C1-C3 alkyl; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN, and NHR 7 , and R 7is selected from H and C1-C3 alkyl; A is absent; and R 5 Together with Ar where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused arylene or fused heteroarylene ring, which is optionally substituted by 1, 2, 3 or 4 R 9 group substitution; and

[0164] Each R 9 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, and CN; and

[0165] Provided that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)vinyl]-1-piperidinyl]-2-propen-1-one.

[0166] Embodiment 2. In embodiment 2, a compound of any one of embodiments 1, 1A, A and B is provided, wherein bond b is a double bond and R 1a is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0167] Embodiment 3. In embodiment 3, a compound of any one of embodiments 1, 1A, A and B is provided, wherein bond b is a triple bond and R 1a and R 8 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0168] Embodiment 4. In embodiment 4, a compound of any one of embodiments A and 1-3 is provided, wherein R 1 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0169] Embodiment 5. In embodiment 5, a compound of any one of embodiments A and 1-3 is provided, wherein R 1 is Me; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0170] Embodiment 6. In embodiment 6, a compound of any one of embodiments 1-3 is provided, wherein R 1 is -CH2N(Me)2; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0171] Embodiment 7a. In embodiment 7a, a compound of any one of embodiments A and 1-3 is provided, wherein R 1 Selected from H and C 1-3or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof.

[0172] Embodiment 7. In embodiment 7, provided is a compound of any one of embodiments A, 1-3, and 7a, wherein R 1 is selected from H and Me; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0173] Embodiment 8. In embodiment 8, a compound of any one of embodiments A, B, and 1-7 is provided, wherein R 2 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0174] Embodiment 9. In embodiment 9, a compound of any one of embodiments 1-7 is provided, wherein R 2 is F; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0175] Embodiment 10. In embodiment 10, a compound of any one of embodiments 1-7 is provided, wherein R 2 is -OH; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0176] Embodiment 11. In embodiment 11, a compound of any one of embodiments 1-7 is provided, wherein R 2 C 1-3 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates. In embodiment 11, there is provided a compound of any one of embodiments A, B and 1-7, wherein R 2 C 1-2 or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof.

[0177] Embodiment 12. In embodiment 12, a compound of any one of embodiments A, B, and 1-7 is provided, wherein R 2 is H, methyl or ethyl; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0178] Embodiment 13a. In embodiment 13a, a compound of any one of embodiments 1-7 is provided, wherein R 2 For-OC 1-3 or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof.

[0179] Embodiment 13. In embodiment 13, a compound of any one of embodiments A, B, and 1-7 is provided, wherein R 2is -OMe; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0180] Embodiment 14. In embodiment 14, a compound of any one of embodiments 1-7 is provided, wherein R 2 is -NH-heteroaryl or -NH-(substituted heteroaryl); or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0181] Embodiment 15. In embodiment 15, a compound of any one of embodiments 1-7 is provided, wherein R 2 is an unsubstituted heteroaryl (in some embodiments, pyrazolyl) or a substituted heteroaryl (in some embodiments, pyrazolyl); or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof. In embodiment 15, a compound of any one of embodiments A, B, and 1-7 is provided, wherein R 2 is an unsubstituted 5-membered heteroaryl group (in some embodiments, pyrazolyl); or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0182] Embodiment 16. In embodiment 16, there is provided a compound of any one of embodiments A and 1-7, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, wherein R 2 is H, methyl, ethyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), or unsubstituted heteroaryl (in some embodiments, pyrazolyl).

[0183] Embodiment 17. In embodiment 17, a compound of any one of embodiments A, B, and 1-7 is provided, wherein R 2 is H, methyl, ethyl or unsubstituted pyrazolyl; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0184] Embodiment 18. In embodiment 18, a compound of any one of embodiments A, B, and 1-17 is provided, wherein R 3 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0185] Embodiment 19. In embodiment 19, a compound of any one of embodiments 1-17 is provided, wherein R 3 is F; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0186] Embodiment 20. In embodiment 20, a compound of any one of embodiments 1-17 is provided, wherein R 3is methyl or ethyl; or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates. In embodiment 20, there is provided a compound of any one of embodiments A, B, 1 and 2-17, wherein R 3 is methyl; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0187] Embodiment 21. In embodiment 21, provided are compounds of embodiments A, B, and any one of 1, 2, and 4-20, wherein bond b is a double bond and R 8 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0188] Embodiment 22. In embodiment 22, compounds of any one of embodiments A, B, and 1, 2, and 4-20 are provided, wherein bond b is a double bond and R 8 is F; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0189] Embodiment 23. In embodiment 23, provided is a compound of any one of embodiments 1, 2, and 4-20, wherein bond b is a double bond and R 8 is CN; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0190] Embodiment 24. In embodiment 24, a compound of any one of embodiments 1, 2, and 4-20 is provided, wherein bond b is a double bond and R 8 is Me; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0191] Embodiment 25. In embodiment 25, compounds of any one of embodiments A, B, and 1-24 are provided, wherein bonds a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar according to i); and / or stereoisomers and / or pharmaceutically acceptable salts and / or solvates thereof.

[0192] Embodiment 26a. In embodiment 26a, there is provided a compound of embodiment 25 (which belongs to embodiments A, 1 and 2-24), or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, wherein X 1 is absent, CH2, CH(OH) or C(CH3)2.

[0193] Embodiment 26. In embodiment 26, compounds of embodiment 25 are provided, wherein X 1or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0194] Embodiment 27. In embodiment 27, a compound of embodiment 25 is provided, wherein X 1 is CH2; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0195] Embodiment 28. In embodiment 28, a compound of any one of embodiments A, B, 1 and IA is provided, which is according to the following formula:

[0196]

[0197] or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0198] Embodiment 29. In embodiment 29, a compound of any one of embodiments 25-28 is provided, wherein R 4 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0199] Embodiment 30. In embodiment 30, a compound of any one of embodiments 25-28 is provided, wherein R 4 is C1-C4 alkyl (methyl); or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0200] Embodiment 31. In embodiment 31, a compound of any one of embodiments 25-28 is provided, wherein R 4 is cyclopropyl; or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0201] Embodiment 32. In embodiment 32, a compound of any one of embodiments 25-28 is provided, wherein R 4 is F; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0202] Embodiment 33. In embodiment 33, a compound of any one of embodiments 25-28 is provided, wherein R 4 is Cl; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0203] Embodiment 34. In embodiment 34, a compound of any one of embodiments 25-28 is provided, wherein R 4 is -OH; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0204] Embodiment 35. In embodiment 35, a compound of any one of embodiments 25-28 is provided, wherein R 4 is -OMe; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0205] Embodiment 36. In embodiment 36, a compound of any one of embodiments 25-28 is provided, wherein R 4 is CN; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0206] Embodiment 37. In embodiment 37, a compound of any one of embodiments 25-28 is provided, wherein R 4 NHR 7 , and R 7 is selected from H and C1-C3 alkyl; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0207] Embodiment 38. In embodiment 38, compounds of embodiment 25 are provided, wherein X 1 and R 4 Together with the carbon to which they are attached, they form a C4-C6 cycloalkylene group; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0208] Embodiment 39. In embodiment 39, a compound of embodiment 25 or 38 is provided, wherein X 1 and R 4 Together with the carbon to which they are attached, they form a C4 cycloalkylene or a C6 cycloalkylene; or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0209] Embodiment 40. In embodiment 40, provided is a compound of any one of embodiments 25-39, wherein bond a is a double bond; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0210] Embodiment 41. In embodiment 41, a compound of any one of embodiments 25-40 is provided, wherein bond a is a double bond and R 5 and R 6 Each is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0211] Embodiment 42. In embodiment 42, a compound of any one of embodiments 25-41 is provided, wherein bond a is a double bond and is cis; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0212] Embodiment 43. In embodiment 43, a compound of any one of embodiments 25-41 is provided, wherein bond a is a double bond and is trans; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0213] Embodiment 44. In embodiment 44, a compound of any one of embodiments 25-39 is provided, wherein bond a is a triple bond and R 5 and R 6 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0214] Embodiment 45. In embodiment 45, a compound of any one of embodiments A, B, and 1-24 is provided, wherein bond a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar according to ii).

[0215] Embodiment 46. In embodiment 46, a compound of embodiment 45 is provided, wherein m is 1; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0216] Embodiment 47. In embodiment 47, a compound of embodiment 45 is provided, wherein m is 2; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0217] Embodiment 48. In embodiment 48, a compound of any one of embodiments 45-47 is provided, wherein X 1 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0218] Embodiment 48a. In embodiment 48a, a compound of embodiment 45 (which belongs to any one of embodiments A, 1 and 2-24), or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, wherein m is 0 and X 1 Not for non-existence.

[0219] Embodiment 48b. In embodiment 48b, a compound of any one of embodiments 45-47 is provided (each of which is subject to any one of embodiments A, 1, and 2-24), wherein X 1 is absent or selected from CH2, O, CH2O and OCH2.

[0220] Embodiment 48c. In embodiment 48c, a compound of any one of embodiments 45-47 is provided, wherein X 1is CH2, CH2CH2 or CH(CH3), preferably CH2; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof. In a sub-embodiment of embodiment 48c, there is provided a 1 A compound containing CH2.

[0221] Embodiment 49. In embodiment 49, a compound of any one of embodiments 45-48c is provided, wherein R 5 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0222] Embodiment 50. In embodiment 50, provided is a compound of any one of embodiments 25-49, wherein A is absent; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0223] Embodiment 51a. In embodiment 51a, a compound of any one of embodiments 25-44 (each of which is subordinate to any one of embodiments A, 1 and 2-24), or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, is provided, wherein A is selected from CH2, CH(OH), CH(OCH3)2 and C(CH3)2.

[0224] Embodiment 51. In embodiment 51, a compound of any one of embodiments 25-50 is provided, wherein Ar is aryl, which is optionally substituted by 1, 2, 3 or 4 R 9 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0225] Embodiment 52a. In embodiment 52a, a compound of any one of embodiments 20-46, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, is provided, wherein Ar is phenyl, which is optionally substituted by 1, 2, 3 or 4 R 9 Group substituted (in some embodiments, the phenyl group is optionally substituted with 1 R 9 replace).

[0226] Embodiment 52. In embodiment 52, a compound of any one of embodiments 25-51 is provided, wherein Ar is phenyl, which is optionally replaced by 1, 2, 3 or 4 R 9 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0227] Embodiment 53a. In embodiment 53a, a compound of any one of embodiments 20-46, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof, is provided, wherein Ar is heteroaryl, (preferably oxazolyl, imidazolyl or pyridinyl), which is optionally replaced by 1, 2, 3 or 4 R 9 Group substituted (in some embodiments, the heteroaryl is optionally substituted with 1 R 9 replace).

[0228] Embodiment 53. In embodiment 53, a compound of any one of embodiments 25-50 is provided, wherein Ar is heteroaryl, preferably oxazolyl, imidazolyl or pyridinyl, which is optionally substituted by 1, 2, 3 or 4 R 9 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0229] Embodiment 54. In embodiment 54, a compound of any one of embodiments 1-24 is provided, wherein bond a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar according to iii).

[0230] Embodiment 55. In embodiment 55, a compound of embodiment 54 is provided, wherein X 1 does not exist, and R 4 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0231] Embodiment 56. In embodiment 56, a compound of any one of embodiments 1-24 is provided, wherein bond a, X 1 、X 2 、R 4 、R 5 、R 6 , A and Ar according to iv).

[0232] Embodiment 57. In embodiment 57, a compound of embodiment 56 is provided, wherein X 2 is CH; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0233] Embodiment 58. In embodiment 58, a compound of embodiment 56 is provided, wherein X 2 is N; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0234] Embodiment 59. In embodiment 59, a compound of any one of embodiments 56-58 is provided, wherein X1 does not exist and R 4 is H; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0235] Embodiment 60. In embodiment 60, a compound of any one of embodiments 56-59 is provided, wherein X 3 is O, NH, N(Me); or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0236] Embodiment 61. In embodiment 61, a compound of any one of embodiments 56-60 is provided, wherein Ar 1 is benzo or pyrido, which is optionally replaced by 1, 2, 3 or 4 R 9 or its stereoisomers and / or pharmaceutically acceptable salts and / or solvates.

[0237] Embodiment 62. In embodiment 62, a compound of any one of embodiments 1-61 is provided, wherein each R 9 independently selected from C1-C6 alkyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl and C1-C6 alkoxy; or each R 9 independently selected from methyl, ethynyl, F, CF3 and methoxy; or stereoisomers and / or pharmaceutically acceptable salts and / or solvates thereof.

[0238] Embodiment 63. In embodiment 63, a compound of any one of embodiments 1-62 is provided, wherein there are 1 or 2 R 9 and which are independently selected; or stereoisomers and / or pharmaceutically acceptable salts and / or solvates thereof.

[0239] Embodiment 64. In embodiment 64, a compound of any one of embodiments 1-63 is provided, wherein one R 9 is CF3; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0240] Embodiment 65a. In embodiment 65a, a compound of any one of embodiments 1-64 is provided, wherein for or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0241] Embodiment 65. In embodiment 65, a compound of any one of embodiments 1-64 is provided, wherein for or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0242] Embodiment 66. In embodiment 66, a compound of any one of embodiments 1-65 is provided, wherein for or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0243] Embodiment 67. In embodiment 67, a compound of any one of embodiments 1-65 is provided, wherein for or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0244] Embodiment 68. In embodiment 68, a compound of any one of embodiments 1-65 is provided, wherein for or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0245] Embodiment 69. In embodiment 69, a compound of embodiment 1 is provided, which is selected from the compounds in Table 1; or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof.

[0246] Embodiment 70. In embodiment 70, there is provided a compound of embodiment 1 selected from the group consisting of:

[0247] or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0248] Embodiment 71. In embodiment 71, a pharmaceutical composition is provided, comprising a pharmaceutically effective amount of a compound according to any one of embodiments 1-106 or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof; and a pharmaceutically acceptable carrier.

[0249] Embodiment 72. In embodiment 72, a method of treating cancer in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-106, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof; or a pharmaceutical composition of embodiment 71.

[0250] Embodiment 73. In embodiment 73, the method of embodiment 72 is provided, wherein the cancer is selected from 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, digestive tract / gastrointestinal cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye or eye cancer, rectal cancer, colorectal cancer, cervical cancer, oral cancer, benign and malignant tumors, stomach cancer, uterine corpus, testicular cancer, renal cancer, throat cancer, cancer), acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal and squamous cell carcinomas, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, mouth / throat cancer, esophageal cancer, larynx cancer, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

[0251] Embodiment 74. In embodiment 74, the method of embodiment 72 is provided, wherein the cancer is selected from glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).

[0252] Embodiment 75. In embodiment 75, a method of any one of embodiments 72-74 is provided, wherein the method further comprises 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.

[0253] Embodiment 75. In embodiment 75, a method of any one of embodiments 72-74 is provided, wherein the method further comprises administering one or more additional anti-cancer therapies simultaneously or sequentially, preferably wherein the one or more additional therapies comprise a KRAS G12C and / or G12D inhibitor, more preferably wherein the KRAS G12C and / or G12D inhibitor is sotorasib or adagrasib.

[0254] Embodiment 76. In embodiment 76, a method of inhibiting TEAD1, 2, 3 and / or 4 in a subject or sample is provided, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-106, or a stereoisomer and / or pharmaceutically acceptable salt and / or solvate thereof; or a pharmaceutical composition of embodiment 71.

[0255] Embodiment 77. In embodiment 77, the method of embodiment 76 is provided, wherein TEAD1 is selectively inhibited relative to TEAD2, 3, and 4.

[0256] Table 1 shows the structures of the compounds described in the Examples of the present disclosure.

[0257] Table 1. TEAD inhibitor compounds

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] In some or any embodiments, provided herein are:

[0267] (a) a compound as described herein, such as any one of Formula (I), (II), any embodiment of the compound herein, and Compounds 1-106, and pharmaceutically acceptable salts and compositions thereof;

[0268] (b) compounds as described herein, e.g., any of Formula (I), (II), any embodiment of the compounds 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;

[0269] (c) methods for preparing a compound as described herein, e.g., a compound of Formula (I), (II), any embodiment herein, and any of Compounds 1-106, as described in more detail elsewhere herein;

[0270] (d) a pharmaceutical formulation comprising a compound as described herein, e.g., any one of Formula (I), (II), any embodiment herein, and Compounds 1-106, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

[0271] (e) a method of 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 as described herein, e.g., any one of Formula (I), (II), any embodiment of the present invention, and Compounds 1-106, or a pharmaceutically acceptable salt or composition thereof;

[0272] (f) a method of treating cancer in a subject comprising administering a therapeutically or prophylactically effective amount of a compound as described herein, e.g., any one of Formula (I), (II), any embodiment of the present invention, and Compounds 1-106, or a pharmaceutically acceptable salt or composition thereof;

[0273] (g) a pharmaceutical formulation comprising a compound as described herein, e.g., any of Formula (I), (II), any embodiment herein, and Compounds 1-106, or a pharmaceutically acceptable salt thereof, and one or more other effective agents for treating cancers and / or conditions modulated by TEAD1, 2, 3, and / or 4, optionally in a pharmaceutically acceptable carrier or diluent;

[0274] (h) a method of treating cancer in a subject comprising administering a therapeutically or prophylactically effective amount of a compound as described herein, e.g., any of Formula (I), (II), any embodiment of the compound herein, and Compounds 1-106, a pharmaceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for treating cancers and / or conditions modulated by TEAD1, 2, 3, and / or 4; and

[0275] (i) A method for treating a condition related to TEAD1, 2, 3 and / or 4 function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound as described herein, e.g., any one of Formula (I), (II), any embodiment of the present invention, and Compounds 1-106, a pharmaceutically acceptable salt or composition thereof, in combination and / or alternating administration with one or more agents for treating cancer.

[0276] (j) Use of any compound described herein, e.g., any of Formula (I), (II), any embodiment of the compound herein, and Compounds 1-106, or a composition comprising any compound described herein, e.g., any of Formula (I), (II), any embodiment of the compound herein, and Compounds 1-106, for treating a condition described herein associated with TEAD1, 2, 3, and / or 4 function (e.g., cancer), optionally in combination and / or alternation with one or more agents for treating cancer.

[0277] Isomers and optically active compounds

[0278] It should be understood that the compounds provided herein have multiple chiral centers and can exist and be separated in optically active and racemic forms. It should be understood that any racemic, optically active, diastereoisomers, geometric isomers, tautomers or other stereoisomeric forms, mixtures or combinations thereof of the compounds provided herein with the useful properties described herein are within the scope of the present invention. It is well known in the art how to prepare optically active forms (in some or any embodiments, the racemic form is resolved by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by separation using chiral stationary phase chromatography).

[0279] In some or any embodiments, methods of obtaining optically active materials (in some embodiments, compounds that are substantially pure or "substantially free" of unspecified isomers or "substantially absent" of unspecified isomers) are known in the art and include at least the following.

[0280] i) Physical separation of crystals - a technique whereby macroscopic crystals of individual stereoisomers are manually separated. This technique can be used if crystals of the separated stereoisomers exist, i.e. the material is agglomerated and the crystals are visually distinct;

[0281] ii) simultaneous crystallization - a technique whereby the individual stereoisomers are crystallized separately from a solution of the racemate, which is possible only if the latter is agglomerated in the solid state;

[0282] iii) Enzymatic resolution - a technique whereby the different reaction rates of stereoisomers with enzymes are exploited to partially or completely separate racemates;

[0283] iv) Enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis utilizes an enzymatic reaction to obtain a stereomerically pure or enriched synthetic precursor of the desired stereoisomer;

[0284] v) Chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved by using chiral catalysts or chiral auxiliaries;

[0285] vi) Diastereomeric separation - a technique in which a racemic compound is converted into its individual diastereomers by reacting it with an enantiomerically pure reagent (chiral auxiliary). The resulting diastereomers are then separated by chromatography or crystallization, taking advantage of their now more pronounced structural differences, after which the chiral auxiliary is removed to yield the desired enantiomer;

[0286] vii) Primary and secondary asymmetric transformations - techniques whereby the diastereomers from the racemate are brought into equilibrium to produce a predominance of the diastereomer from the desired enantiomer in solution or whereby preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium so that ultimately, in principle, all of the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then liberated from the diastereomers;

[0287] viii) Kinetic resolution - This technique is the use of unequal reaction rates of stereoisomers with chiral, non-racemic reagents or catalysts under kinetic conditions to achieve partial or complete resolution of racemates (or further resolution of partially resolved compounds);

[0288] ix) Stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from achiral starting materials and where the stereochemical integrity is not compromised or is only minimally compromised during the synthetic process;

[0289] x) Chiral liquid chromatography - a technique for separating the stereoisomers of a racemate in a liquid mobile phase by exploiting the different interactions of the stereoisomers of the racemate with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral materials to stimulate different interactions;

[0290] xi) Chiral gas chromatography - a technique whereby the racemate is volatilized and the stereoisomers are separated by exploiting their different interactions in the gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[0291] xii) Chiral solvent extraction - a technique whereby stereoisomers are separated by taking advantage of the preferential solubility of one stereoisomer in a specific chiral solvent;

[0292] xiii) Transport across chiral membranes – A technique whereby a racemate is placed in contact with a thin membrane barrier. This barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemate to pass through.

