TW202328119A - Azole compounds - Google Patents

Abstract

Compounds of Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including autoimmune diseases, inflammatory conditions and/or cancers.

Description

Azole compound

This application relates to compounds that are TEAD inhibitors and methods of using the same to treat conditions such as autoimmune disorders, inflammatory conditions, and cancer.

illustrate

Transcriptional enhanced associate domain (TEAD) transcription factor is a key component of Hippo signaling pathway. Human TEAD proteins include four paralogous transcription factors, each with an N-terminal TEA domain, a DNA-binding domain, a proline-rich region, and a C-terminal YAP/TAZ-binding domain. TEAD proteins have been implicated in playing a role in development, cell proliferation, regeneration, and tissue homeostasis.

Some embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents, Excipients, or combinations thereof.

Some embodiments described herein pertain to a method for treating the disorders, conditions, and/or diseases described herein, which may comprise administering to a subject suffering from the disorders, conditions, and/or diseases described herein An effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) salt) pharmaceutical composition. Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of a disorder, condition, and/or disease described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof) for use in the treatment of the disorders, conditions, and/or diseases described herein. In some embodiments, the disorder, condition, and/or disease may be selected from autoimmune disorders, inflammatory conditions, and cancer.

Some embodiments described herein relate to a method for inhibiting the replication of a malignant growth or tumor, which may comprise combining the growth or the tumor with an effective amount of a compound described herein (such as a compound of formula (I) or pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is caused by Caused by said cancer. Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of malignant growths or tumors caused by the cancers described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof), for inhibiting the replication of malignant growth or tumor, wherein the malignant growth or the tumor is caused by the cancer described herein.

Some embodiments described herein pertain to a method for treating a cancer described herein, which may comprise administering to a subject having a cancer described herein a malignant growth or tumor with an effective amount of a compound described herein (e.g. compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