[0293] In some or any embodiments, a composition of a compound is provided, comprising a substantially pure specified stereoisomer (e.g., enantiomer, diastereomer) or geometric isomer of the compound. In some or any embodiments, in the methods and compounds disclosed herein, the compound is substantially free of its other stereoisomers (e.g., enantiomer, diastereomer) and / or geometric isomers. In some or any embodiments, the composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight of a particular compound, the remainder comprising its other chemical species, geometric isomers and / or stereoisomers (e.g., enantiomer, diastereomer).

[0294] Isotopically enriched compounds

[0295] Also provided herein are isotopically enriched compounds.

[0296] As used herein, the term "isotopic composition" refers to the amount of each isotope present in a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom, unless otherwise specified. Atoms having their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds described herein are intended to represent any stable isotope of that atom. For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural isotopic composition.

[0297] The term "isotopic enrichment" as used herein, and unless otherwise specified, refers to the amount of a particular isotope at a given atom in a molecule as a percentage of the natural isotopic abundance of that atom. In some or any embodiments, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0298] As used herein, the term "isotopically enriched" and unless otherwise specified, refers to atoms having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0299] Isotopic enrichment of drugs (in some or any embodiments, deuteration) has previously been demonstrated in several classes of drugs to improve pharmacokinetic ("PK"), pharmacodynamic ("PD"), and toxicity profiles. See, e.g., 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).

[0300] In some or any embodiments, isotopic enrichment of a drug can be used to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve a desired effect, (4) reduce the dose necessary to achieve a desired effect, (5) increase the formation of active metabolites (if formed), and / or (6) inhibit the production of harmful metabolites in specific tissues and / or create more effective drugs and / or safer drugs for use in combination therapy, whether or not the combination therapy is intended.

[0301] Replacing an atom with one of its isotopes typically results in a change in the reaction rate of a chemical reaction. This phenomenon is called the kinetic isotope effect ("KIE"). For example, if a C–H bond breaks during the rate-determining step (i.e., the step with the highest transition state energy) of a chemical reaction, replacing the hydrogen with deuterium results in a reduced reaction rate, and the process slows down. This phenomenon is called the 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).

[0302] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C–H bond is broken and the same reaction in which deuterium replaces hydrogen. The DKIE can range from approximately 1 (without isotope effects) to very large numbers, such as 50 or greater, meaning that the reaction can be 50 times slower or more when deuterium replaces hydrogen. High DKIE values ​​may be due in part to a phenomenon called tunneling, a consequence of the uncertainty principle. Tunneling is attributed to the small mass of the hydrogen atom and occurs because transition states involving protons can sometimes form without the required activation energy. Because deuterium has a greater mass than hydrogen, it statistically has a much lower probability of this phenomenon occurring.

[0303] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with 2 neutrons in its nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a low-energy beta particle that is unable to penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but large quantities must be ingested to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before dangerous levels are reached. Substituting tritium ("T") for hydrogen results in a stronger bond than deuterium and produces a numerically larger isotope effect. Similarly, substituting isotopes for other elements, including but not limited to, with 13 C or 14 C replaces carbon, 33 S. 34 S or 36 S replaces sulfur, 15 N replaces nitrogen and 17 O or 18 O replacing oxygen may also lead to similar kinetic isotope effects.

[0304] For example, DKIE has been used to reduce the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching posits that when xenobiotics are sequestered by phase I enzymes, they may transiently bind and rebind in various conformations before undergoing a 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 promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in varying proportions of known metabolites as well as novel metabolites. This novel metabolic profile may confer greater or lesser toxicity.

[0305] In some embodiments, the compounds described herein can be used as radiopharmaceuticals, such as, for example, imaging agents. In one instance, the radiopharmaceutical is a positron emission tomography (PET) imaging agent. In such embodiments, substitution of atoms in the compound with a radionuclide (e.g., a positron emitting isotope) allows for the synthesis of radiopharmaceuticals that can be used as imaging agents. In some embodiments, the radionuclides that can be substituted in the compounds described herein include, but are not limited to, 18 F. 11 C. 13 N. 15 O. 76 Br and 124 1. 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.

[0306] Animals express various enzymes that are used to clear foreign substances, such as therapeutic agents, from their circulatory systems. In some or any embodiments, such enzymes include cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of drug compounds involve the oxidation of carbon-hydrogen (C–H) bonds to carbon-oxygen (C–O) or carbon-carbon (C–C) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have pharmacokinetic, pharmacodynamic, and acute and long-term toxicity characteristics that are significantly different from those of the parent compound. For many drugs, such oxidations are rapid. Therefore, these drugs often require administration of multiple or higher daily doses.

[0307] Thus, isotopic enrichment of the compounds provided herein at certain positions, compared to similar compounds having natural isotopic compositions, can result in detectable KIEs that can affect the pharmacokinetic, pharmacological, and / or toxicological profiles of the compounds provided herein.

[0308] General solution

[0309] Scheme 1. Synthesis of Formula (I)

[0310]

[0311] Scheme 1 illustrates the synthesis of formula (I) compound according to some aspects and embodiments of the present disclosure. Although only E (trans) isomer is shown in scheme 1 for simplicity, cis and / or trans isomer may produce and can be separated by common chromatographic method. In some aspects, a mixture of stereoisomers (for example, enantiomers, diastereomers) and / or geometric isomers (for example, regioisomers, cis and trans isomers, Z and E isomers) can be produced, and (chirality) chromatographic separation single stereoisomers (for example, enantiomers, diastereomers) and / or geometric isomers (for example, regioisomers, cis and trans isomers, Z and E isomers) can be used to obtain its single stereoisomers (for example, enantiomers, diastereomers) and / or geometric isomers (for example, regioisomers, cis and trans isomers, Z and E isomers). Compounds of formula (I) can be prepared by other routes, several of which are described in the experimental section.

[0312] Scheme 2. General synthesis of some compounds of formula (I)

[0313]

[0314] Scheme 2 illustrates the synthesis of compounds of formula (I) according to some aspects and embodiments of the present disclosure. In some aspects, mixtures of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be produced, and individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain their single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers).

[0315] Scheme 3. General synthesis of some compounds of formula (I)

[0316]

[0317] Scheme 3 illustrates the synthesis of compounds of formula (I) according to some aspects and embodiments of the present disclosure. The aldehyde functional group in can be alternatively a cyclic ketone or a lactone. Although only E isomers are shown in Scheme 3 for simplicity, a specific Z or E olefin isomer can be obtained for the double bond to which Ar is connected. In some aspects, a mixture of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be produced, and (chiral) chromatography can be used to separate single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) to obtain their single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers).

[0318] Scheme 4. General synthesis of some compounds of formula (I)

[0319]

[0320] 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, a specific Z or E alkene isomer can be obtained (only the E isomer is shown in Scheme 4 for simplicity). In certain aspects, a mixture of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be produced, and the individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain their single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers).

[0321] Scheme 5. General synthesis of some compounds of formula (I)

[0322]

[0323] 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, a specific Z or E olefin isomer can be obtained (only the E isomer is shown in Scheme 5 for simplicity). In some aspects, a mixture of stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be produced, and individual stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers) can be separated using (chiral) chromatography to obtain their single stereoisomers (e.g., enantiomers, diastereomers) and / or geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers).

[0324] Pharmaceutical formulations and methods of treatment and administration

[0325] The term "treatment" is used interchangeably herein with the term "treatment method" and refers to both 1) therapeutic treatment or measures that cure, alleviate, lessen the symptoms of, and / or prevent the progression of a diagnosed pathological condition, disease, or disorder, and 2) prophylactic / preventative measures. Individuals in need of treatment may include those already suffering from a particular medical disease or disorder as well as those who may eventually develop the disorder (i.e., those in need of preventative measures).

[0326] In some or any embodiments, "treating" or "treatment" of any condition or disorder refers to improving a condition or disorder present in a subject, including prophylactic improvement. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may be imperceptible to the subject. In yet another embodiment, "treating" or "treatment" includes modulating a condition or disorder physically (e.g., stabilization of perceptible symptoms) or physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of a condition or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating a condition (e.g., cancer) or one or more parameters of a condition (e.g., cancer) (e.g., tumor size or tumor growth rate), or delaying the progression of a condition (e.g., cancer) or one or more parameters of a condition (e.g., cancer) (e.g., tumor size or tumor growth rate), or reducing the severity of a condition (e.g., cancer) or one or more parameters of a condition (e.g., cancer) (e.g., tumor size or tumor growth rate). In yet another embodiment, "treating" or "treatment" includes prophylactic administration of a compound as described herein. In some embodiments, "treating" or "treatment" of a disease includes: (1) inhibiting the disease, i.e., arresting (i.e., stabilizing) or reducing the development of the disease or its clinical symptoms; or (2) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0327] The term "subject" as used herein refers to any individual or patient on whom the subject methods are performed. Generally, the subject is a human, although as will be appreciated by those skilled in the art, the subject may be an animal.

[0328] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to an amount of the subject compound or composition that will elicit the biological or medical response being sought in a tissue, system, animal, individual, or human upon administration of the compound. A biological or medical response includes one or more of the following: (1) preventing a disease; e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or display the pathology or symptoms of the disease, (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptoms) in an individual who is experiencing or displaying 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 displaying the pathology or symptoms of the disease, condition, or disorder. In general, a response is an improvement in a patient's symptoms or a desired biological outcome.

[0329] Also disclosed herein are pharmaceutical compositions comprising compounds disclosed herein (including compounds according to formula (I), (II), any embodiment of the present invention, and any of compounds 1-106). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with the compounds of the present invention and that does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that can be used for these compositions include, but are not limited to, ion exchangers, aluminum oxide, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0330] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, and self-emulsifying drug delivery systems (SEDDS) such as α-tocopherol, polyethylene glycol 1000 succinate or other similar polymer delivery matrices.

[0331] In pharmaceutical compositions comprising only compounds as described herein (including compounds according to formula (I), (II), any embodiment of the present invention, and any one of compounds 1-106) as active ingredients, the method of administering these compositions may additionally comprise the step of administering an additional agent or therapy to the subject. Such therapies include, but are not limited to, anemia therapies, diabetes therapies, hypertension therapies, cholesterol therapies, 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 tumor diseases. In another embodiment, the therapy is anemia therapies, diabetes therapies, hypertension therapies, cholesterol therapies, 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 tumor diseases. Other pharmacological therapies may include any other drug or biologic in any drug class. For example, other drug classes can include allergy / cold / otolaryngology therapy, analgesics, anesthetics, anti-inflammatory drugs, antibacterial drugs, antivirals, asthma / pulmonary therapy, cardiovascular therapy, dermatology therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy or rheumatology therapy. In another embodiment, the therapy is selected from anti-inflammatory drugs, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy and rheumatology therapy. 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-angiogenic compounds.

[0332] In another embodiment, the compounds disclosed herein (including compounds according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) are used together with another anticancer agent, for example, one or more selected from EGFR inhibitors, MEK inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, immune checkpoint inhibitors, and chemotherapeutic agents for tumor diseases.

[0333] The compounds of the present disclosure (including compounds according to formula (I), (II), any embodiment herein, and any of compounds 1-106) can be used in a conventional manner to control the diseases described herein, including but not limited to cancer. One of ordinary skill in the art can select such treatment methods, their dosage levels, and requirements from available methods and techniques. For example, the compounds of the present disclosure can be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from cancer in a pharmaceutically acceptable manner and in an amount effective to treat the cancer.

[0334] Alternatively, the compounds of the present disclosure (including compounds according to formula (I), (II), any embodiment herein, and any of compounds 1-106) can be used in compositions and methods for treating or protecting individuals against diseases described herein, including but not limited to cancer, over a long period of time. The compounds can 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, the compounds of the present disclosure can be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines and administered in a prophylactically effective amount to protect individuals against diseases described herein, including but not limited to cancer, over a long period of time.

[0335] As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compound (including any one of the compounds according to formula (I), (II), any embodiment herein, and compounds 1-106) can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Therefore, the present disclosure provides a single unit dosage form, which comprises the compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. When a patient or individual is exposed to two agents simultaneously, two or more agents are generally considered to be administered "in combination". In many embodiments, when a patient or individual simultaneously shows treatment-related levels of agents in a specific target tissue or sample (e.g., in the brain, in serum, etc.), two or more agents are considered to be administered "in combination".

[0336] When the compounds of the present disclosure (including compounds according to formula (I), (II), any embodiment herein, and any one of compounds 1-106) are administered in combination therapy with other agents, they can be administered to the patient sequentially or simultaneously. Alternatively, a pharmaceutical or preventive composition according to the present disclosure comprises a compound as described herein (including compounds according to formula (I), (II), any embodiment herein, and any one of compounds 1-106) in combination with another therapeutic or preventive agent. Additional therapeutic agents that are typically administered to treat a specific disease or condition may be referred to as "agents suitable for the disease or condition being treated."

[0337] The compounds used in the compositions and methods of the present disclosure can also be modified by adding suitable functionalities 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.

[0338] According to one embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, such as a mammal, preferably a human. Such pharmaceutical compositions are used to improve, treat or prevent any disease described herein, including but not limited to cancer in a subject.

[0339] The medicaments of the present disclosure are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and various other pharmaceutically acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mark Publishing Company, Easton, Pennsylvania, 1980). The preferred form depends on the intended mode of administration and therapeutic application. The composition may also include, depending on the desired formulation, a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a vehicle commonly used to formulate pharmaceutical compositions for administration to animals or humans. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0340] In some embodiments, the present disclosure provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more of the compounds (including any one of the compounds according to formula (I), (II), any embodiment herein, and compounds 1-106), formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents for the treatment of diseases as described herein, including but not limited to cancer. Although it is possible for the compound to be administered alone, it is preferred that the compound (including any one of the compounds according to formula (I), (II), any embodiment herein, and compounds 1-106) be administered as a pharmaceutical formulation (composition) as described herein. The compound (including any one of the compounds according to formula (I), (II), any embodiment herein, and compounds 1-106) can be formulated for administration in any convenient manner for human medicine or veterinary medicine, similar to other drugs.

[0341] As described in detail, the pharmaceutical compositions of the present disclosure can be specially formulated for administration in solid or liquid form, including those suitable for the following: oral administration, e.g., douches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., tablets for oral, sublingual and systemic absorption, pills, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous or epidural injection, e.g., as a sterile solution or suspension, or a sustained-release formulation; topical application, e.g., as a cream, ointment or controlled-release patch or spray applied to the skin, lungs or mouth; intravaginal or intrarectal, e.g., as a vaginal suppository, cream or foam; sublingual; ophthalmic; transdermal; or nasal, lung and to other mucosal surfaces.

[0342] Wetting agents, emulsifiers and lubricants, 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 compositions.

[0343] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0344] The preparation used according to the present disclosure includes preparations suitable for oral, nasal, local (including oral and sublingual), rectal, vaginal and / or parenteral administration. Preparations can be presented in unit dosage form conveniently and can be prepared by any method well-known in the pharmaceutical field. The amount of the active component that can be combined with a carrier material to produce a single dose form can depend on the host being treated and specific mode of administration and change. The amount of the active component that can be combined with a carrier material to produce a single dose form generally can be the amount of the compound producing the therapeutic effect. Generally speaking, the scope of this amount can be from about 1% to about 99% of the active component. In some embodiments, the scope of this amount can be from about 5% to about 70%, from about 10% to about 50%, or from about 20% to about 40%.

[0345] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle formers (e.g., bile acids), or polymeric carriers (e.g., polyesters and polyanhydrides); and a compound of the present disclosure (including compounds according to Formula (I), (II), any embodiments herein, and any one of compounds 1-106). In certain embodiments, the aforementioned formulations render the compounds of the present disclosure (including compounds according to Formula (I), (II), any embodiments herein, and any one of compounds 1-106) orally bioavailable.

[0346] The method for preparing a formulation or composition comprising the compound (including any one of the compounds according to formula (I), (II), any embodiment of the present invention, and compounds 1-106) includes the step of introducing the compound of the present invention (including any one of the compounds according to formula (I), (II), any embodiment of the present invention, and compounds 1-106) into contact with a carrier and optionally one or more auxiliary components. In general, the formulation can be prepared by uniformly and intimately introducing the compound of the present invention (including any one of the compounds according to formula (I), (II), any embodiment of the present invention, and compounds 1-106) into contact with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0347] Pharmaceutical compositions can be in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oily suspensions. Such suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils (e.g., olive oil or castor oil, especially their polyoxyethylated versions). These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants (e.g., those described in the Swiss Pharmacopoeia) or similar alcohols. Other commonly used surfactants (such as Tweens, Spans and other emulsifying agents or bioavailability enhancers) which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0348] In some cases, it may be desirable to slow the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effect. This can be accomplished by using a liquid suspension of crystalline or amorphous material that is poorly water soluble. The rate of absorption of the drug then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0349] Injectable depot forms are prepared by forming a microencapsulation matrix of the compound (including any one of the compounds according to Formula (I), (II), any embodiment herein, and compounds 1-106) in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid). Depending on the ratio of drug to polymer and the properties of the specific 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 encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0350] The pharmaceutical composition of the present disclosure can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets and aqueous suspensions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions and solutions and propylene glycol are orally administered, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents can be added.

[0351] Formulations suitable for oral administration as described herein can be in the form of capsules, cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and gum arabic 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 lozenge (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present disclosure (including compounds according to formula (I), (II), any embodiment herein, and any one of compounds 1-106) as the active ingredient. The compounds described herein (including compounds according to formula (I), (II), any embodiment herein, and any one of compounds 1-106) can also be administered as pills, electuaries, or pastes.

[0352] 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, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retardants, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols.

[0353] Tablets can be made by optionally using one or more auxiliary components to compress or mold. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be made in a suitable machine, wherein the mixture of powdered compounds is moistened with an inert liquid diluent. If a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or granular form, or in the form of a lozenge or lozenge. The amount of the solid carrier can vary, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation can be, for example, in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable liquid such as an ampoule or a non-aqueous liquid suspension. When the composition is in capsule form, any conventional packaging method is suitable, for example, using the above-mentioned carrier in a hard gelatin capsule shell.

[0354] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may alternatively or additionally be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be formulated for rapid release, for example, by freeze-drying. They may be sterilized by, for example, filtration through a bacteria-retaining filter or by introducing 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 may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0355] Liquid dosage forms for oral administration of the compounds of the present disclosure (including compounds according to formula (I), (II), any embodiment herein, and any of compounds 1-106) include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0356] 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.

[0357] The suspension, in addition to the active compound (including the compound according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106), may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxyhydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0358] Pharmaceutical compositions of the present disclosure can also be applied in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present disclosure (including any one of the compound according to formula (I), (II), any embodiment herein and compound 1-106) with a suitable non-irritating excipient, which 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. When the desired treatment relates to an area or organ that is easily accessible by topical application, the topical application of the pharmaceutical compositions of the present disclosure is especially useful. For local application to the skin, the pharmaceutical composition should be configured to a suitable ointment containing an active ingredient suspended or dissolved in a carrier. The carrier for topical application of a compound of the present disclosure (including any one of the compound according to formula (I), (II), any embodiment herein and compound 1-106) includes but is not limited to mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing an active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitol monostearate, polysorbate-60, cetyl esters wax, hexadecanol, 2-octyldodecanol, benzyl alcohol, and water. Pharmaceutical compositions of the present disclosure may also be topically applied to the lower intestinal tract via rectal suppository formulations or with suitable enema formulations. Topically applied transdermal patches are also included in the present disclosure.

[0359] The pharmaceutical compositions of the present disclosure can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0360] For ophthalmic use, the pharmaceutical composition can 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 benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0361] Transdermal patches have the additional advantage of providing controlled delivery of a compound of the present disclosure (including any one of the compound of any embodiment herein and compound 1-106) to the whole body. Dissolving or dispersing the compound in a suitable medium can make such dosage forms. Absorption enhancers can also be used to increase the flux of the compound through the skin. A rate-controlled membrane is provided or the compound is dispersed in a polymer matrix or a gel to control the speed of such flux.

[0362] Examples of suitable aqueous and non-aqueous carriers that can 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. Suitable fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the desired particle size in the case of dispersions, and by the use of surfactants.

[0363] Such compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Including one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc., may be desirable in certain embodiments. Including isotonic agents, such as sugars, sodium chloride, etc., into the composition may be alternatively or additionally desirable. In addition, extended absorption of the injectable drug form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0364] In certain embodiments, the compound (including any one of the compound according to formula (I), (II), any embodiment herein, and compounds 1-106) or pharmaceutical preparation is administered orally. In other embodiments, the compound (including any one of the compound according to formula (I), (II), any embodiment herein, and compounds 1-106) or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0365] When the compounds described herein (including compounds according to Formula (I), (II), any of the embodiments herein, and any of Compounds 1-106) are administered to humans and animals as pharmaceuticals, they can be administered per se or as pharmaceutical compositions containing, for example, 0.1% to 99.5% of the active ingredient in combination with a pharmaceutically acceptable carrier. In some embodiments, 0.5% to 90% of the active ingredient can be used.

[0366] The preparations described herein can be administered orally, nasally (e.g., by spray), parenterally, intravaginally, intracisternal, rectally, or topically (e.g., by powder, ointment, or drops), including buccal and sublingual administration. They are, of course, administered in a form suitable for the relevant route of administration. For example, they are administered in the form of tablets or capsules, injections, inhalants, eye drops, ointments, suppositories, etc., for example, by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. Preferably, they are administered orally.

[0367] Regardless of the route of administration chosen, the compounds described herein (including compounds according to Formula (I), (II), any embodiment herein, and any of Compounds 1-106) can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0368] 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 that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0369] The term "administration of" and / or "administering" should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount 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, intracortical, transdermal, tracheal, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual, buccal, rectal, vaginal, nasal, ophthalmic administration, as well as infusion, inhalation and aerosolization.

[0370] The term "cancer" refers to a group of diseases characterized by abnormal and uncontrolled cell proliferation that begins in one site (primary site) with the potential to invade and spread to other sites (secondary sites, metastases), which distinguishes cancer (malignant tumors) from benign tumors. Almost all organs can be affected, resulting in the emergence of more than 100 types of cancer that can affect humans. Cancer can be caused by a variety of factors, including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, smoking and / or alcohol consumption, obesity, poor diet, lack of physical activity, or any combination thereof.

[0371] Exemplary cancers described by the National Cancer Institute include: adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, adrenocortical carcinoma, childhood adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, childhood cerebellar astrocytoma, childhood brain astrocytoma, extrahepatic bile duct cancer, bladder cancer, childhood bladder cancer, bone cancer, osteosarcoma / malignant fibrous histiocytoma, childhood brain stem glioma, adult brain tumor, childhood brain stem glioma brain tumor, childhood cerebellar astrocytoma brain tumor, childhood brain Astrocytoma / Glioma Brain Tumor, Ependymoma Brain Tumor, Medulloblastoma Brain Tumor, Supratentorial Primitive Neuroectodermal Tumor Brain Tumor, Visual Pathway and Hypothalamic Glioma Brain Tumor, Childhood Brain Tumor (Other), Breast Cancer, Breast Cancer and Pregnancy, Childhood Breast Cancer, Male Breast Cancer, Childhood Bronchial Adenoma / Carcinoid, Childhood Carcinoid Tumor, Gastrointestinal Carcinoid Tumor, Adrenal Cortical Carcinoma, Islet Cell Carcinoma, Cancer of Unknown Primary, Primary Central Nervous System Lymphoma, Cerebellar Astrocytoma, Childhood Brain Astrocytoma / Glioma, Cervical Cancer, Childhood Childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disease, clear cell sarcoma of the tendon sheath, colon cancer, childhood colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, childhood ependymoma, epithelial ovarian cancer, esophageal cancer, childhood esophageal cancer, Ewing family of tumors, childhood extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, intraocular melanoma eye cancer, retinoblastoma eye cancer, gallbladder cancer, stomach (gastric) cancer, childhood stomach (gastric) cancer, gastrointestinal carcinoid tumors, childhood extracranial germ cell tumors, extragonadal germ cell tumors ovarian germ cell tumor, gestational trophoblastic tumor, childhood brainstem glioma, childhood visual pathway and hypothalamic glioma, hairy cell leukemia, head and neck cancer, adult (primary) hepatocellular (liver) cancer, childhood (primary) hepatocellular (liver) cancer, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, hypopharyngeal cancer, childhood hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma (endocrine pancreas), Kaposi sarcoma, kidney cancer, laryngeal cancer cancer), childhood laryngeal cancer, adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, adult (primary) liver cancer, childhood (primary) liver cancer, non-small cell lung cancer, small cell lung cancer, adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, chronic lymphocytic leukemia, AIDS-related lymphoma, central nervous system (primary) lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, adult non-Hodgkin lymphoma,Non-Hodgkin's lymphoma in children, Non-Hodgkin's lymphoma during pregnancy, Primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, Male breast cancer, Malignant mesothelioma in adults, Malignant mesothelioma in children, Malignant thymoma, Medulloblastoma in children, Melanoma, Intraocular melanoma, Merkel cell carcinoma, Malignant mesothelioma, Metastatic squamous neck cancer with occult primary, Multiple endocrine neoplasia syndrome in children, Multiple myeloma / plasma cell neoplasms, Mycosis fungoides, Myelodysplastic syndrome, Chronic myeloid leukemia, Acute myeloid leukemia in children, Multiple myeloma, Chronic myeloproliferative disorders, Nasal and paranasal sinus cancer, Nasopharyngeal cancer, pediatric nasopharyngeal cancer, neuroblastoma, adult non-Hodgkin's lymphoma, pediatric non-Hodgkin's lymphoma, non-Hodgkin's lymphoma during pregnancy, non-small cell lung cancer, childhood oral cancer, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, childhood ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, childhood pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, childhood pineal and supratentorial primitive neuroectodermal tumors, 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 in adults, Primary liver cancer in children, Prostate cancer, Rectal cancer, Renal cell (kidney) cancer, Renal cell cancer in children, Transitional cell carcinoma of the renal pelvis and ureter, Retinoblastoma, Rhabdomyosarcoma in children, Salivary gland cancer, Salivary gland cancer in children, Ewing's family of tumors, Kaposi's sarcoma, Malignant fibrous histiocytoma of bone, Osteosarcoma sarcoma, Rhabdomyosarcoma sarcoma in children, Soft tissue sarcoma in adults, Soft tissue sarcoma in children, Sézary syndrome, Skin cancer, Skin cancer in children, Skin cancer (melanoma), Merkel cell skin cancer, Small cell lung cancer, small bowel cancer, adult soft tissue sarcoma, childhood soft tissue sarcoma, metastatic squamous neck cancer with occult primary, stomach (gastric) cancer, childhood stomach (gastric) cancer, childhood supratentorial primitive neuroectodermal tumor, cutaneous T-cell lymphoma, testicular cancer, childhood thymoma, malignant thymoma, thyroid cancer, childhood thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, gestational trophoblastic tumor, childhood cancer of unknown primary site, rare childhood cancers, transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine sarcoma, vaginal cancer, childhood visual pathway and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0372] In certain aspects, the cancer includes lung cancer, breast cancer, colorectal cancer, prostate cancer, stomach cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, non-Hodgkin lymphoma, leukemia, pancreatic cancer, kidney cancer, endometrial cancer, head and neck cancer, lip cancer, oral cancer, thyroid cancer, brain cancer, ovarian cancer, melanoma, gallbladder cancer, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, Hodgkin lymphoma, testicular cancer, and Kaposi's sarcoma.

[0373] The compounds of the present disclosure (including any one of the compounds according to formula (I), (II), any embodiment herein and compounds 1-106) can be administered in combination with one or more additional therapeutic agents. The phrases "combination therapy", "combined with..." and the like refer to the simultaneous use of more than one drug or treatment to increase the response. The TEAD1, 2, 3 and / or 4 inhibitors of the present disclosure can be used, for example, in combination with other drugs or treatments for the treatment of cancer. In various aspects, the compound (including any one of the compounds according to formula (I), (II), any embodiment herein and compounds 1-106) is administered before, simultaneously with, or after the administration of a chemotherapeutic agent.

[0374] Anti-cancer therapies that can be used in combination with the compounds disclosed herein refer to any therapy or treatment that can be used to treat cancer. Anti-cancer therapies include, but are not limited to, small molecule or macromolecule therapies, surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapies. In some or any embodiments, the additional anti-cancer therapy is a KRAS G12C and / or G12D inhibitor; in some embodiments, the KRAS G12C and / or G12D inhibitor is sotolacib or adagracilib.

[0375] In some or any embodiments, combination therapies may include, but are not limited to, a compound disclosed herein (including any of Compounds 1-106) administered in combination with 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.

[0376] Examples of chemotherapeutic or anticancer agents include, but are not limited to, dactinomycin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, adriamycin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, nitrogen mustard, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, panitumumab, erbitux (cetuximab), matuzumab, IMC-IIF 8, TheraCIM hR3, denosumab, Avastin (bevacizumab), Humira (adalimumab), Herceptin (trastuzumab), Remicade (infliximab), Rituximab, Synagis (palivizumab), Mylotarg (gemtuzumab ozogamicin), Laputiva (efalizumab), Tasabli (natalizumab), Zenapax (daclizumab), NeutroSpec (technetium (99mTc) famosumab), tocilizumab, ProstaScint (indium-111 labeled cabomabamab (pentetide), Bexar (tositumomab), Zevarin (ibrutinib conjugated to yttrium-90 (IDEC-Y2B8)), Soler (omalizumab), Rituxan (rituximab), Leopro (abciximab), Mibucampus (alemtuzumab), Simlek (basiliximab), LeukoScan (sulixomab), CEA-scan (acitumomab), Verma (nofitumomab), Panorex (edrecolomab), Alemtuzumab, CDP 870, natalizumab, gilotinib (afatinib), limparib (olaparib), perjeta (pertuzumab), Autdiv (nivolumab), bosutinib (bosutinib), cabozantinib (cabozantinib), Ogiventricular (trastuzumab-DKST), Sutent (sunitinib malate), Adnestris (brentuximab), Alexanz (alectinib), Calcifa (acalabrutinib), Yeskata (ciloleucel), Verzenio (abemasikliib), Keytruda (pembrolizumab), Alicopter (copanlisib), Nelinkus (neratinib), Imfenzi (durvalumab), Dazarex (daratumumab), Tysenter (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).

[0377] In another embodiment, the present disclosure claims the use of a compound of formula (I) or a stereoisomer thereof, and / or a pharmaceutically acceptable salt, and / or a solvate thereof, in the treatment of any cancer indication in which YAP is located 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.

[0378] In yet another embodiment, the disclosed compounds (including compounds according to Formula (I), (II), any embodiments herein, and compounds 1-106) or pharmaceutical compositions thereof can disrupt the interaction of YAP with TEAD1, 2, 3, and / or 4. In certain embodiments, the disclosed compounds (including compounds according to Formula (I), (II), any embodiments herein, and compounds 1-106) or pharmaceutical compositions thereof can prevent YAP from binding to TEAD1, 2, 3, and / or 4. In some embodiments, the disclosed compounds (including compounds according to Formula (I), (II), any embodiments herein, and compounds 1-106) or pharmaceutical compositions thereof can compete with YAP for binding to TEAD1, 2, 3, and / or 4. In some embodiments, the disclosed compounds (including compounds according to Formula (I), (II), any embodiments herein, and compounds 1-106) or pharmaceutical compositions 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 selectively bind to TEAD1 compared to other TEAD isoforms.

[0379] "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients in the formulation and will not be harmful to the recipient thereof. For example, a carrier, diluent or excipient or a combination thereof can be administered to a subject together with the TEAD1, 2, 3 and / or 4 inhibitors of the present disclosure (including any one of the compounds according to Formula (I), (II), any embodiment herein, and compounds 1-106) without causing any undesirable biological effects or interacting in an undesirable manner with the TEAD1, 2, 3 and / or 4 inhibitor in the pharmaceutical composition (the pharmaceutical composition containing the TEAD1, 2, 3 and / or 4 inhibitor).

[0380] In treatment, the dosage of medicament is optionally in the range of from about 0.0001mg / kg to 100mg / kg, about 0.01mg / kg to 5mg / kg, about 0.15mg / kg to 3mg / kg, 0.5mg / kg to 2mg / kg and about 1mg / kg to 2mg / kg of subject's body weight. In other embodiments, the dosage is in the range of from about 100mg / kg to 5g / kg, about 500mg / kg to 2mg / kg and about 750mg / kg to 1.5g / kg of subject's body weight. For example, depending on the type and severity of the disease, the medicament of about 1 μ g / kg to 15mg / kg (for example, 0.1-20mg / kg) is the candidate dosage for use to the patient, no matter, for example, by one or more separate administrations, or by continuous infusion. Typical daily dosage is in the range of from about 1 μ g / kg to 100mg / kg or more, depending on the factors mentioned above. For repeated administrations lasting several days or longer, depending on the patient's condition, treatment continues until the desired disease symptoms suppress the appearance. However, other dosage regimens may be useful. The unit dose can be in the range of, for example, about 5 mg to 500 mg, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. The progress of therapy is monitored by conventional techniques and assays.

[0381] In some embodiments, the agent is administered to a human patient in an effective amount (or dose) of less than about 1 μg / kg, such as about 0.35 to 0.75 μg / kg or about 0.40 to 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, or about 10 to 30, or about 15 to 25 μg / subject. In some embodiments, the absolute dose of the agent is about 20 μg, or about 30 μg, or about 40 μg.

[0382] In various embodiments, the dosage of the agent can be determined by the weight of the human patient. For example, for a pediatric human patient of 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), the absolute dosage of the agent is about 2 μg; or for a pediatric human patient of about 6 to 8 kg (e.g., about 6, or about 7, or about 8 kg), about 3 μg; or for a pediatric human patient of about 9 to 13 kg (e.g., 9, or about 10, or about 11, or about 12, or about 13 kg), about 5 μg; or for a pediatric human patient of about 14 to about 20 kg (e.g., about 14, or about 16, or about 18, or about 20 kg), about 8 μg; or for a pediatric human patient of 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 of about 31 to about 33 kg (e.g., about 31, or about 32, or about 33 kg); 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 greater than about 114 kg (e.g., about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0383] In certain embodiments, the medicament according to the method provided herein is subcutaneous (sc), intravenous (iv), intramuscular (im), intranasal or topically applied. The administration of medicament described herein (including any one of the compound according to formula (I), (II), any embodiment of this paper and compound 1-106) can be independently one to four times a day or one to four times a month or one to six times a year or every two, three, four or five years. Administration can continue for one day or one month, two months, three months, six months, one year, two years, three years interval, and can even continue for the lifetime of human patients. Dosage can be used as a single dose or divided into multiple doses. In some embodiments, medicament is administered about 1 to 3 times (e.g., 1, or 2 or 3 times).

[0384] Synthesis Example

[0385] The examples presented below explore the synthesis and characterization of TEAD1, 2, 3 and / or 4 inhibitors for the applications discussed. The following examples are provided to further illustrate embodiments of the present invention, but are not intended to limit the scope of the invention. Although they are typical of those that may be used, other procedures, methodologies or techniques known to those skilled in the art may also be used instead.

[0386] As used herein, the symbols and conventions used in these methods, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with the symbols and conventions used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: aq. (aqueous solution); calcd. (calculated); avg. (average); ESI (electrospray ionization); HPLC (high pressure liquid chromatography); g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimoles per liter); μM (micromoles per liter); Hz (hertz); MHz (megahertz); mmol (millimoles); h, hr, or hr s (hours); min (minutes); MS (mass spectrometry); ppm (parts per million); rt or rt (room temperature); sat. (saturated); TLC (thin layer chromatography); ACN (acetonitrile); BOC (tert-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 (methanesulfonyl chloride); MTBE (methyl tert-butyl ether); PE (petroleum ether); TEA (triethylamine); HATU (tetramethyluronium hexafluorophosphate azabenzotriazole); HOBT (hydroxybenzotriazole), Red-Al (bis(2-methoxyethoxy)hexafluorophosphate); The present invention also includes the following: sodium bis(trimethylsilyl)aluminum hydride), DMF (dimethylformamide), TBAF (tetra-n-butylammonium fluoride), LiHMDS (lithium bis(trimethylsilyl)amide), HMPA (hexamethylphosphoramide), AcOH (acetic acid), TMSOTf (trimethylsilyl trifluoromethanesulfonate), mCPBA (m-chloroperbenzoic acid), DIBALH (diisobutylaluminum hydride), LDA (lithium diisopropylamide), TFA (trifluoroacetic acid) and THF (tetrahydrofuran).

[0387] For all of the following examples, standard post-processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in degrees Celsius. Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methodology set forth herein is intended to illustrate applicable chemistry through the use of specific examples and does not indicate the scope of this disclosure.

[0388] 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

[0389]

[0390] Synthesis route:

[0391]

[0392] Synthesis of tert-butyl 3-{3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1-yl}azetidine-1-carboxylate

[0393] [5-(trifluoromethyl)-1,2-oxazol-3-yl] diethyl methylphosphonate (300mg, 1.045mmol), tert-butyl 3-(2-oxoethyl)azetidine-1-formate (250mg, 1.255mmol), stirring bar and THF (10mL) are added in 50mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (176mg, 1.568mmol) at 0°C. The reaction mixture is stirred at room temperature for 2 hours, then diluted with water (30mL), and extracted with EtOAc (50mL x 2). The combined extracts are 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 light yellow oil. MS (ESI) C 15 H 19 The calculated mass of F3N2O3 is 332.13 m / z, and the measured mass is 277.00 [M+H-56] + .

[0394] Synthesis of 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate

[0395] 3-{3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-ene-1-yl}azetidine-1-carboxylic acid tert-butyl ester (270 mg, 0.812 mmol), a stirring bar and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until uniform, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-[3-(azetidine-3-yl)prop-1-ene-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2-trifluoroacetate as a light brown oil (300 mg, crude product). MS (ESI) C 10 H 11The calculated mass of F3N2O is 232.08 m / z, and the measured mass is 233.05 [M+H] + .

[0396] 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

[0397] By 3- [3- (azetidine -3- bases) propylene -1- alkene -1- bases] -5- (trifluoromethyl) -1,2- oxazole 2,2,2- trifluoroacetate (300mg, 0.866mmol), stirring bar, EtN (438mg, 4.328mmol), DCM (8mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (118mg, 1.304mmol) in DCM (2mL).The mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).The organic extracts merged are washed with salt water, use anhydrous NaSODry, filter and be concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 6) to give a mixture, which was purified by chiral HPLC using (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% in 20 minutes B; wavelength: 220 / 254 nm; RT1 (min): 14.806; sample solvent: EtOH--HPLC; injection volume: 0.4 mL; number of runs: 9) were further separated to obtain 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) C 13 H 13 The calculated mass of F3N2O2 is 286.09 m / z, and the measured mass is 287.05 [M+H] + , 1HNMR (300MHz, DMSO-d6) δ7.59(q,J=1.1Hz,1H),6.46(dt,J=11.7,1.5Hz,1H),6.29(dd,J=17.0,10.2Hz,1H),6.21–6.12(m,1H),6.08(dd,J=1 7.0,2.4Hz,1H),5.65(dd,J=10.2,2.4Hz,1H),4.35–4.26(m,1H),4.06–3.97(m,1H),3.94–3.85(m,1H),3.66–3.56(m,1H),2.84–2.71(m,3H) 19 F NMR (282MHz, DMSO-d6)δ (ppm): -62.98).

[0398] 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

[0399]

[0400] Synthesis route:

[0401]

[0402] 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

[0403] By 3- [3- (azetidine -3- bases) propylene -1- alkene -1- bases] -5- (trifluoromethyl) -1,2- oxazole 2,2,2- trifluoroacetate (300mg, 0.866mmol), stirring bar, EtN (438mg, 4.328mmol), DCM (8mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (118mg, 1.304mmol) in DCM (2mL).The mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).The organic extracts merged are washed with salt water, use anhydrous NaSODry, filter and be concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 6) to give a mixture, which was purified by chiral HPLC using (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% in 20 minutes B; wavelength: 220 / 254 nm; RT2 (min): 16.998; sample solvent: EtOH--HPLC; injection volume: 0.4 mL; number of runs: 9) were further separated to obtain 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) C 13 H 13 The calculated mass of F3N2O2 is 286.09 m / z, and the measured mass is 287.10 [M+H] + , 1HNMR(300MHz,DMSO-d6)δ7.79(q,J=1.1Hz,1H),6.74(dt,J=16.1,6.5Hz,1H),6.59 (dt,J=16.1,1.3Hz,1H),6.31(dd,J=17.0,10.2Hz,1H),6.09(dd,J=17.0,2.4Hz,1H ),5.65(dd,J=10.2,2.4Hz,1H),4.36–4.28(m,1H),4.09–3.99(m,1H),3.89(dd,J= 8.6,5.5Hz,1H),3.62(dd,J=10.0,5.6Hz,1H),2.87–2.71(m,1H),2.62–2.54(m,2H) 19 FNMR(282MHz,DMSO-d6)δ(ppm):-63.31)

[0404] Example 3: Synthesis of 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0405]

[0406] Synthesis route:

[0407]

[0408] Synthesis of [3-methoxy-4-(trifluoromethyl)phenyl]methanol

[0409] By 3-methoxy-4-(trifluoromethyl) benzoic acid (3g, 13.627mmol), stirring bar, BH3 THF solution (40mL) join in microwave vial (40mL x 2).Gained mixture is stirred at room temperature and spend the night, then pour into ice-cold water and extract with DCM (50mL x 3).By the layer salt water washing merged, use anhydrous sodium sulfate drying, filter and concentrate under vacuum pressure, obtain [3-methoxy-4-(trifluoromethyl) phenyl] methanol (2.02g, crude product), be white solid.

[0410] Synthesis of [3-methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate

[0411] [3-Methoxy-4-(trifluoromethyl)phenyl]methanol (1 g, 4.851 mmol), a stirring 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 room temperature for 2 hours, diluted with water (10 mL), and extracted with DCM (10 mL x 3). The combined layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum pressure to give [3-methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate (1 g, crude product) as a yellow oil.

[0412] Synthesis of diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate

[0413] [3-Methoxy-4-(trifluoromethyl)phenyl]methyl methanesulfonate (1 g, 3.518 mmol), a stirring bar, and P(OEt)3 (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 pressure. The residue was purified by reverse phase chromatography (0%-62% ACN / 10 mM NH4HCO3 water) to give diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate as a green oil. MS (ESI) C 13 H 18 The calculated mass of F3O4P is 326.09 m / z, and the measured mass is 327.05 [M+H] + .

[0414] Synthesis of tert-Butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

[0415] Diethyl [3-methoxy-4-(trifluoromethyl)phenyl]methylphosphonate (620 mg, 1.900 mmol), a stirring 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 and stirred until homogeneous, then treated with potassium tert-butoxide (323 mg, 2.878 mmol) in batches at 0 ° C. The resulting mixture was stirred at room temperature for 6 hours, then diluted with water (10 mL) and extracted with EA (10 mL x 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%-17% EA in PE) to give tert-butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate as a green oil. MS (ESI) C 18H 22 The calculated mass of F3NO3 is 357.16 m / z, and the measured mass is 302.00 [M-56+H] + .

[0416] Synthesis of 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine hydrochloride

[0417] tert-Butyl 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate (380 mg, 1.063 mmol), a stirring bar, and 1,4-dioxane (3 mL) were added to a 25 mL round-bottom flask and stirred until homogeneous, then treated dropwise with 4M HCl in 1,4-dioxane (4.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine hydrochloride (320 mg, crude) as a white solid. MS (ESI) C 13 H 14 The calculated mass of F3NO is 257.10 m / z, and the measured mass is 258.00 [M+H] + .

[0418] Synthesis of 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0419] 3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidine (150mg, 0.583mmol), stirring bar, triethylamine (294mg, 2.905mmol) and DCM (3mL) are added to 25mL round-bottom flask and stirred until homogeneous, then treated dropwise with a solution of acryloyl chloride (52.5mg, 0.593mmol) in DCM (0.5mL) at 0°C. The reaction mixture is stirred at room temperature for 1 hour, then diluted with water (5mL) and extracted with DCM (5mL x 3). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative 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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-[(E)-2-[3-methoxy-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one (18.7 mg) as a yellow oil. MS (ESI) C 16 H 16 The calculated mass of F3NO2 is 311.11 m / z, and the measured mass is 312.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.55(d,J=8.1Hz,1H),7.35(s,1H),7.14(d,J=8.0Hz,1H ),6.82(dd,J=15.9,8.2Hz,1H),6.58(d,J=15.9Hz,1H),6.33(dd,J=16.9,10.3H z,1H),6.12(d,J=16.8,2.2Hz,1H),5.68(d,J=10.2,2.2Hz,1H),4.52-4.44(m,1 H),4.23-4.09(m,2H),3.96-3.90(s,3H),3.90-3.82(m,1H),3.56-3.44(m,1H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.26.

[0420] Example 4: Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0421]

[0422] Synthesis route:

[0423]

[0424] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate

[0425] 4-(Bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (0.5 g, 1.945 mmol), a stirring bar, and P(OEt)3 (5 mL) were added to a 20 mL vial. The resulting mixture was stirred at 100°C overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH3CN / 10 mM NH4HCO3 water (30%-60%) to give diethyl [3-(trifluoromethyl)phenyl]methylphosphonate as a light yellow oil (0.575 g, 94.07%). MS (ESI) C 12 H 15 The calculated mass of F4O3P is 314.2 m / z, and the measured mass is 315.2 [M+H] + .

[0426] Synthesis of tert-Butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

[0427] Diethyl [2-fluoro-4-(trifluoromethyl)phenyl]methylphosphonate (575 mg, 1.830 mmol), tert-butyl 3-formylazetidine-1-carboxylate (406 mg, 2.192 mmol), a stirring bar and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (308 mg, 2.745 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with EA (100 mL x 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]vinyl]azetidine-1-carboxylate as a light yellow oil. MS (ESI) C 17 H 19 The calculated mass of F4NO2 is 345.1 m / z, and the measured mass is 290.05 [M+H-56] + .

[0428] Synthesis of (E)-3-(3-fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate

[0429] tert-Butyl 3-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]ethyl}azetidine-1-carboxylate (200 mg, 0.579 mmol), a stirring 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 room temperature for 1 hour and then concentrated in vacuo to give the crude product (E)-3-(3-fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a yellow solid (280 mg). MS (ESI) C 12 H 11 The calculated mass for F4N is 245.1 m / z, and the measured mass is 246.05 [M+H] + .

[0430] Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0431] (E)-3-(3-Fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate (280 mg, 0.779 mmol), triethylamine (410 mg, 4.052 mmol), a stirring bar and DCM (8 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (110 mg, 1.215 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was further purified by preparative-chiral-HPLC using (column: XBridgePrep 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: 33% B to 63% B, 63% B in 7 minutes; wavelength: 254 nm; RT1 (min): 5.87) to give 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one as a white solid. MS (ESI) C 15 H 13 The calculated mass of F4NO is 299.10 m / z, and the measured mass is 300.10 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.78-7.71(m,1H),7.64(d,J=12.5Hz,1H),7.49-7.45(m,1H),6.91-6.82(m,1H),6.65-6.58(m,1H),6.37 -6.28(m,1H),6.15-6.09(m,1H),5.72-5.65(m,1H),4.54-4.43(m,1H),4.24-4.09(m,2H),3.90-3.82(m,1H),3.57-3.48(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-59.62,-59.69,-116.18,-116.30.

[0432] Example 5: Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0433]

[0434] Synthesis route:

[0435]

[0436] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate

[0437] 1-(Bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (500 mg, 1.945 mmol), a stirring bar and P(OEt) 3 (5 mL) were added to a 40 mL vial. The resulting mixture was stirred at 100 ° C overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH 3 CN / 10 mM NH 4 HCO 3 water (30%-60%) to give [3-(trifluoromethyl)phenyl]methylphosphonic acid diethyl ester as a light yellow oil. MS (ESI) C 12 H 15 The calculated mass of F4O3P is 314.2 m / z, and the measured mass is 315.2 [M+H] + .

[0438] Synthesis of tert-Butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

[0439] Diethyl [2-fluoro-4-(trifluoromethyl)phenyl]methylphosphonate (537mg, 1.709mmol), tert-butyl 3-formylazetidine-1-formate (380mg, 2.052mmol), a stirring bar and THF (10mL) were added to a 100mL round-bottom flask and stirred until uniform, then treated with potassium tert-butoxide (287mg, 2.558mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100mL) and extracted with EA (100mL x 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]vinyl]azetidine-1-formate as a light yellow oil. MS (ESI) C 17 H 19 The calculated mass of F4NO2 is 345.1 m / z, and the measured mass is 289.95 [M+H-56] + .

[0440] Synthesis of (E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate

[0441] tert-Butyl 3-[(E)-2-[2-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate (200 mg, 0.579 mmol), a stirring 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 room temperature for 1 hour and then concentrated in vacuo to give the crude product (E)-3-(2-fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a yellow solid (250 mg). MS (ESI) C 12 H 11 The calculated mass for F4N is 245.1 m / z, and the measured mass is 246.45 [M+H] + .

[0442] Synthesis of 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0443] (E)-3-(2-Fluoro-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate (264 mg, 0.735 mmol), a stirring bar, triethylamine (387 mg, 3.824 mmol) and DCM (8 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (104 mg, 1.149 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, 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 preparative-chiral-HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one as an off-white solid (71.5 mg). MS (ESI) C 15 H 13 The calculated mass of F4NO is 299.10 m / z, and the measured mass is 300.10 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.93-7.84(m,1H),7.74-7.66(m,1H),7.62-7.55(m,1H),6.90-6.81(m,1H),6.71-6.62(m,1H),6.38- 6.26(m,1H),6.16-6.06(m,1H),5.72-5.63(m,1H),4.51-4.43(m,1H),4.22-4.11(m,2H),3.90-3.81(m,1H),3.64-3.51(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-61.00,-116.43.

[0444] Example 6: Synthesis of 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]piperidin-1-yl}prop-2-en-1-one

[0445]

[0446] Synthesis route:

[0447]

[0448] Synthesis of tert-Butyl 4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]piperidine-1-carboxylate

[0449] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (300 mg, 1.013 mmol), a stirring bar, tert-butyl 4-formylpiperidine-1-carboxylate (259 mg, 1.214 mmol), and THF (8 mL) were added to a dried 50 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0°C and potassium tert-butoxide (170 mg, 1.515 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and quenched with water, 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]vinyl]piperidine-1-carboxylate as a light yellow solid. MS (ESI) C 19 H 24 The calculated mass of F3NO2 is 355.2 m / z, and the measured mass is 300.05 [M+H-56] + .

[0450] Synthesis of (E)-4-(4-(trifluoromethyl)phenyl)piperidine 2,2,2-trifluoroacetate

[0451] Tert-butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (270 mg, 0.760 mmol), a stirring bar, and DCM (10 mL) were added to a 50 mL round-bottom flask dried and purged with nitrogen and stirred until homogeneous, followed by the addition of trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to afford (E)-4-(4-(trifluoromethyl)phenyl)piperidine 2,2,2-trifluoroacetate (330 mg, crude) as a light yellow semi-solid. MS (ESI) C 14 H 16 The calculated mass for F3N is 255.1 m / z, and the measured mass is 256.05 [M+H] +

[0452] Synthesis of 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]piperidin-1-yl}prop-2-en-1-one

[0453] (E)-4-(4-(Trifluoromethyl)phenylvinyl)piperidine 2,2,2-trifluoroacetate (330 mg, 0.894 mmol), a stirring bar, DCM (6 mL), and Et3N (452 ​​mg, 4.467 mmol) were added to a 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 hour, then quenched with water and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography using ACN / 10 mM NH4HCO3 water (5-60%) to give 1-{4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]piperidin-1-yl}prop-2-en-1-one as a yellow solid. MS (ESI) C 17 H 18 The calculated mass of F3NO is 309.15 m / z, and the measured mass is 310.15 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ7.72-7.56(m,4H),6.89-6.75(m,1H),6.50(s,2H),6.14-6.03(m,1H),5. 71-5.61(m,1H),4.51-4.37(m,1H),4.14-4.01(m,1H),3.21-3.05(m,1H),2.83-2.65(m,1H),2.45 -2.35(m,1H),1.87-1.72(m,2H),1.39-1.17(m,2H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.79.

[0454] Example 7: Synthesis of (E)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0455]

[0456] Synthesis route:

[0457]

[0458] Synthesis of tert-butyl 3-fluoro-3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

[0459] 4-[4-(Trifluoromethyl)phenoxy]benzoic acid (1 g, 3.543 mmol), 1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (2 g, 9.124 mmol), N,O-dimethylhydroxylamine hydrochloride (1.8 g, 18.454 mmol), a stirring bar and ACN (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was 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 portions at room temperature. The resulting mixture was stirred at 25 ° C overnight and then diluted with water. The resulting mixture was extracted with DCM (20 mL x 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. 1 H NMR (300MHz, DMSO-d6) δ4.40(d,J=11.2Hz,1H),4.32(d,J=11.0Hz,1H),4.06(d,J=1 1.0Hz,1H),3.98(d,J=11.0Hz,1H),3.70(s,3H),3.18(d,J=1.6Hz,3H),1.39(s,9H).

[0460] Synthesis of tert-Butyl 3-Fluoro-3-Formylazetidine-1-carboxylate

[0461] 3-Fluoro-3-[methoxy(methyl)carbamoyl]azetidine-1-tert-butyl formate (750mg, 2.860mmol), THF (2mL, 24.686mmol) and a stirring bar were added to a 20mL vial and stirred until uniform, then treated dropwise with DIBAL-H (4mL, 19.716mmol) at -78°C. The resulting mixture was stirred at -78°C for 2h, then quenched with water, filtered and washed with DCM (20mL). The resulting mixture was extracted with DCM (5mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-fluoro-3-formylazetidine-1-tert-butyl formate (700mg, 120.46%) as a yellow oil.

[0462] Synthesis of tert-butyl 3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0463] 3- fluoro- 3- formyl azetidine -1- tert-butyl formate (700mg, 3.445mmol), [5- (trifluoromethyl) -1,2- oxazole -3- bases] diethyl methylphosphonate (112mg, 0.390mmol), stirring bar and THF (7mL) are added to 20mL vial and stirred until homogeneous, then processed with potassium tert-butoxide (482mg, 4.295mmol) in batches at room temperature. The resulting mixture is stirred at 25 ° C overnight and then quenched with water. The resulting mixture is extracted with DCM (10mL x 3). The combined organic layer is 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]vinyl}azetidine-1-carboxylate (280 mg, 24.17%) as a white solid. MS (ESI) C 14 H 16 The calculated mass of F4N2O3 is 336.00 m / z, and the measured mass is 322.05 [M+H+CH3CN] + .

[0464] Synthesis of 3-(2-(3-fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0465] tert-Butyl 3-fluoro-3-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl}azetidine-1-carboxylate (280 mg, 0.833 mmol), DCM (2.5 mL) and a stirring bar were added to an 8 mL vial and stirred until homogeneous, then treated dropwise with TFA (0.5 mL, 6.732 mmol) at room temperature. The resulting mixture was stirred at 25 ° C for 2 hours and concentrated in vacuo to give 3-(2-(3-fluoroazetidine-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (400 mg, 203.42% crude) as a yellow oil. MS (ESI) calculated mass for C9H8F4N2O was 236.00 m / z, found to be 237.00 [M+H] + .

[0466] Synthesis of (E)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0467] 3-(2-(3-fluoroazetidine-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (378 mg, 1.386 mmol), TEA (808 mg, 7.985 mmol), a stirring bar and DCM (4 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with acryloyl chloride (216 mg, 2.386 mmol) at room temperature. The resulting mixture was stirred overnight at 25 ° C and then quenched with water. The resulting mixture was extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting mixture was then purified by preparative 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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-fluoro-3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidin-1-yl}prop-2-en-1-one (53.5 mg) as a white solid. MS (ESI) C 12 H 10 The calculated mass of F4N2O2 is 290.07 m / z, and the measured mass is 290.95 [M+H] + ; 1 HNMR(300MHz,DMSO-d6)δ7.83(s,1H),7.28-7.09(m,1H),6.96-6.83(m,1H),6.43-6.2 8(m,1H),6.23-6.10(m,1H),5.80-5.68(m,1H),4.70-4.48(m,2H),4.40-4.14(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-63.31,-152.45.

[0468] Example 8: Synthesis of (Z)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0469]

[0470] Synthesis route:

[0471]

[0472] Synthesis of (Z)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0473] 3-(2-(3-fluoroazetidine-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (378 mg, 1.386 mmol), TEA (808 mg, 7.985 mmol), a stirring bar and DCM (4 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with acryloyl chloride (216 mg, 2.386 mmol) at room temperature. The resulting mixture was stirred at 25 ° C overnight and then quenched with water. The resulting mixture was extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting mixture was then purified by preparative 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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-{3-fluoro-3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidin-1-yl}prop-2-en-1-one (4.9 mg, 1.22%) as a yellow oil. MS (ESI) C 12 H 10 The calculated mass of F4N2O2 is 290.07 m / z, and the measured mass is 291.00 [M+H] + ; 1 HNMR(300MHz,DMSO-d6)δ7.46(s,1H),6.78-6.68(m,1H),6.67-6.51(m,1H),6.39-6.24(m ,1H),6.19-6.07(m,1H),6.76-6.66(m,1H),4.64-4.52(m,2H),4.29(s,1H),4.22(s,1H); 19 F NMR(282MHz,DMSO-d6)δ-62.96,-143.89.

[0474] Example 9: Synthesis of 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0475]

[0476] Synthesis route:

[0477]

[0478] (followed by SFC separation)

[0479] Synthesis of tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate

[0480] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (300 mg, 1.013 mmol), a stirring bar, tert-butyl 3-formylpyrrolidine-1-carboxylate (242 mg, 1.215 mmol), and THF (8 mL) were added to a dried 50 mL round-bottom flask and stirred until homogeneous. The reaction vessel was then cooled to 0°C and potassium tert-butoxide (170 mg, 1.515 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with EA (100 mL x 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]vinyl]pyrrolidine-1-carboxylate as a light yellow oil. MS (ESI) C 18 H 22 The calculated mass of F3NO2 is 341.2 m / z, and the measured mass is 286.00 [M+H-56] +

[0481] Synthesis of (E)-3-(4-(trifluoromethyl)phenylvinyl)pyrrolidine 2,2,2-trifluoroacetate

[0482] tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (150 mg, 0.439 mmol), a stirring bar, and DCM (10 mL) were added to a 50 mL round-bottom flask that was oven-dried and purged with nitrogen and stirred until homogeneous. Trifluoroacetic acid (2 mL) was then added. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to afford (E)-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate as a light brown semisolid. MS (ESI) C 13 H 14 The calculated mass of F3N is 241.1 m / z, and the measured mass is 242.05 [M+H] +

[0483] Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one

[0484] (E)-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (154 mg, 0.433 mmol), a stirring bar, DCM (6 mL), and Et3N (219 mg, 2.164 mmol) were added to a 50 mL round-bottom flask that was oven-dried and purged with nitrogen, and the resulting mixture was stirred until homogeneous. The reaction vessel 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 room temperature for 2 hours, 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%-55%) to give 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one as a light yellow solid product. MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.74-7.62(m,4H),6.69-6.45(m,3H),6.18-6.09(m,1H),5.74- 5.62(m,1H),3.89-3.51(m,3H),3.23-2.96(m,2H),2.18-2.01(m,1H),1.95-1.69(m,1H), 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.83.

[0485] Synthesis of 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0486] The racemic product was further separated by SFC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 21 minutes; wavelength: 220 / 254 nm; RT1 (min): 14.491 (first isomer); sample solvent: EtOH--HPLC; injection volume: 0.4 mL; number of runs: 2) to give one stereoisomer, designated as (S) (first eluting isomer), 1-[(3S)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one, as a white solid (4.7 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.15 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.74-7.62(m,4H),6.69-6.45(m,3H),6.18-6.09(m,1H),5.74- 5.62(m,1H),3.89-3.51(m,3H),3.23-2.96(m,2H),2.18-2.01(m,1H),1.95-1.69(m,1H). 19 FNMR(376MHz,DMSO-d6)δ(ppm):-60.82.

[0487] Example 10: Synthesis of 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0488]

[0489] Synthesis of 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0490] The racemic product was separated by SFC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 21 minutes; 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, designated as R (second eluting isomer), 1-[(3R)-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one, as a white solid (3.8 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.74-7.62(m,4H),6.69-6.45(m,3H),6.18-6.09(m,1H),5.74-5 .62(m,1H),3.89-3.51(m,3H),3.23-2.96(m,2H),2.18-2.01(m,1H),1.95-1.69(m,1H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.82.

[0491] Example 11: Synthesis of 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0492]

[0493] Synthesis route:

[0494]

[0495] Synthesis of (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate

[0496] (5-(Trifluoromethyl)pyridin-2-yl)methanol (1.0 g, 5.646 mmol), a stirring bar, Et3N (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 room temperature for 1 hour, then quenched with water (50 mL) and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified on a silica gel column eluted with EA / PE (0-50%) to give (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate as a light yellow solid. MS (ESI) calculated mass for C8H8F3NO3S was 255.02 m / z, found 255.90 [M+H] + .

[0497] Synthesis of Diethyl ((5-(Trifluoromethyl)pyridin-2-yl)methyl)phosphonate

[0498] 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 to 110° C. and stirred overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH 3 CN / 10 mM NH 4 HCO 3 water (5%-60%) to give diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate as a light brown liquid. MS (ESI) C 11 H 15 The calculated mass of F3NO3P is 297.07 m / z, and the measured mass is 298.00 [M+H] + .

[0499] Synthesis of tert-Butyl 3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate

[0500] 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 stirring 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 room temperature for 2 hours, then diluted with water (30 mL) and extracted with EtOAc (50 mL x 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-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate as a light yellow oil. MS (ESI) C 16 H 19 The calculated mass of F3N2O2 is 328.14 m / z, and the measured mass is 273.15 [M+H-56] + .

[0501] Synthesis of 2-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)pyridine 2,2,2-trifluoroacetate

[0502] tert-Butyl 3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidine-1-carboxylate (410 mg, 1.249 mmol), a stirring bar and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 2-(2-(azetidine-3-yl)vinyl)-5-(trifluoromethyl)pyridine 2,2,2-trifluoroacetate as a light brown oil (600 mg, crude). MS (ESI) C 11 H 11 The calculated mass of F3N2 is 228.09 m / z, and the measured mass is 229.10 [M+H] + .

[0503] Synthesis of 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0504] By 2- (2- (azetidine -3- bases) vinyl) -5- (trifluoromethyl) pyridine 2,2,2- trifluoroacetate (600mg, 1.753mmol), stirring bar, Et3N (888mg, 8.775mmol), DCM (13mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (206mg, 2.276mmol) in DCM (2mL).Mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).By the organic extract washed with salt water merged, use anhydrous Na2SO4 dry, filter and be concentrated in vacuo. The residue was purified by HPLC using (column: XBridgePrep 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 minutes; wavelength: 254 nm; RT1 (min): 6; number of runs: 0) to give 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1-yl)prop-2-en-1-one as a light orange solid (121.1 mg). MS (ESI) C 14 H 13 The calculated mass of F3N2O is 282.10 m / z, and the measured mass is 283.00 [M+H] + , 1 HNMR (300MHz, DMSO-d6) δ8.92–8.86(m,1H),8.21–8.13(m,1H),7.68(d,J=8.3Hz,1H),7.18(dd,J=15.7,8.2Hz,1H),6.73(dd,J=15.7,1.1Hz,1H) ,6.40–6.27(m,1H),6.17–6.06(m,1H),5.68(dd,J=10.3,2.4Hz,1H),4.5 2–4.43(m,1H),4.23–4.11(m,2H),3.92–3.82(m,1H),3.67–3.51(m,1H). 19 F NMR(282MHz,DMSO-d6)δ-60.68.

[0505] Example 12: Synthesis of 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0506]

[0507] Synthesis route:

[0508]

[0509] Synthesis of Methyl [2-(Trifluoromethyl)-1,3-thiazol-5-yl]methyl Methanesulfonate

[0510] [2-(Trifluoromethyl)-1,3-thiazol-5-yl]methanol (1.0 g, 5.460 mmol), a stirring bar, Et3N (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 room temperature for 1 hour, then quenched with water (50 mL) and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified on a silica gel column eluted with EA / PE (0-50%) to give [2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl methanesulfonate as a light yellow oil. MS (ESI) calculated mass for C6H6F3NO3S2: 260.97 m / z, measured: 261.95 [M+H] + .

[0511] Synthesis of diethyl [2-(trifluoromethyl)-1,3-thiazol-5-yl]methylphosphonate

[0512] 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 to 110°C and stirred overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH3CN / 10 mM NH4HCO3 water (5%-60%) to give [2-(trifluoromethyl)-1,3-thiazol-5-yl]methylphosphonic acid diethyl ester as a light brown liquid. MS (ESI) C9H 13 The calculated mass of F3NO3PS is 303.03 m / z, and the measured mass is 304.00 [M+H] + .

[0513] Synthesis of tert-butyl 3-{2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl}azetidine-1-carboxylate

[0514] 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 stirring bar and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (222 mg, 1.978 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, then diluted with water (30 mL) and extracted with EtOAc (50 mL x 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]vinyl}azetidine-1-carboxylate as a light yellow oil. MS(ESI)C 14 H 17 The calculated mass for F3N2O2S is 334.36 m / z, and the measured mass is 278.95 [M+H-56] + .

[0515] Synthesis of 5-[2-(azetidin-3-yl)vinyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate

[0516] tert-Butyl 3-{2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl}azetidine-1-carboxylate (300 mg, 0.897 mmol), a stirring bar and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 5-[2-(azetidine-3-yl)vinyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate as a light brown oil (400 mg, crude). MS (ESI) C9H9F3N2S calculated mass was 234.04 m / z and measured value was 235.00 [M+H] + .

[0517] Synthesis of 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0518] By 5- [2- (azetidine -3- bases) vinyl] -2- (trifluoromethyl) -1,3- thiazole 2,2,2- trifluoroacetate (400mg, 1.149mmol), stirring bar, Et3N (596mg, 5.890mmol), DCM (10mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (156mg, 1.724mmol) in DCM (2mL).The mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).The organic extracts merged are washed with salt water, use anhydrous Na2SO4 dry, filter and be concentrated in vacuo. The residue was purified by HPLC using (column: XBridgePrep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / LNH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25% B to 55% B, 55% B in 7 minutes; wavelength: 254nm; RT1 (min): 6.10) to give a mixture, which was purified by Achiral SFC using (column: YMC-Actus SIL, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 50mL / min; gradient: isocratic 13% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 254 nm; RT1 (min): 5.43; sample solvent: MeOH--HPLC; injection volume: 1 mL; number of runs: 13) to further separate 1-{3-[(Z)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one as a colorless oil (27.8 mg). MS (ESI) C 12 H 11 The calculated mass for F3N2OS is 288.05 m / z, and the measured mass is 289.05 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ8.12(s,1H),6.80(d,J=11.4Hz,1H),6.36-6.26(m,2H),6.11(dd,J=17.0,2.3Hz,1H ),5.67(dd,J=10.2,2.3Hz,1H),4.63-4.55(m,1H),4.33-4.25(m,1H),4.09-4.02(m,1H),3.85-3.72(m,2H) 19 F NMR(282MHz,DMSO-d6)δ(ppm):-59.81).

[0519] Example 13: Synthesis of 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0520]

[0521] Synthesis route:

[0522]

[0523] Synthesis of 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0524] By 5- [2- (azetidine -3- bases) vinyl] -2- (trifluoromethyl) -1,3- thiazole 2,2,2- trifluoroacetate (400mg, 1.149mmol), stirring bar, Et3N (596mg, 5.890mmol), DCM (10mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (156mg, 1.724mmol) in DCM (2mL).The mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).The organic extracts merged are washed with salt water, use anhydrous Na2SO4 dry, filter and be concentrated in vacuo. The residue was purified by HPLC using (column: XBridgePrep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / LNH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25% B to 55% B, 55% B in 7 minutes; wavelength: 254nm; RT1 (min): 6.10) to give a mixture, which was purified by Achiral SFC using (column: YMC-Actus SIL, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 50mL / min; gradient: isocratic 13% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 254 nm; RT2 (min): 6.37; sample solvent: MeOH--HPLC; injection volume: 1 mL; number of runs: 13) further separated to give 1-{3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5-yl]vinyl]azetidin-1-yl}prop-2-en-1-one as a white solid (85.0 mg), MS (ESI) C 12 H 11The calculated mass for F3N2OS is 288.05 m / z, and the measured mass is 289.05 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),6.86(d,J=15.8Hz,1H),6.66(dd,J=15.8,8.0Hz,1H),6.31(dd,J=17.0,10.3Hz,1H),6.10( dd,J=17.0,2.3Hz,1H),5.67(dd,J=10.3,2.3Hz,1H),4.50-4.41(m,1H),4.21-4.07(m,2H),3.89-3.80(m,1H),3.59-3.45(m,1H) 19 F NMR(282MHz,DMSO-d6)δ(ppm):-60.00).

[0525] Example 14: Synthesis of 1-(3-(3-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0526]

[0527] Synthesis route:

[0528]

[0529] Synthesis of diethyl (3-(trifluoromethyl)benzyl)phosphonate

[0530] A mixture of 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.0 g, 4.183 mmol) and triethyl phosphite (10 mL) was heated to 110° C. and stirred overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH 3 CN / 10 mM NH 4 HCO 3 water (5%-60%) to give diethyl (3-(trifluoromethyl)benzyl)phosphonate as a light brown liquid. MS (ESI) C 12 H 16 The calculated mass of F3O3P is 296.08 m / z, and the measured mass is 397.00 [M+H] + .

[0531] Synthesis of tert-Butyl 3-(3-(Trifluoromethyl)phenyl)azetidine-1-carboxylate

[0532] Diethyl (3-(trifluoromethyl)benzyl)phosphonate (500 mg, 1.688 mmol), a stirring 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). After the mixture was stirred at room temperature for 20 minutes, tert-butyl 3-formylazetidine-1-carboxylate (375 mg, 2.025 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, 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)phenyl)azetidine-1-carboxylate as a light yellow oil. MS (ESI) C 17 H 20 The calculated mass of F3NO2 is 327.14 m / z, and the measured mass is 272.00 [M+H-56] + .

[0533] Synthesis of 3-(3-(trifluoromethyl)phenylvinyl)azetidine 2,2,2-trifluoroacetate

[0534] 3-(3-(trifluoromethyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (120 mg, 0.367 mmol), a stirring bar and DCM (5 mL) were added to a 50 mL round-bottom flask and stirred until uniform, then treated with TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-(3-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a light brown oil (130 mg, crude product). MS (ESI) C 12 H 12 The calculated mass of F3N is 227.09 m / z, and the measured mass is 228.10 [M+H] + .

[0535] Synthesis of 1-(3-(3-(trifluoromethyl)phenylvinyl)azetidin-1-yl)prop-2-en-1-one

[0536] By 3- (3- (trifluoromethyl) styryl) azetidine 2,2,2- trifluoroacetate (130mg, 0.381mmol), stirring bar, Et3N (193mg, 1.907mmol), DCM (5mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with the solution of acryloyl chloride (52mg, 0.575mmol) in DCM (1mL).The mixture is stirred at room temperature for 1 hour, is then quenched with water (30mL) and extracted with DCM (50mL x 3).The organic extracts merged are washed with salt water, use anhydrous Na2SO4 dry, filter and be concentrated in vacuo. The residue was purified by HPLC using (column: XSelect CSH PrepC18 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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-(3-(3-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one as a light yellow oil (32.5 mg). MS (ESI) C 15 H 14 The calculated mass of F3NO is 281.10 m / z, and the measured mass is 282.15 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.79–7.72(m,1H),7.64–7.50(m,2H),6.83–6.72(m,1H),6.68–6.58(m,1H),6.38–6.28(m,1H ),6.17–6.06(m,1H),5.68(dd,J=10.3,2.3Hz,1H),4.47(t,J=8.5Hz,1H),4.21–4.09(m,2H),3.90–3.81(m,1H),3.56–3.44(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-61.16.

[0537] Example 15: Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0538]

[0539] Synthesis route:

[0540]

[0541] Synthesis of diethyl [4-(trifluoromethyl)phenyl]methylphosphonate

[0542] A mixture of 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.0 g, 4.183 mmol) and triethyl phosphite (10 mL) was heated to 110° C. and stirred overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CH 3 CN / 10 mM NH 4 HCO 3 water (5%-60%) to give diethyl [4-(trifluoromethyl)phenyl]methylphosphonate as a light brown liquid. MS (ESI) C 12 H 16 The calculated mass of F3O3P is 296.08 m / z, and the measured mass is 397.00 [M+H] + .

[0543] Synthesis of tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

[0544] Diethyl [4-(trifluoromethyl)phenyl]methylphosphonate (500 mg, 1.688 mmol), a stirring 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). After the mixture was stirred at room temperature for 20 minutes, tert-butyl 3-formylazetidine-1-carboxylate (375 mg, 2.025 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, 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-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate as a light yellow semi-solid. MS (ESI) C 17 H 20 The calculated mass of F3NO2 is 327.14 m / z, and the measured mass is 272.05 [M+H-56] + .

[0545] Synthesis of 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidine 2,2,2-trifluoroacetate

[0546] tert-Butyl 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate (300 mg, 0.916 mmol), a stirring bar and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidine 2,2,2-trifluoroacetate as a light brown oil (340 mg, crude). MS (ESI) C 12 H 12 The calculated mass of F3N is 227.09 m / z, and the measured mass is 228.10 [M+H] + .

[0547] Synthesis of 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0548] By 3- [(E) -2- [4- (trifluoromethyl) phenyl] vinyl] azetidine 2,2,2- trifluoroacetate (340mg, 0.996mmol), stirring bar, Et3N (505mg, 4.990mmol), DCM (7mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed dropwise with a solution of acryloyl chloride (135mg, 1.492mmol) in DCM (1mL). The mixture is stirred at room temperature for 1 hour, then quenched with water (30mL) and extracted with DCM (50mL x 3). The organic extracts merged are washed with salt water, used anhydrous Na2SO4 dry, filtered and concentrated in vacuo. The residue was purified by HPLC using (column: XSelect CSH PrepC18 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 minutes; wavelength: 254 nm) to give 1-{3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]azetidin-1-yl}prop-2-en-1-one as a light yellow solid (69.5 mg). MS (ESI) C 15 H 14 The calculated mass of F3NO is 281.10 m / z, and the measured mass is 282.00 [M+H] + ; 1H NMR (300MHz, DMSO-d6) δ7.77–7.59(m,4H),6.83–6.70(m,1H),6.68–6.55(m,1H),6.40–6.25(m,1H),6.18–6.03( m,1H),5.68(dd,J=10.2,2.4Hz,1H),4.52–4.41(m,1H),4.24–4.06(m,2H),3.91–3.78(m,1H),3.61–3.42(m,1H), 19 FNMR(282MHz,DMSO-d6)δ(ppm):-60.85

[0549] Example 16: Synthesis of 1-(3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0550]

[0551] Synthesis route:

[0552]

[0553] 3-((diethoxy(methylene)-λ 5 Synthesis of 5-(trifluoromethyl)isoxazole

[0554] (5-(Trifluoromethyl)isoxazol-3-yl)methyl methanesulfonate (800 mg, 3.263 mmol), a stirring bar, and P(OEt)3 (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 purified by reverse phase chromatography on C18 (ACN / H2O (0.05% NH4HCO3) = 5-50%) to give 3-((diethoxy(methylene)-λ 5 -phosphono)methyl)-5-(trifluoromethyl)isoxazole, as a light yellow oil (735 g, 78.44%). MS (ESI) C9H 13 The calculated mass of F3NO4P is 287.05 m / z, and the measured mass is 288.05 [M+H] + .

[0555] Synthesis of tert-butyl 3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0556] 3-((diethoxy(methylene)-λ 5-phosphonyl)methyl)-5-(trifluoromethyl)isoxazole (300 mg, 1.052 mmol), a stirring 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 hour. The reaction mixture was then quenched with water (10 mL), extracted with EA (3 x 20 mL), and the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness. The obtained residue was then purified by 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) C 15 H 19 The calculated mass of F3N2O3 is 332.13 m / z, and the measured mass is 276.95 [M+H-56] + ).

[0557] Synthesis of 3-(2-(3-methylazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0558] tert-Butyl 3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (283 mg, 0.852 mmol), a stirring bar, and DCM (9 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (3 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-(2-(3-methylazetidine-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a red oil (402 mg, crude, MS (ESI) C 10 H 11 The calculated mass of F3N2O is 232.08 m / z, and the measured mass is 233.10 [M+H] + ).

[0559] Synthesis of 1-(3-methyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0560] By 3- (2- (3- methylazetidine -3- bases) vinyl) -5- (trifluoromethyl) isoxazole 2,2,2- trifluoroacetate (402mg, 1.161mmol), stirring bar, TEA (588mg, 5.811mmol) and DCM (8mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (210mg, 2.320mmol).The mixture is stirred at room temperature for 1 hour, then quenched with water (20mL) and extracted with DCM (3x 30mL).The organic extracts merged are washed with salt water, use anhydrous Na2SO4 drying, filter and vacuum concentrate. The residue was purified by HPLC using (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 minutes; 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 light yellow solid (62.2 mg). MS (ESI) C 13 H 13 The calculated mass of F3N2O2 is 286.09 m / z, and the measured mass is 287.00 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.90-7.79(m,1H),7.19-7.07(m,1H),6.70-6.58(m,1H),6.40-6.27(m,1H),6.20-6.07(m ,1H),5.76-5.65(m,1H),4.37-4.21(m,1H),4.16-4.05(m,1H),4.02-3.92(m,1H),3.85-3.74(m,1H),1.48(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-63.33].

[0561] Example 17: Synthesis of 1-(3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0562]

[0563] Synthesis route:

[0564]

[0565] Synthesis of tert-Butyl 3-Formyl-3-methoxyazetidine-1-carboxylate

[0566] At -70 DEG C under nitrogen atmosphere, to (COCl) 2(1.1g, 8.657mmol) in DCM (5mL) solution of DMSO (1.3g, 16.651mmol) in DCM (4mL) was added dropwise. After stirring for 30 minutes, a solution of 3-(hydroxymethyl)-3-methoxyazetidine-1-tert-butyl formate (0.9g, 4.142mmol) in DCM (5mL) was added dropwise and continued to stir for 30 minutes. Et3N (3.4g, 33.592mmol) in DCM (4mL) was added to the mixture and the resulting mixture was stirred at -70 DEG C for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water (20mL) and extracted with DCM (3x 40mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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) C 10 H 17 The calculated mass of NO4 is 215.11 m / z, and the measured value is 177.95 [M+H-56+18] + ).

[0567] Synthesis of tert-butyl 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate

[0568] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (400 mg, 1.350 mmol), a stirring 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 hour. The reaction mixture was then quenched with water (10 mL), extracted with EA (3 x 20 mL), and the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness. The obtained residue was then purified by silica gel chromatography (0-30% EA / PE) to give tert-butyl 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate as a pale yellow oil (449 mg, 93.04%, MS (ESI) C 18 H 22 The calculated mass of F3NO3 is 357.16 m / z, and the measured mass is 302.10 [M+H-56] + ).

[0569] Synthesis of 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate

[0570] 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.560 mmol), a stirring bar, and DCM (6 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a colorless oil (239 mg, crude product). MS (ESI) C 13 H 14 The calculated mass of F3NO is 257.10 m / z, and the measured mass is 258.15 [M+H] + .

[0571] Synthesis of 1-(3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0572] By 3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate (239mg, 0.644mmol), stirring bar, TEA (326mg, 3.222mmol) and DCM (5mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (117mg, 1.293mmol).Mixture is stirred at room temperature for 1 hour, is then quenched with water (20mL) and extracted with DCM (3x 30mL).By the organic extract washed with salt water merged, use anhydrous Na2SO4 drying, filter and vacuum concentrate. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-(3-methoxy-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one as an off-white solid (79.5 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO2 is 311.11 m / z, and the measured mass is 312.05 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ7.80-7.62(m,4H),6.92-6.84(m,1H),6.72-6.63(m,1H),6.42-6.30(m,1H),6.18-6.10(m ,1H),5.75-5.67(m,1H),4.43-4.34(m,1H),4.33-4.26(m,1H),4.15-4.06(m,1H),4.03-3.94(m,1H),3.21(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.93].

[0573] Example 18: Synthesis of 1-(3-methyl-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0574]

[0575] Synthesis route:

[0576]

[0577] Synthesis of tert-Butyl 3-Formyl-3-methylazetidine-1-carboxylate

[0578] At -70 DEG C under nitrogen atmosphere, to (COCl)2(1.0g, 10.243mmol) in DCM (5mL) solution of DMSO (1.6g, 20.479mmol) in DCM (5mL) was added dropwise. After stirring for 30 minutes, a solution of 3-(hydroxymethyl)-3-methoxyazetidine-1-tert-butyl formates (1.0g, 4.969mmol) in DCM (5mL) was added dropwise and continued to stir for 30 minutes. Et3N (4.0g, 39.528mmol) in DCM (5mL) was added to the mixture and the resulting mixture was stirred at -70 DEG C for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water (20mL) and extracted with DCM (3x 40mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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) C 10 H 17 The calculated mass of NO3 is 199.12 m / z, and the measured value is 218.05 [M+H+18] + .

[0579] Synthesis of tert-butyl 3-methyl-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate

[0580] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (500 mg, 1.688 mmol), a stirring 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 hour. The reaction mixture was then quenched with water (10 mL), extracted with EA (3 x 20 mL), and the combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The obtained residue was then purified by silica gel chromatography (0-30% EA / PE) to give tert-butyl 3-methyl-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate as a colorless oil (412 mg, 71.50%). MS(ESI)C 18 H 22 The calculated mass of F3NO2 is 341.16 m / z, and the measured mass is 286.00 [M+H-56] + .

[0581] Synthesis of 3-Methyl-3-(4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate

[0582] 3-Methyl-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.586 mmol), a stirring bar, and DCM (6 mL) were added to a 50 mL round-bottom flask and stirred until uniform, then treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-methyl-3-(4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a light yellow oil (423 mg, crude product). MS (ESI) C 13 H 14 The calculated mass of F3N is 241.11 m / z, and the measured mass is 242.10 [M+H] + .

[0583] Synthesis of 1-(3-methyl-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0584] By 3- methyl -3- (4- (trifluoromethyl) styryl) azetidine 2,2,2- trifluoroacetate (423mg, 1.191mmol), stirring bar, TEA (602mg, 5.949mmol) and DCM (8mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (216mg, 2.386mmol).Mixture is stirred at room temperature for 1 hour, is then quenched with water (20mL) and extracted with DCM (3x 30mL).By the organic extract washed with salt water merged, use anhydrous Na2SO4 dry, filter and be concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 5.72) to give 1-(3-methyl-3-(4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one as a light yellow oil (38.6 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.12 m / z, and the measured mass is 296.05 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ7.72-7.61(m,4H),6.86-6.78(m,1H),6.65-6.57(m,1H),6.37-6.28(m,1H),6.15-6.06(m,1H), 5.68(dd,J=10.3,2.3Hz,1H),4.28-4.22(m,1H),4.08-4.02(m,1H),4.01-3.94(m,1H),3.79-3.71(m,1H),1.48(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.83.

[0585] Example 19: Synthesis of 1-(3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0586]

[0587] Synthesis route:

[0588]

[0589] Synthesis of diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate

[0590] A mixture of 1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene (500 mg, 1.858 mmol) and P(OEt) (5 mL) was heated to 110°C and stirred overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography using CHCN / 10 mM NHHCO water (5%-60%) to give diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate as a white solid (408 mg, 67.30%). MS (ESI) C 13 H 18 The calculated mass of F3O4P is 326.09 m / z, and the measured mass is 327.10 [M+H] + .

[0591] Synthesis of tert-butyl 3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidine-1-carboxylate

[0592] Diethyl (2-methoxy-4-(trifluoromethyl)benzyl)phosphonate (408 mg, 1.251 mmol), a stirring 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, then treated with t-BuOK (211 mg, 1.880 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with water (20 mL), extracted with EA (3 x 30 mL), and the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The obtained residue was then subjected to silica gel chromatography (30%-40% EA / PE) to give tert-butyl 3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidine-1-carboxylate as a colorless oil (231 mg). MS (ESI) C 18 H 22 The calculated mass of F3NO3 is 357.15 m / z, and the measured mass is 302.10 [M+H-56] + .

[0593] Synthesis of 3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate

[0594] tert-Butyl 3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidine-1-carboxylate (231 mg, 0.646 mmol), a stirring bar, and DCM (5 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidine 2,2,2-trifluoroacetate as a red oil (281 mg, crude product). MS (ESI) C 13 H 14 The calculated mass of F3NO is 257.10 m / z, and the measured mass is 258.15 [M+H] + .

[0595] Synthesis of 1-(3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0596] 3- (2- methoxy -4- (trifluoromethyl) styryl) azetidine 2,2,2- trifluoroacetate (281mg, 0.757mmol), stirring bar, TEA (383mg, 3.785mmol) and DCM (5mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (137mg, 1.514mmol). The gained mixture is stirred at room temperature for 1 hour, then quenched with water (10mL) and extracted with DCM (10mL x 3). The organic extracts merged are washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm) to give 1-(3-(2-methoxy-4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one as a white solid (100.2 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO2 is 311.11 m / z, and the measured mass is 312.15 [M+H] + , 1H NMR(300MHz,DMSO-d6)δ7.78-7.65(m,1H),7.37-7.18(m,2H),6.80-6.59(m,2H),6.39-6.21(m,1H),6.18-6 .02(m,1H),5.74-5.60(m,1H),4.54-4.37(m,1H),4.24-4.06(m,2H),3.96-3.75(m,4H),3.62-3.44(m,1H). 19 F NMR(282MHz,DMSO-d6)δ-60.80.

[0597] Example 20: Synthesis of 1-(6-(4-(trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0598]

[0599] Synthesis route:

[0600]

[0601] Synthesis of tert-Butyl 6-(4-(Trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0602] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (330 mg, 1.114 mmol), a stirring 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 hours. The reaction mixture was then quenched with water (20 mL), extracted with EA (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified on a silica gel column eluting with EA / PE (10%-30%) to give tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate as a light yellow oil (287 mg). MS(ESI)C 20 H 24 The calculated mass of F3NO2 is 367.18 m / z, and the measured mass is 312.00 [M+H-56] + .

[0603] Synthesis of 6-(4-(trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate

[0604] tert-Butyl 6-(4-(trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]heptane-2-carboxylate (287 mg, 0.781 mmol), a stirring bar, and DCM (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (3 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 6-(4-(trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate as a red solid (284 mg). MS (ESI) C 15 H 16 The calculated mass for F3N is 267.12 m / z, and the measured mass is 268.05 [M+H] + .

[0605] Synthesis of 1-(6-(4-(trifluoromethyl)phenylvinyl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0606] By 6-(4-(trifluoromethyl) styryl)-2-azaspiro [3.3] heptane 2,2,2-trifluoroacetate (284mg, 0.745mmol), stirring rod, Et N (377mg, 3.726mmol) and DCM (10mL) are added in 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (135mg, 1.492mmol).Mixture is stirred at room temperature 1 hour, then quenched with water (20mL) and extracted with DCM (3x 30mL).By the organic extract salt water washing merged, use anhydrous Na SO Drying, filter and vacuum concentration. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm) to give 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one as a white solid (65.9 mg). MS (ESI) C 18 H 18 The calculated mass of F3NO is 321.13 m / z, and the measured mass is 322.05 [M+H] + , 1H NMR(300MHz,DMSO-d6)δ7.74-7.57(m,4H),6.64-6.51(m,1H),6.50-6.41(m,1H),6.37-6.20(m,1H),6.13-6.02(m,1H),5.71 -5.61(m,1H),4.29(s,1H),4.14(s,1H),4.00(s,1H),3.85(s,1H),3.09-2.91(m,1H),2.48-2.33(m,2H),2.24-2.06(m,2H). 19 F NMR(282MHz,DMSO-d6)δ-60.80.

[0607] Example 21: Synthesis of (E)-1-(3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidin-1-yl)prop-2-en-1-one

[0608]

[0609] Synthesis route:

[0610]

[0611] Synthesis of diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate

[0612] To a stirred solution of [5-(trifluoromethyl)-1,2-oxazol-3-yl]methyl methanesulfonate (1 g, 4.079 mmol, 1 eq) in toluene was added P(OEt) (2.03 g, 12.237 mmol, 3 eq). The resulting mixture was stirred at 100°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient over 10 minutes; detector, UV 254 nm. This afforded diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (600 mg, 51.22%) as a light yellow oil.

[0613] Synthesis of tert-Butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidine-1-carboxylate

[0614] At -60 ° C, to a stirred solution of [5- (trifluoromethyl) -1,2- oxazol-3-yl] diethyl methylphosphonate (600 mg, 2.089 mmol, 1 equivalent) in THF was added LiHMDS (524.41 mg, 3.133 mmol, 1.5 equivalents) dropwise. The mixture was stirred at -60 ° C for 1 minute. Next, a solution of tert-butyl 3-formylazetidine-1-carboxylate (464.39 mg, 2.507 mmol, 1.2 equivalents) in THF was added dropwise and stirring was continued for 15 minutes at -60 ° C; the reaction mixture was then allowed to warm to room temperature overnight. The reaction was quenched at room temperature by adding saturated NH4Cl (aqueous solution) (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with saturated NaCl (aqueous solution) (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. This afforded tert-butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidine-1-carboxylate (200 mg, 30.07%) as a light yellow oil.

[0615] Synthesis of 1-{3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0616] To a stirred solution of tert-butyl 3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidine-1-carboxylate (100 mg, 0.314 mmol, 1 eq) in DCM was added TFA (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The crude product was used directly in the next step without further purification.

[0617] To a stirred solution of 3-[(E)-2-(azetidine-3-yl)vinyl]-5-(trifluoromethyl)-1,2-oxazole (100 mg, 0.458 mmol, 1 equivalent) in DCM was added TEA (139.14 mg, 1.374 mmol, 3 equivalents) and the mixture was stirred for 10 minutes. Next, acryloyl chloride (62.23 mg, 0.687 mmol, 1.5 equivalents) was added dropwise to the solution at 0 ° C under a nitrogen atmosphere. Under a nitrogen atmosphere, the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3x 10 mL). The combined organic layer was washed with water (2x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC using the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 254 nm) to afford 1-{3-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]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. 1 H NMR (400MHz, chloroform-d) δ7.26 (s, 1H), 6.82 (s, 1H), 6.70–6.48 (m, 2H), 6.36 (dd, J = 17.0, 1.8Hz, 1H), 6. 19(dd,J=17.0,10.3Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),4.43(s,2H),4.06(s,2H),3.56(m,1H).

[0618] Example 22: Synthesis of 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0619]

[0620] Synthesis route:

[0621]

[0622] Synthesis of tert-butyl 6-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0623] 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 stirring bar and THF (10 mL) were added to a 40 mL vial and stirred until homogeneous, then treated with potassium tert-butoxide (176 mg, 1.568 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0-30% EtOAc / PE) to give tert-butyl 6-[-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil. MS (ESI) C 17 H 21 The calculated mass of F3N2O3 is 358.15 m / z, and the measured mass is 304.15 [M-56+H] +

[0624] Synthesis of 3-(2-(2-azaspiro[3.3]hept-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0625] tert-Butyl 6-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl}-2-azaspiro[3.3]heptane-2-carboxylate (370 mg, 1.032 mmol), a stirring bar and DCM (5 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give 3-(2-(2-azaspiro[3.3]heptane-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a white solid (580 mg). MS (ESI) C 14 H 14 The calculated mass of F6N2O3 is 258.24 m / z, and the measured mass is 259.00 [M+H] +

[0626] Synthesis of 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0627] 3-(2-(2-Azaspiro[3.3]hept-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (580 mg, 2.246 mmol), triethylamine (0.79 g, 7.807 mmol), a stirring bar and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.41 g, 4.492 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was purified by preparative-chiral-HPLC using (column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 10 minutes; wavelength: 220 / 254 nm; RT2 (min): 7.102; sample solvent: EtOH--HPLC; injection volume: 0.3 mL) to give 1-{6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one as a white solid. MS (ESI) C 15 H 15 The calculated mass of F3N2O2 is 312.11 m / z, and the measured mass is 313.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.83-7.76(m,1H),6.92-6.78(m,1H),6.54-6.43(m,1H),6.34-6.19(m,1H),6.13-5 .96(m,1H),5.72-5.56(m,1H),4.33-3.83(m,4H),3.15-2.99(m,1H),2.49-2.40(m,2H),2.23-2.08(m,2H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-62.28.

[0628] Example 23: Synthesis of 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0629]

[0630] Synthesis route:

[0631]

[0632] Synthesis of 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0633] 3-(2-(2-Azaspiro[3.3]hept-6-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (580 mg, 2.246 mmol), triethylamine (0.79 g, 7.807 mmol), a stirring bar and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.41 g, 4.492 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was purified by preparative-chiral-HPLC using (column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 10 minutes; wavelength: 220 / 254 nm; RT1 (min): 6.862; sample solvent: EtOH--HPLC; injection volume: 0.3 mL) to give 1-{6-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one as a light yellow solid (4.8 mg). MS (ESI): C 15 H 15 The calculated mass of F3N2O2 is 312.11 m / z, and the measured mass is 313.10 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.52(s,1H),6.39-6.18(m,3H),6.18-6.01(m,1H),5.74- 5.57(m,1H),4.41-3.77(m,4H),3.52(m,1H),2.53-2.34(m,2H),2.23-1.96(m,2H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-62.94.

[0634] Example 24: Synthesis of 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one

[0635]

[0636] Synthesis route:

[0637]

[0638] Synthesis of tert-Butyl 7-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0639] 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 stirring bar and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with potassium tert-butoxide (181 mg, 1.613 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by 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) C 19 H 25 The calculated mass of F3N2O3 is 386.18 m / z, and the measured mass is 331.15 [M-56+H] + .

[0640] Synthesis of 3-(2-(2-azaspiro[3.5]non-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0641] Tert-butyl 7-{2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl}-2-azaspiro[3.5]nonane-2-carboxylate (360 mg, 0.932 mmol), a stirring bar and DCM (5 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give 3-(2-(2-azaspiro[3.5]nonane-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a white solid (520 mg). MS (ESI) C 14 H 14 The calculated mass of F6N2O3 is 258.24 m / z, and the measured mass is 259.00 [M+H] + .

[0642] Synthesis of 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one

[0643] 3-(2-(2-Azaspiro[3.5]non-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (520 mg, 1.353 mmol), triethylamine (685 mg, 6.769 mmol), a stirring 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 room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was purified by preparative HPLC using (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 minutes; wavelength: 254 nm) to give 1-{7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one as a white solid (76.5 mg). MS (ESI) C 17 H 19 The calculated mass of F3N2O2 is 340.14 m / z, and the measured mass is 341.15 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.59(s,1H),6.71-6.60(m,1H),6.48-6.38(m,1H),6.33-6.19(m,1H),6.14-5.97(m,1H),5.64-5 .52(m,1H),3.92-3.52(m,4H),2.21(s,1H),1.96-1.80(m,2H),1.77-1.64(m,2H),1.59-1.38(m,2H),1.31-1.11(m,2H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-63.29.

[0644] Example 25: Synthesis of 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one

[0645]

[0646] Synthesis route:

[0647]

[0648] Synthesis of 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one

[0649] 3-(2-(2-Azaspiro[3.5]non-7-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (520 mg, 1.353 mmol), triethylamine (685 mg, 6.769 mmol), a stirring 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 room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was purified by preparative HPLC using (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 minutes; wavelength: 254 nm) to give 1-{7-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]-2-azaspiro[3.5]non-2-yl}prop-2-en-1-one as a light yellow solid (40.8 mg). MS (ESI) C 17 H 19 The calculated mass of F3N2O2 is 340.14 m / z, and the measured mass is 341.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.59(s,1H),6.73-6.60(m,2H),6.47-6.40(m,1H),6.32-6.20(m,1H),6.08-5.98(m,1H),5.63-5 .53(m,1H),3.89-3.48(m,4H),2.21(s,1H),1.93-1.82(m,2H),1.77-1.64(m,2H),1.57-1.44(m,2H),1.31-1.12(m,2H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-62.93,-62.97,-63.30.

[0650] Example 26: Synthesis of 1-{3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0651]

[0652] Synthesis route:

[0653]

[0654] Synthesis of 3-(2-(azetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate

[0655] tert-Butyl 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (300 mg, 0.943 mmol), a stirring bar, and DCM (5 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with TFA (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give 3-(2-(azetidine-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate as a crude yellow oil (290 mg). MS (ESI) calculated mass for C9H9F3N2O was 218.07 m / z, found 219.10 [M+H] + .

[0656] Synthesis of 1-{3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3-yl]vinyl]azetidin-1-yl}prop-2-en-1-one

[0657] 3-(2-(Azetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2-trifluoroacetate (300 mg, 0.949 mmol), a stirring 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), then cooled to 0 ° C. (ice / water) and acryloyl chloride (172 mg, 1.90 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a crude product, which was further purified by preparative-HPLC using (column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 25% B to 25% B in 13 minutes; 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]vinyl]azetidin-1-yl}prop-2-en-1-one as a yellow solid (6.9 mg). MS (ESI): C12 H 11 The calculated mass of F3N2O2 is 272.08 m / z, and the measured mass is 273.10 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 6.64 (s, 1H), 6.47-6.27 (m, 3H), 6.27-6.15 (m, 1H), 5.76-5.67 (m, 1H), 4.68-4.36 (m, 2H), 4.16-3.87 (m, 3H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-64.05.

[0658] Example 27: Synthesis of (S*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0659]

[0660] Synthesis route:

[0661]

[0662] Synthesis of (S*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0663] 3-[(E)-2-[4-(Trifluoromethyl)phenyl]vinyl]pyrrolidin-3-ol hydrochloride (550 mg, 1.873 mmol), triethylamine (758 mg, 7.492 mmol), a stirring bar and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with a solution of acryloyl chloride (203 mg, 2.248 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by preparative-HPLC (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 27% B to 57% B, 57% B in 7 minutes; wavelength: 254nm; RT1 (min): 5.75) and preparative-chiral-HPLC (column: Lux 5umCellulose-2, 2.12*25cm, 5μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 10% B to 10% in 29 minutes B; wavelength: 220 / 254 nm; RT2 (min): 26.631; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) to give (single stereoisomer, absolute stereochemistry randomly assigned as S)(S*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one (59.8 mg) as a white solid. MS (ESI) C 16 H 16 The calculated mass of F3NO2 is 311.11 and the measured mass is 312.15 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.75-7.62(m,4H),6.82(dd,J=16.0,4.0Hz,1H),6.74-6.47(m,2H),6.23-6.08 (m,1H),5.76-5.59(m,1H),5.45-5.28(m,1H),3.85-3.60(m,2H),3.59-3.37(m,2H),2.21-1.80(m,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.83.

[0664] Example 28: Synthesis of (R*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0665]

[0666] Synthesis route:

[0667]

[0668] Synthesis of tert-butyl 3-hydroxy-3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate

[0669] To a solution of 1-ethynyl-4-(trifluoromethyl)benzene (3.03 g, 17.817 mmol) in THF (35 mL) was added butyl lithium (7.77 mL, 19.436 mmol) at -78°C under nitrogen. After stirring for 30 minutes, a solution of 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 room temperature for 2 hours. The reaction was quenched with NH4Cl and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The obtained 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) C 18 H 20 The calculated mass of F3NO3 is 355.15, and the measured mass is 300.15 [M-56+H] + .

[0670] Synthesis of tert-butyl (E)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0671] 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 room temperature and stirred for 2 hours. EA and saturated aqueous potassium sodium tartrate (Rochelle salt) were added, and the mixture was vigorously stirred for 2 hours. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by silica gel chromatography (EA / PE = 0-40%) to give tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]ethynyl]pyrrolidine-1-carboxylate (2.8 g, 87.01%) as a white solid. MS (ESI) C18 H 22 The calculated mass of F3NO3 is 357.16, and the measured mass is 283.95 [M-56-18+H] + .

[0672] Synthesis of (E)-3-(4-(trifluoromethyl)phenylvinyl)pyrrolidin-3-ol hydrochloride

[0673] To a solution of tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (700 mg, 1.959 mmol) in 1,4-dioxane (15 mL) was added HCl (7 mL, 4 M solution in dioxane). The resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated. The obtained residue was purified by reverse phase chromatography on C18 (ACN / H2O (0.05% TFA) = 5-30%) to give 3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-3-ol hydrochloride (600 mg, crude) as a yellow solid. MS (ESI) C 13 H 15 The calculated mass of ClF3NO is: 293.08, the measured value is: 257.95 [M-HCl+H] + .

[0674] Synthesis of (R*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0675] 3-[(E)-2-[4-(Trifluoromethyl)phenyl]vinyl]pyrrolidin-3-ol hydrochloride (550 mg, 1.873 mmol), triethylamine (758 mg, 7.492 mmol), a stirring bar and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous. The mixture was then treated with a solution of acryloyl chloride (203 mg, 2.248 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by preparative-HPLC (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 27% B to 57% B, 57% B in 7 minutes; wavelength: 254nm; RT1 (min): 5.75) and preparative-chiral-HPLC (column: Lux 5umCellulose-2, 2.12*25cm, 5μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 10% B to 10% B in 29 minutes B; wavelength: 220 / 254 nm; RT1 (min): 22.356; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) to obtain (single stereoisomer, absolute stereochemistry randomly assigned as R)(R*,E)-1-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one (62.8 mg) as a white solid. MS (ESI) C 16 H 16 The calculated mass of F3NO2 is 311.11 and the measured mass is 312.15 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.76-7.60(m,4H),6.82(dd,J=16.0,4.0Hz,1H),6.74-6.47(m,2H),6.22-6.07 (m,1H),5.75-5.59(m,1H),5.43-5.29(m,1H),3.85-3.59(m,2H),3.59-3.37(m,2H),2.20-1.81(m,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.83.

[0676] Example 29: Synthesis of 1-[(3S*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0677]

[0678] Synthesis route:

[0679]

[0680] Synthesis of tert-Butyl 3-Formyl-3-methylpyrrolidine-1-carboxylate

[0681] (COCl)2 (1.063 g, 8.375 mmol), a stirring bar, and DCM (10 mL) were added to a dried and nitrogen-purged 100 mL round-bottom flask and stirred until homogeneous. 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 minutes, a solution of tert-butyl 3-(hydroxymethyl)-3-methoxyazetidine-1-carboxylate (900 mg, 4.180 mmol) in DCM (5 mL) was added dropwise and stirring continued for 30 minutes. Et3N (3.382 g, 33.421 mmol) was added to the mixture, and the resulting mixture was stirred at -70 ° C for 30 minutes, then warmed to room temperature and stirred for 2 hours. 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 Na2SO4, filtered and concentrated in vacuo to give tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate as a light yellow oil (1 g, crude). MS (ESI) C 11 H 19 The calculated mass of NO3 is 213.10 m / z, and the measured mass is 158.15 [M+H-56] + .

[0682] Synthesis of tert-butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate

[0683] tert-Butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (1 g, 4.689 mmol), a stirring 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-methylpropane-2-olate (701 mg, 6.247 mmol). The resulting mixture was stirred at room temperature for 2 hours before being quenched with water and extracted with EA (100 mL x 2). The combined organic layers were 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 afford tert-butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate as a light yellow oil (958 mg, 86.23%). MS(ESI)C 19 H 24 The calculated mass of F3NO2 is 355.18 m / z, and the measured mass is 300.05 [M+H-56] + .

[0684] Synthesis of (E)-3-methyl-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate

[0685] tert-Butyl 3-methyl-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (958 mg, 2.696 mmol), a stirring 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 room temperature for 2 hours and then concentrated in vacuo to afford (E)-3-methyl-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate as a yellow oil (1.26 g, crude, MS (ESI) C 14 H 16 The calculated mass for F3N is 255.12 m / z, and the measured mass is 256.05 [M+H] + )

[0686] Synthesis of 1-[(3S*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0687] (E)-3-Methyl-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.26 g, 3.412 mmol), a stirring 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 Et3N (1.724 g, 17.037 mmol) was added for 2 minutes. Then, a solution of acryloyl chloride (615 mg, 6.795 mmol) in DCM (10 mL) was added dropwise for 5 minutes. The resulting mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with DCM (100 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative 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 minutes; wavelength: 254 nm) to give a racemic product. The racemic product was further separated by SFC (column: CHIRALPAK 1H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 7% B to 7% B in 18 minutes; wavelength: 220 / 254 nm; RT1 (min): 12.588; sample solvent: EtOH--HPLC; injection volume: 0.3 mL) to give (single stereoisomer, absolute stereochemistry randomly assigned as S) 1-[(3S*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one) as a colorless oil (119.4 mg). MS (ESI) C 17 H 18 The calculated mass of F3NO is 309.10 m / z, and the measured mass is 310.15 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.66(m,4H),6.65-6.53(m,3H),6.14(dt,J=16.8,2.8Hz,1H),5.67 (ddd,J=10.3,4.3,2.4Hz,1H),3.71-3.43(m,4H),2.13-1.73(m,2H),1.24(d,J=3.1Hz,3H); 19 F NMR(282MHz,DMSO-d6)δ(ppm):-60.82.

[0688] Example 30: Synthesis of 1-[(3R*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one)

[0689]

[0690] Synthesis route:

[0691]

[0692] Synthesis of 1-[(3R*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one)

[0693] (E)-3-Methyl-3-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.26 g, 3.412 mmol), a stirring 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 Et3N (1.724 g, 17.037 mmol) was added for 2 minutes, followed by a solution of acryloyl chloride (615 mg, 6.795 mmol) in DCM (10 mL) added dropwise for 5 minutes. The resulting mixture was stirred at room temperature for 2 hours, 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 preparative 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 minutes; wavelength: 254 nm; RT1 (min): 6) to give a racemic product. The racemic product was further separated by SFC (column: CHIRALPAK 1H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 7% B to 7% B in 18 minutes; wavelength: 220 / 254 nm; RT2 (min): 15.997; sample solvent: EtOH--HPLC; injection volume: 0.3 mL) to obtain (single stereoisomer, absolute stereochemistry randomly assigned as R) 1-[(3R*)-3-methyl-3-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one) as a colorless oil (128.6 mg). MS (ESI) C 17 H 18The calculated mass of F3NO is 309.10 m / z, and the measured mass is 310.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.66 (m, 4H), 6.65-6.52 (m, 3H), 6.14 (ddd, J = 16.8, 3.2, 2.4Hz, 1H), 5. 67(ddd,J=10.3,4.3,2.5Hz,1H),3.73-3.41(m,4H),2.13-1.74(m,2H),1.24(d,J=3.1Hz,3H); 19 FNMR(282MHz,DMSO-d6)δ(ppm):-60.81.

[0694] Example 31: Synthesis of 1-{3-ethyl-4-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one

[0695]

[0696] Synthesis route:

[0697]

[0698] Synthesis of 1-tert-Butyl-3-ethyl-(3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate

[0699] Ethyl (3R,4R)-1-benzyl-4-ethylpyrrolidine-3-carboxylate (2.5 g, 9.565 mmol), a stirring 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 hour. 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 hours and then concentrated in vacuo. The residue was purified by 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) C 14 H 25 The calculated mass of NO4 is 271.18 m / z, and the measured value is 216.15 [M+H-56] + .

[0700] Synthesis of tert-Butyl (3R,4R)-3-ethyl-4-(hydroxymethyl)pyrrolidine-1-carboxylate

[0701] 1-tert-Butyl-3-ethyl-(3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate (2.5 g, 9.213 mmol), a stirring bar, and THF (40 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous, then treated with 1 M LiAlH4 (11 mL, 11.000 mmol) at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then warmed to room temperature and treated with water (0.9 g) and Na2SO4. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by 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) C 12 H 23 The calculated mass of NO3 is 229.17 m / z, and the measured value is 174.05 [M+H-56] + .

[0702] Synthesis of tert-Butyl (3R,4R)-3-Ethyl-4-Formylpyrrolidine-1-carboxylate

[0703] (COCl) 2 (990 mg, 7.800 mmol), a stirring bar and DCM (15 mL) were added to a 100 mL round-bottom flask and stirred until uniform, then cooled to -78 ° C (dry ice / EtOH) under N2, and DMSO (1.23 g, 15.743 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C (dry ice / EtOH) for 0.5 hours under N2, and then treated dropwise with a solution of (3R, 4R) -3-ethyl -4- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester (900 mg, 3.925 mmol) in DCM (3 mL). The resulting mixture was stirred at -78 ° C (dry ice / EtOH) for 0.5 hours under N2, 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 N2 for 10 minutes, then warmed to room temperature and continued stirring for 2 hours. 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 obtain (3R, 4R)-3-ethyl-4-formylpyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. MS (ESI) C 12 H 21 The calculated mass of NO3 is 227.15 m / z, and the measured value is 172.05 [M+H-56]+ .

[0704] Synthesis of tert-butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidine-1-carboxylate

[0705] 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 stirring 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 hour, then diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% EA / PE) to afford tert-butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) C 20 H 26 The calculated mass of F3NO2 is 369.19 m / z, and the measured mass is 314.05 [M+H-56] + .

[0706] Synthesis of 3-ethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate

[0707] tert-Butyl 3-ethyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidine-1-carboxylate (870 mg, 2.355 mmol), a stirring bar, and DCM (15 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with TFA (5 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give 3-ethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, crude) as a yellow solid. MS (ESI) C 17 H 19 The calculated mass of F6NO is 269.14 m / z, and the measured mass is 270.05 [M+H] + .

[0708] Synthesis of 1-{3-ethyl-4-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one

[0709] 3-Ethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, 3.496 mmol), a stirring bar, DIEA (2.7 g, 20.890 mmol), DCM (28 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with a solution of acryloyl chloride (0.38 g, 4.198 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour 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 minutes; wavelength: 254 nm; RT1 (min): 5.25) to give a 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 minutes; 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]vinyl]pyrrolidin-1-yl}prop-2-en-1-one as an off-white solid. MS (ESI): C 18 H 20 The calculated mass of F3NO is 323.15 m / z, and the measured mass is 324.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.62–7.82(m,2H),7.52(t,J=8.7Hz,2H),6.39–6.88(m,2H),6.13(dt,J=16.8,2.6Hz,1H),5.57–5.84(m,2H),3.62–4.1 3(m,2H),3.40–3.62(m,1H),3.09–3.20(m,1H),2.78–3.05(m,1H),1.79 –2.19(m,1H),1.31–1.55(m,1H),1.09–1.21(m,1H),0.65–1.00(m,3H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.92.

[0710] Example 32: Synthesis of 1-{3-ethyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one

[0711]

[0712] Synthesis route:

[0713]

[0714] Synthesis of 1-{3-ethyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one

[0715] 3-Ethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.34 g, 3.496 mmol), a stirring bar, DIEA (2.7 g, 20.890 mmol), DCM (28 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated dropwise with a solution of acryloyl chloride (0.38 g, 4.198 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour 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 minutes; wavelength: 254 nm; RT1 (min): 5.25) to give a 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 minutes; 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]vinyl]pyrrolidin-1-yl}prop-2-en-1-one as a white solid. MS (ESI): C 18 H 20 The calculated mass of F3NO is 323.15 m / z, and the measured mass is 324.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.60–7.74(m,4H),6.54–6.72(m,2H),6.30–6.51( m,1H),6.15(dd,J=16.8,2.5Hz,1H),5.55–5.80(m,1H),3.70–3.99(m,2H), 3.39–3.49,2.91–3.07(m,1H),3.12–3.27(m,1H),2.55–2.78(m,1H),1.83 –2.13(m,1H),1.41–1.71(m,1H),1.10–1.40(m,1H),0.90(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.85.

[0716] Example 33: Synthesis of (S*)-1-(3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0717]

[0718] Synthesis route:

[0719]

[0720] Synthesis of tert-Butyl 4-(Hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate

[0721] 1-(tert-Butyloxycarbonyl)-4,4-dimethylpyrrolidine-3-carboxylic acid (1 g, 4.110 mmol), a stirring bar and THF (7 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with a solution of borane in THF (1 M, 8.2 mL, 8.200 mmol). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was then quenched with MeOH (15 mL) and stirred for an additional 0.5 hour, then concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% DCM / MeOH) to give tert-butyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate as a colorless oil (853 mg, 90.50%). MS (ESI) C 12 H 23 The calculated mass of NO3 is 229.17 m / z, and the measured value is 174.10 [M+H-56] + .

[0722] Synthesis of tert-Butyl 4-Formyl-3,3-dimethylpyrrolidine-1-carboxylate

[0723] At -70 DEG C under nitrogen atmosphere, to (COCl) 2(941mg, 7.414mmol) in DCM (4mL) solution of DMSO (1158mg, 14.821mmol) in DCM (4mL) was added dropwise. After stirring for 30 minutes, a solution of 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-tert-butyl formate (850mg, 3.707mmol) in DCM (4mL) was added dropwise and continued to stir for 30 minutes. Et3N (3000mg, 29.646mmol) in DCM (4mL) was added to the mixture, and the resulting mixture was stirred at -70 DEG C for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water (20mL) and extracted with DCM (3x 40mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-formyl-3,3-dimethylpyrrolidine-1-carboxylate (825 mg, 97.92%). MS (ESI) C 12 H 21 The calculated mass of NO3 is 227.15 m / z, and the measured value is 172.05 [M+H-56] + .

[0724] Synthesis of tert-Butyl 3,3-Dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0725] 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 stirring 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 hour. The reaction mixture was then quenched with water (20 mL) and extracted with EA (3 x 40 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, 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)phenyl)pyrrolidine-1-carboxylate as a light yellow oil (842 mg, 84.39%). MS (ESI) C 20 H 26 The calculated mass of F3NO2 is 369.19 m / z, and the measured mass is 314.10 [M+H-56] + .

[0726] Synthesis of 3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate

[0727] tert-Butyl 3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (840 mg, 2.274 mmol), a stirring bar and DCM (9 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated in vacuo to give 3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate as a dark yellow oil (1.3 g, crude product). MS (ESI) C 15 H 18 The calculated mass for F3N is 296.14 m / z, and the measured mass is 270.05 [M+H] + .

[0728] Synthesis of (S*)-1-(3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0729] 3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (1.3 g, 3.391 mmol), TEA (1.7 g, 16.800 mmol), a stirring bar and DCM (20 mL) were added to a 50 mL round-bottom flask and stirred until uniform, 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 hour. The reaction mixture was then quenched with water (20 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (5%-50% ACN / 10 mM NH4HCO3 water) to give a crude product, which was further purified by preparative 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 to 70% B, 70% B in 7 minutes; wavelength: 254 nm; RT1 (min): 5.87) to give (single stereoisomer, absolute stereochemistry randomly assigned to S) (S*)-1-(3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one as a colorless oil (83.3 mg, 7.55%). MS (ESI) C 18 H 20The calculated mass of F3NO is 323.15 m / z, and the measured mass is 324.10 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.76-7.64(m,4H),6.68-6.52(m,2H),6.50-6.38(m,1H),6.15(ddd,J=16.8,2.4,1.3Hz,1H),5.67(dt,J=10.3,2.5 Hz,1H),3.77(ddd,J=64.1,11.4,8.0Hz,1H),3.65-3.51(m,1H),3.51-3.29(m,2H),2.71(dd,J=40.9,8.6Hz,1H),1.08(s,3H),0.91(s,3H), 19 F NMR(376MHz,DMSO-d6)δ-60.84.

[0730] Example 34: Synthesis of 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile

[0731]

[0732] Synthesis route:

[0733]

[0734] Synthesis of tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate

[0735] At -70 ° C under a nitrogen atmosphere, to a solution of diisopropylamine (8.3g, 82.024mmol) in THF (20mL) was added a hexane solution of n-butyllithium (2.5M, 33mL, 82.500mmol). After stirring for 30 minutes, a solution of tert-butyl 3-cyanoazetidine-1-formate (5.0g, 27.439mmol) in THF (40mL) was added and continued to stir for 1 hour. 1,2,3-benzotriazole-1-ylmethanol (8.2g, 54.977mmol) was added to the above mixture. The resulting mixture was stirred for another 2 hours at -70 ° C. The reaction mixture was then quenched with water (100mL) and extracted with EA (3x 200mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (5%-50% ACN / 0.05% TFA in water) to give tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (2.0 g, 34.34%) as a white solid. MS (ESI) C 10 H 16The calculated mass of N2O3 is 212.12 m / z, and the measured mass is 157.05 [M+H-56] + .

[0736] Synthesis of tert-Butyl 3-cyano-3-formylazetidine-1-carboxylate

[0737] At -70 ° C under a nitrogen atmosphere, to a solution of (COCl) 2 (1.2g, 9.455mmol) in DCM (5mL) was added dropwise a solution of DMSO (1.5g, 19.199mmol) in DCM (5mL). After stirring for 30 minutes, a solution of tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-formate (1g, 4.711mmol) in DCM (5mL) was added dropwise and continued to stir for 30 minutes. A solution of TEA (3.8g, 37.552mmol) in DCM (5mL) was added to the mixture, and the resulting mixture was stirred at -70 ° C for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water (20mL) and extracted with DCM (3x30mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, 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) C 10 H 14 The calculated mass of N2O3 is 210.10 m / z, and the measured mass is 173.00 [M+H-56+18] + .

[0738] Synthesis of tert-butyl 3-cyano-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate

[0739] 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 stirring 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 hour. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, 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) C 15 H 16 The calculated mass of F3N3O3 is 343.11 m / z, and the measured mass is 288.00 [M+H-56] + .

[0740] Synthesis of 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate

[0741] tert-Butyl 3-cyano-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (147 mg, 0.428 mmol), a stirring bar, and DCM (2 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours 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) C 10 The calculated mass of H8F3N3O is 243.06 m / z, and the measured mass is 244.05 [M+H] +

[0742] Synthesis of 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-3-carbonitrile

[0743] 3-(2-(5-(trifluoromethyl)isoxazole-3-yl)vinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate (200mg, 0.560mmol), TEA (283mg, 2.797mmol), stirring bar and DCM (4mL) are added into 50mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (101mg, 1.116mmol). The gained mixture is stirred at room temperature for 1 hour under nitrogen atmosphere, then quenched with water (20mL) and extracted with DCM (3x30mL).The organic extracts merged are washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (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): C 13 H 10 The calculated mass of F3N3O2 is 297.07 m / z, and the measured mass is 298.00 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.83(s,1H),7.23(d,J=16.0Hz,1H),6.86(d,J=16.1Hz,1H),6.31(dd,J=17.0,10.2Hz,1H),6.16(dd, J=17.0,2.2Hz,1H),5.76(dd,J=10.3,2.2Hz,1H),4.84(d,J=9.1Hz,1H),4.50(dd,J=17.6,9.7Hz,2H),4.22(d,J=10.3Hz,1H), 19 F NMR(376MHz,DMSO-d6)δ-63.32.

[0744] Example 35: Synthesis of (E)-1-(3-methoxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0745]

[0746] Synthesis route:

[0747]

[0748] Synthesis of tert-butyl (E)-3-methoxy-3-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0749] To a solution of tert-butyl 3-hydroxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (700 mg, 1.959 mmol) in DMF (10 mL) at 0°C under nitrogen was added NaH (94 mg, 2.351 mmol, 60%). After stirring for 30 minutes, methyl iodide (334 mg, 2.351 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by silica gel chromatography (EA / PE = 0-25%) to give tert-butyl 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (670 mg, 92.10%) as a colorless oil. MS (ESI) C 19 H 24 The calculated mass of F3NO3 is: 371.17, the measured mass is: 743.25 [2M+H] + .

[0750] Synthesis of (E)-3-methoxy-3-(4-(trifluoromethyl)phenyl)pyrrolidine hydrochloride

[0751] To a solution of tert-butyl 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]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 room temperature for 2 hours. The resulting mixture was concentrated to give 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine hydrochloride (560 mg, crude) as a brown oil. MS (ESI) C 14 H 17 The calculated mass of ClF3NO is 307.10 and the measured mass is 272.15 [M-HCl+H] + .

[0752] Synthesis of (E)-1-(3-methoxy-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0753] To a solution of 3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine hydrochloride (560 mg, 1.820 mmol) in DCM (8 mL) was added triethylamine (736 mg, 7.280 mmol) and acryloyl chloride (165 mg, 1.820 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by preparative 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 minutes; wavelength: 254 nm; RT1 (min): 8.89) to give 1-{3-methoxy-3-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidin-1-yl}prop-2-en-1-one (22.0 mg) as a yellow semisolid. MS (ESI): C 17 H 18 The calculated mass of F3NO2 is 325.13, and the measured mass is 326.05 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.82-7.64(m,4H),6.83-6.73(m,1H),6.67-6.52(m,2H),6.21-6.09(m,1H) ,5.75-5.62(m,1H),3.87-3.50(m,3H),3.47-3.37(m,1H),3.16(d,J=5.7Hz,3H),2.38-1.93(m,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.93.

[0754] Example 36: Synthesis of 1-(3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0755]

[0756] Synthesis route:

[0757]

[0758] Synthesis of 1-tert-butyl-3-ethyl-4-methoxypyrrolidine-1,3-dicarboxylate

[0759] 1-tert-Butyl-3-ethyl-4-hydroxypyrrolidine-1,3-dicarboxylate (1 g, 3.857 mmol), MeI (2.7 g, 19.022 mmol), a stirring bar and DCM (20 mL) were added to a 40 mL vial and stirred until homogeneous, then treated with Ag2O (2.7 g, 11.651 mmol). The resulting mixture was stirred at 40 ° C overnight under a nitrogen atmosphere, then filtered and washed with DCM (mL). The filtrate was washed with brine, dried over anhydrous Na2SO4, 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) C 13 H 23 The calculated mass of NO5 is 273.16 m / z, and the measured mass is 218.15 [M+H-56] + .

[0760] Synthesis of tert-Butyl 3-(Hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate

[0761] 1-tert-Butyl-3-ethyl-4-methoxypyrrolidine-1,3-dicarboxylate (430 mg, 1.573 mmol), a stirring 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 allowed to warm to room temperature and stirred under nitrogen for 2 hours, then quenched with water (142 mg, 7.865 mmol) and anhydrous Na2SO4 and stirred for 20 minutes. 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 light yellow oil (340 mg, 93.44%). MS (ESI) C 11 H 21 The calculated mass of NO4 is 231.15 m / z, and the measured value is 176.10 [M+H-56] + .

[0762] Synthesis of tert-Butyl 3-Formyl-4-methoxypyrrolidine-1-carboxylate

[0763] At -70 ° C under a nitrogen atmosphere, 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). After stirring for 30 minutes, a solution of tert-butyl 3-(hydroxymethyl)-4-methoxypyrrolidine-1-formate (340 mg, 1.470 mmol) in DCM (2 mL) was added dropwise and continued to stir for 30 minutes. A solution of TEA (1190 mg, 11.760 mmol) in DCM (1 mL) was added to the mixture and the resulting mixture was stirred at -70 ° C for 10 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water and extracted with DCM (3x20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl 3-formyl-4-methoxypyrrolidine-1-carboxylate (320 mg, 94.95%) as a dark yellow oil. MS (ESI) C 11 H 19 The calculated mass of NO4 is 229.13 m / z, and the measured value is 174.20 [M+H-56] + .

[0764] Synthesis of tert-Butyl 3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0765] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (320 mg, 1.080 mmol), tert-butyl 3-formyl-4-methoxypyrrolidine-1-carboxylate (297 mg, 1.295 mmol), a stirring 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 hour. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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)phenyl)pyrrolidine-1-carboxylate as a colorless oil (180 mg, 41.02%). MS(ESI)C 19 H 24 The calculated mass of F3NO3 is 371.17 m / z, and the measured mass is 316.10 [M+H-56] + .

[0766] Synthesis of 3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate

[0767] tert-Butyl 3-methoxy-4-(4-(trifluoromethyl)phenylvinyl)pyrrolidine-1-carboxylate (180 mg, 0.485 mmol), a stirring bar and DCM (3 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated in vacuo. The residue was purified by reverse phase chromatography (5%-50% ACN / 0.05% TFA in water) to give 3-methoxy-4-(4-(trifluoromethyl)phenylvinyl)pyrrolidine 2,2,2-trifluoroacetate as a black solid (174 mg, crude). MS (ESI) C 14 H 16 The calculated mass of F3NO is 271.12 m / z, and the measured mass is 272.15 [M+H] + .

[0768] Synthesis of 1-(3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0769] 3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (147 mg, 0.382 mmol), TEA (193 mg, 1.907 mmol), stirring bar and DCM (2 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (69 mg, 0.762 mmol). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere, then quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC using (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 minutes; wavelength: 254 nm; RT1 (min): 5.25) to give 1-(3-methoxy-4-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one as a light yellow oil (15.1 mg). MS (ESI) C 17 H 18 The calculated mass of F3NO2 is 325.13 m / z, and the measured mass is 326.05 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ7.76-7.60(m,4H),6.73-6.51(m,2H),6.46(dd,J=1 6.0,7.9Hz,1H),6.15(dd,J=16.8,2.4Hz,1H),5.73-5.64(m,1H),3.96-3.88 (m,1H),3.88-3.78(m,1H),3.71(dd,J=12.9,5.5Hz,1H),3.67-3.56(m,1H), 3.56-3.47(m,1H),3.46-3.38(m,1H),3.38-3.26(m,2H),3.20-3.00(m,1H), 19 F NMR(376MHz,DMSO-d6)δ-60.85.

[0770] Example 37: Synthesis of 1-acryloyl-3-(4-(trifluoromethyl)phenyl)azetidine-3-carbonitrile

[0771]

[0772] Synthesis route:

[0773]

[0774] Synthesis of tert-butyl 3-cyano-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate

[0775] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (650 mg, 2.194 mmol), tert-butyl 3-cyano-3-formylazetidine-1-carboxylate (554 mg, 2.635 mmol), a stirring 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 for 1 hour under a nitrogen atmosphere. The reaction mixture was then quenched with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, 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)phenyl)azetidine-1-carboxylate (157 g, 20.31%) as a white solid. MS(ESI)C 18 H 19 The calculated mass of F3N2O2 is 352.14 m / z, and the measured mass is 297.05 [M+H] + .

[0776] Synthesis of 3-(4-(trifluoromethyl)phenylvinyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate

[0777] 3-cyano-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (150 mg, 0.426 mmol), a stirring bar and DCM (3 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated in vacuo to give 3-(4-(trifluoromethyl)phenyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate as a light yellow oil (214 mg, crude product). MS (ESI) C 13 H 11 The calculated mass of F3N2 is 252.09 m / z, and the measured mass is 253.00 [M+H] + .

[0778] Synthesis of 1-Acryloyl-3-(4-(Trifluoromethyl)phenyl)azetidine-3-carbonitrile

[0779] 3-(4-(trifluoromethyl)phenyl)azetidine-3-carbonitrile (214 mg, 0.604 mmol), TEA (306 mg, 3.024 mmol), stirring bar and DCM (4 mL) are added into 50 mL round-bottom flask and stirred until homogeneous, then processed with acryloyl chloride (109 mg, 1.204 mmol). The gained mixture is stirred at room temperature for 1 hour under a nitrogen atmosphere, then quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The organic extracts merged are washed with salt water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC using (column: Xselect CSH C18 OBD column 30*150mm 5μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 30% B to 60% B, 60% B in 10 minutes; wavelength: 254nm; RT1 (min): 8.25) to give 1-acryloyl-3-(4-(trifluoromethyl)phenyl)azetidine-3-carbonitrile as a white solid (39.6mg). MS (ESI) C 16 H 13 The calculated mass of F3N2O is 306.10 m / z, and the measured mass is 307.05 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ7.85-7.68(m,4H),7.02-6.84(m,2H),6.39-6.25(m,1H),6.22-6.12(m,1H ),5.81-5.70(m,1H),4.89-4.76(m,1H),4.61-4.51(m,1H),4.49-4.39(m,1H),4.33-4.22(m,1H), 19 F NMR(376MHz,DMSO-d6)δ-60.99.

[0780] Example 38: Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0781]

[0782] Synthesis route:

[0783]

[0784] Synthesis of tert-Butyl 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate

[0785] 1-iodo-4-(trifluoromethyl)benzene (650 mg, 2.390 mmol), a stirring bar, TEA (10 mL) and tert-butyl 3-ethynylpyrrolidine-1-carboxylate (466 mg, 2.387 mmol) were added to a 25 mL round-bottom flask dried and purged with nitrogen and stirred until uniform. The mixture was then treated with CuI (91 mg, 0.478 mmol) and Pd(PPh 3 ) 2 Cl 2 (335 mg, 0.477 mmol) in batches at room temperature. The resulting mixture was stirred at 80 ° C for 15 hours under an N 2 atmosphere and cooled to room temperature. It was then quenched with water and extracted with DCM (10 mL x 3). The combined organic layer was 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) C 18 H 20 The calculated mass of F3NO2 is 339.00 m / z, and the measured mass is 325.15 [M-56+CH3CN] + .

[0786] Synthesis of 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate

[0787] Tert-butyl 3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrrolidine-1-carboxylate (640 mg, 1.886 mmol), a stirring 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 hour and then concentrated in vacuo to afford 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (600 mg, crude) as a yellow oil. MS (ESI) C 13 H 12 The calculated mass for F3N is 239.00 m / z, and the measured mass is 240.15 [M+H] + .

[0788] Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0789] 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (500 mg, 2.090 mmol), a stirring 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 room temperature. The resulting mixture was stirred at 0 ° C for 3 hours and then quenched with water. The resulting mixture was extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative-HPLC (column: XBridge Prep PhenylOBD 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 minutes; 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 further purified by preparative-chiral-HPLC (column: CHIRALPAK IA-3, 4.6*50 mm, 3 μm; mobile phase A: hexane (0.1% DEA): EtOH=80:20; flow rate: 1 mL / min; gradient: 0% B to 0% B; injection volume: 5 ul mL) to give 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one (209.1 mg) as a white solid. MS (ESI) C 16 H 14The calculated mass of F3NO is 293.00 m / z, and the measured mass is 294.00 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.77-7.68(m,2H),7.66-7.59(m,2H),6.66-6.52(m,1H),6.23-6.09(m,1H ),5.75-5.63(m,1H),4.00-3.52(m,3H),3.52–3.31(m,2H),2.37-2.18(m,1H),2.14-1.88(m,1H); 19 F NMR(376MHz,DMSO-d6)δ-61.30.

[0790] Example 39: Synthesis of 1-((3S*,4S*)-3-methyl-4-((E)-4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0791]

[0792] Synthesis route:

[0793]

[0794] Synthesis of 1-((3S*,4S*)-3-methyl-4-((E)-4-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0795] To a solution of 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]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 room temperature for 1.5 hours. The reaction was quenched with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by preparative-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 minutes; wavelength: 254 nm) and preparative-chiral-HPLC (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 18 mL / min; gradient: 30% B to 30% B in 13 minutes B; wavelength: 220 / 254 nm; RT2 (min): 10.438; sample solvent: EtOH--HPLC; injection volume: 0.5 mL) to obtain (single stereoisomer, absolute stereochemistry randomly assigned as S,S) 1-[(3S*,4S*)-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one (55.5 mg) as a white solid. MS (ESI) C 17 H 18 The calculated mass of F3NO is 309.13, and the measured mass is 310.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.74-7.59(m,4H),6.69-6.53(m,2H),6.49-6.36(m,1H),6.15(dd,J=16.8,2.5Hz,1H),5.71-5.63(m,1H),3.9 6-3.86(m,1H),3.85-3.72(m,1H),3.49-3.39(m,1H),3.28-3.10(m,1H),2.98-2.84(m,1H),2.19-1.96(m,1H),1.02(d,J=6.5Hz,3H); 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.84.

[0796] Example 40: Synthesis of 1-[(3R*,4R*)-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0797]

[0798] Synthesis route:

[0799]

[0800] Synthesis of tert-Butyl 3-Formyl-4-methylpyrrolidine-1-carboxylate

[0801] To a solution of oxalyl chloride (1.05 g, 8.284 mmol) in DCM (10 mL) was added a solution of DMSO (1.29 g, 16.568 mmol) in DCM (3 mL) at -70 ° C. After stirring for 30 minutes, a solution of 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 hour, a solution of triethylamine (3.35 g, 33.136 mmol) in DCM (3 mL) was added. The resulting mixture was stirred at -70 ° C for 10 minutes and warmed to room temperature for 2 hours. The reaction was quenched with H2O 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 product) as a yellow oil. MS(ESI)C 11 H 19 The calculated mass of NO3 is 213.14 and the measured value is 158.00 [M-56+H] + .

[0802] Synthesis of tert-butyl (E)-3-methyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0803] 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) at 0°C was added t-BuOK (670 mg, 5.978 mmol). After stirring for 10 minutes, the resulting mixture was warmed to room temperature for 1 hour. The reaction was quenched with H2O and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by silica gel chromatography (EA / PE = 0-15%) to give tert-butyl 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine-1-carboxylate (1.04 g, 73.42%) as a yellow oil. MS (ESI) C 19 H 24 The calculated mass of F3NO2 is 355.18, and the measured mass is 300.05 [M-56+H] + .

[0804] Synthesis of (E)-3-methyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine hydrochloride

[0805] To a solution of tert-butyl 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]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 room temperature for 1 hour. The resulting mixture was concentrated to give 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]pyrrolidine hydrochloride (800 mg, crude product). MS (ESI): C 14 H 17 The calculated mass of ClF3N is 291.10 and the measured mass is 256.10 [M-HCl+H] + .

[0806] Synthesis of 1-[(3R*,4R*)-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one

[0807] To a solution of 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]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 room temperature for 1.5 hours. The reaction was quenched with H2O and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by preparative-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 minutes; wavelength: 254 nm) and preparative-chiral-HPLC (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 18 mL / min; gradient: 30% B to 30% B in 13 minutes. B; wavelength: 220 / 254 nm; RT1 (min): 9.179; sample solvent: EtOH--HPLC; injection volume: 0.5 mL) to obtain (single stereoisomer, absolute stereochemistry randomly assigned as R,R) 1-[(3R*,4R*)-3-methyl-4-{2-[4-(trifluoromethyl)phenyl]vinyl}pyrrolidin-1-yl]prop-2-en-1-one (54.8 mg) as a white solid. MS (ESI) C 17 H 18 The calculated mass of F3NO is 309.13, and the measured mass is 310.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.77-7.58(m,4H),6.73-6.53(m,2H),6.50-6.34(m,1H),6.15(dd,J=16.7,2.5Hz,1H),5.73-5.59(m,1H),3.9 8-3.86(m,1H),3.84-3.71(m,1H),3.48-3.40(m,1H),3.28-3.11(m,1H),3.00-2.85(m,1H),2.22-1.94(m,1H),1.02(d,J=6.5Hz,3H); 19 F NMR(376MHz,DMSO-d6)δ(ppm):-60.85.

[0808] Example 41: Synthesis of (S*,Z)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0809]

[0810] Synthesis route:

[0811]

[0812] Synthesis of diethyl [3-(trifluoromethyl)phenyl]methylphosphonate

[0813] 1-(Bromomethyl)-3-(trifluoromethyl)benzene (1 g, 4.183 mmol), a stirring 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 room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography (5%-70% CH3CN / 10 mM NH4HCO3 water) to give diethyl [3-(trifluoromethyl)phenyl]methylphosphonate as a light yellow oil. MS (ESI) C 12 H 16 The calculated mass of F3O3P is 296.08 m / z, and the measured mass is 297.10 [M+H] + .

[0814] Synthesis of tert-Butyl 3-(3-(Trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0815] Diethyl [3-(trifluoromethyl)phenyl]methylphosphonate (400 mg, 1.350 mmol), a stirring 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, then treated with t-BuOK (228 mg, 2.032 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour 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)phenyl)pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) C 17 H 20 The calculated mass of F3NO2 is 327.14 m / z, and the measured mass is 328.14 [M+H] + .

[0816] Synthesis of 3-(3-(trifluoromethyl)phenylvinyl)pyrrolidine 2,2,2-trifluoroacetate

[0817] Tert-butyl 3-(3-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (500 mg, 1.527 mmol), a stirring bar, and DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with TFA (2 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to afford 3-(3-(trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate as a yellow oil (600 mg, crude). MS (ESI) C 13 H 14 The calculated mass of F3N is 241.1 m / z, and the measured mass is 242.05 [M+H] + .

[0818] Synthesis of (S*,Z)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0819] 3-(3-(Trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol) and a stirring bar were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 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.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]vinyl}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 using (column: CHIRALPAK AS-H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 minutes; wavelength: 220 / 254 nm; RT1 (min): 9.056; and a second purification run (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 11.5 minutes B; wavelength: 220 / 254 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) was further purified to give (as a single stereoisomer, the absolute stereochemistry was arbitrarily assigned as S)(S*,Z)-1-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one) as a light yellow oil (3.2 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ7.69–7.55(m,4H),6.65–6.54(m,2H),6.18–6.10(m,1H),5.79–5.62(m,2H ),3.90–3.43(m,3H),3.29–3.09(m,1H),2.72–2.51(m,1H),2.34–1.95(m,1H),1.88–1.69(m,1H)). 19 F NMR(376MHz,DMSO-d6)δ-61.13.

[0820] Example 42: Synthesis of (R*,Z)-1-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0821]

[0822] Synthesis route:

[0823]

[0824] Synthesis of (R*,Z)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0825] 3-(3-(Trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol) and a stirring bar were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 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.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]vinyl}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 using (column: CHIRALPAK AS-H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 minutes; wavelength: 220 / 254 nm; 12.48; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) to give (as a single stereoisomer, the absolute stereochemistry was randomly assigned as R)(R*,Z)-1-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one) as a light yellow oil (8.2 mg). MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.70-7.59(m,4H),6.65-6.54(m,2H),6.17-6.11(m,1H),5.8-5.63(m,2H),3.92-3.82(m, 1H),3.77-3.67(m,1H),3.64-3.49(m,1H),3.22-3.10(m,1H),2.20-1.97(m,1H),1.92-1.67(m,1H),1.24(s,1H). 19F NMR(376MHz,DMSO-d6)δ-61.13.

[0826] Example 43: Synthesis of (R*,E)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0827]

[0828] Synthesis route:

[0829]

[0830] Synthesis of (R*,E)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0831] 3-(3-(Trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol) and a stirring bar were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 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.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]vinyl}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 using (column: CHIRALPAK AS-H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 minutes; wavelength: 220 / 254 nm; RT3 (min): 15.095; sample solvent: EtOH--HPLC; injection volume: 0.4 mL) to give (single stereoisomer, absolute configuration randomly assigned as R)(R*,E)-1-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one) as a light yellow oil. MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.81-7.72(m,2H),7.60-7.53(m,2H),6.69-6.48(m,3H),6.19-6.10(m,1H),5.71-5.65(m,1H),3.86-3 .81(m,1H),3.79-3.66(m,1H),3.63-3.52(m,1H),3.4-3.15(m,1H),3.13-2.93(m,1H),2.20-2.02(m,1H),1.94-1.74(m,1H)).19 F NMR(376MHz,DMSO-d6)δ-61.13.

[0832] Example 44: Synthesis of (S*,E)-1-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)prop-2-en-1-one

[0833]

[0834] Synthesis route:

[0835]

[0836] Synthesis of (S*,E)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one

[0837] 3-(3-(Trifluoromethyl)phenyl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol) and a stirring bar were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (0.24 g, 2.652 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM (50 mL x 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.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 minutes; wavelength: 254 nm; RT1 (min): 6) to give 1-[3-{2-[3-(trifluoromethyl)phenyl]vinyl}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 using (column: CHIRALPAK AS-H, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 16 minutes; 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: hexane (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 15% B to 15% B in 11.5 minutes. B; wavelength: 220 / 254 nm; RT2 (min): 10.22; sample solvent: EtOH--HPLC; injection volume: 0.5 mL) was further purified to obtain (single stereoisomer, absolute configuration randomly designated as S)(S*,E)-1-(3-(3-(trifluoromethyl)phenylvinyl)pyrrolidin-1-yl)prop-2-en-1-one) as a light yellow oil. MS (ESI) C 16 H 16 The calculated mass of F3NO is 295.10 m / z, and the measured mass is 296.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.80–7.72(m,2H),7.60–7.54(m,2H),6.69–6.45(m,3H),6.19–6.11(m,1H),5.69–5 .66(m,1H),3.87–3.48(m,3H),3.39–3.17(m,1H),3.11–2.95(m,1H),2.19–2.01(m,1H),1.91–1.71(m,1H)). 19 F NMR(376MHz,DMSO-d6)δ-61.13.

[0838] Example 45: Synthesis of (E)-1-(3-(3-ethynyl-4-(trifluoromethyl)phenyl)azetidin-1-yl)prop-2-en-1-one

[0839]

[0840] Synthesis route:

[0841]

[0842] Synthesis of (3-bromo-4-(trifluoromethyl)phenyl)methanol

[0843] 3-Bromo-4-(trifluoromethyl)benzoic acid (4 g, 14.869 mmol), a stirring bar and a solution of BH3 in THF (40 mL) were added to a 100 mL round-bottom flask ...

Claims

1. A compound of formula (I), or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof: in: Bond b is a double bond or a triple bond; R 1 Selected from H, C 1-3 Alkyl, morpholin-4-yl and -CH2N(C 1-3 Alkyl)2; When bond b is a triple bond, R 1a is absent; when bond b is a double bond, R 1a is H; R 2 Selected from H, F, -OH, C 1-3 Alkyl, -OC 1-3 alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl; R 3 Selected from H and C 1-3 Alkyl; and When bond b is a triple bond, R 8 is absent; when bond b is a double bond, R 8 Selected from H, F, CN and C 1-3 Alkyl; and i) where the key a, X 1 , X 2 , R 4 , R 5 , R 6 , A and Ar are as follows: Bond a is a double bond or a triple bond; X 1 is absent or selected from O, CH(OH), CH(OCH3), CH2, CH2CH2, CH(CH3) and C(CH3)2, and R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; or X 1 and R 4 Together with the carbon to which they are attached they form a C4-C6 cycloalkylene group; X 2 For X 2a And X 2a is C; When bond a is a triple bond, R 5 is absent; or when bond a is a double bond, R 5 is selected from H, F and C1-C3 alkyl; When bond a is a triple bond, R 6 is absent; or when bond a is a double bond, R 6 is selected from H, F and C1-C3 alkyl; A is absent or selected from O, CH2, CH2CH2, CH(OH), CH(OCH3), C(CH3)2 and CH(CH3); and Ar is aryl or heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 R 9 group substitution; or ii) where the key a, X 1 , X 2 , R 4 , R 5 , R 6 , A and Ar together form: and X 2 For X 2a And X 2a C; R 4 and R 6 Together they form -(CH2) m -; m is 0, 1 or 2; X 1 is absent or selected from CH2, CH2CH2, CH(CH3), O, CH2O and OCH2; R 5 is selected from H, F and C1-C3 alkyl; A is absent or selected from O, CH2, CH2CH2 and CH(CH3); and Ar is aryl or heteroaryl, each of which is optionally replaced by 1, 2, 3 or 4 R 9 group substitution; or iii) where the bonds a and X 1 , X 2 , R 4 , R 5 , R 6 , A and Ar together form: and X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2b And X 2b N; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; R 5 Together with Ar and R 6 and A is absent; or iv) where the key a, X 1 , X 2 , R 4 , R 5 , R 6 , A and Ar together form: and X 1 is absent or selected from O, CH2, CH2CH2 and CH(CH3); X 2 For X 2c And X 2c N or CR 6 , and R 6 is selected from H, F and C1-C3 alkyl; R 4 Selected from H, C1-C4 alkyl, cyclopropyl, F, Cl, -OH, -OC 1-3 Alkyl, CN and NHR 7 , and R 7 is selected from H and C1-C3 alkyl; A is absent; and R 5 Together with Ar Where X 3 is O, NH, N(C1-C3 alkyl), and Ar 1 is a fused arylene or fused heteroarylene ring, wherein Ar 1 The ring is optionally substituted with 1, 2, 3 or 4 R 9 Group substitution; and Each R 9 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy and CN; and Provided that the compound is not 1-[4-[(1E)-2-(2,6-dimethylphenyl)vinyl]-1-piperidinyl]-2-propen-1-one.

2. The compound according to claim 1, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein bond b is a double bond and R 1a For H.

3. The compound according to claim 1, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein bond b is a triple bond and R 1a and R 8 Does not exist.

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

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

6. The compound according to any one of claims 1 to 3, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 1 Selected from H and Me.

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

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

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

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

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

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

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

14. The compound according to any one of claims 1 to 6, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 2 is unsubstituted heteroaryl (in some embodiments, pyrazolyl) or substituted heteroaryl (in some embodiments, pyrazolyl).

15. The compound according to any one of claims 1 to 6, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 2 is H, methyl, ethyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), or unsubstituted heteroaryl (in some embodiments, pyrazolyl).

16. The compound according to any one of claims 1 to 15, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 3 For H.

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

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

19. A compound according to any one of claims 1, 2 and 4-17, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein bond b is a double bond and R 8 For F.

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

21. The compound according to claim 20, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 is absent, CH2, CH(OH) or C(CH3)2.

22. The compound according to claim 20 or 21, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 Does not exist.

23. The compound according to claim 20 or 21, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 For CH2.

24. The compound according to claim 1, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, according to the following formula:

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

26. A compound according to any one of claims 20 to 24, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 4 It is a C1-C4 alkyl (methyl).

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

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

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

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

31. The compound according to claim 20, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 and R 4 Together with the carbon to which they are attached they form a C4-C6 cycloalkylene group.

32. The compound according to claim 20 or 31, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 and R 4 Together with the carbon to which they are attached, they form a C4 cycloalkylene or a C6 cycloalkylene.

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

34. A compound according to any one of claims 20 to 33, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 5 and R 6 Each is H.

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

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

37. A compound according to any one of claims 20 to 32, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein bond a is a triple bond and R 5 and R 6 Does not exist.

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

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

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

41. A compound according to any one of claims 38 to 40, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 Does not exist.

42. The compound according to claim 38, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein m is 0 and X 1 Not for non-existence.

43. A compound according to any one of claims 38 to 40 and 42, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein X 1 It is CH2, CH2CH2, CH(CH3), O, CH2O or OCH2.

44. A compound according to any one of claims 38 to 43, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein R 5 For H.

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

46. ​​A compound according to any one of claims 20-37, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein A is selected from CH2, CH(OH), CH(OCH3) and C(CH3)2.

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

48. A compound according to any one of claims 20 to 46, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein Ar is a heteroaryl (preferably an oxazolyl, imidazolyl or pyridyl) optionally substituted by 1, 2, 3 or 4 R 9 Group substitution (in some embodiments, the heteroaryl group is optionally substituted with 1 R 9 replace).

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

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

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

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

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

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

55. A compound according to any one of claims 51-54, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein Ar 1 is benzo or pyrido, which is optionally substituted by 1, 2, 3 or 4 R 9 Group substitution.

56. A compound according to any one of claims 1 to 55, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein each R 9 independently selected from C1-C6 alkyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl and C1-C6 alkoxy; or each R 9 Independently selected from methyl, ethynyl, F, CF3 and methoxy.

57. A compound according to any one of claims 1 to 56, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein there are 1 or 2 R 9 and they are selected independently.

58. A compound according to any one of claims 1 to 57, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, wherein one R 9 It is CF3.

59. A compound according to any one of claims 1 to 58, or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof, wherein for 60. The compound according to claim 1, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, which is selected from the compounds in Table 1.

61. A compound according to claim 1, or a stereoisomer and / or a pharmaceutically acceptable salt and / or a solvate thereof, selected from the following:

62. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to 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. 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 claims 1-61 or a stereoisomer and / or a pharmaceutically acceptable salt and / or solvate thereof; or a pharmaceutical composition according to claim 62.

64. The method of claim 63, wherein the cancer is selected from 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, digestive tract / gastrointestinal cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye cancer, or cancer of the eye, rectum, colorectum, cervix, oral cavity, benign and malignant tumors, stomach, uterine corpus, testicular cancer, kidney, larynx, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell and squamous cell carcinomas, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, mouth / throat cancer, esophageal cancer, laryngeal cancer, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

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

66. The method according to any one of claims 63-65, wherein the method further comprises the simultaneous or sequential administration of 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 One or more additional therapies including a KRAS G12C and / or G12D inhibitor, or The one or more KRAS G12C and / or G12D inhibitors are sotolacib or adagraciib.

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

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

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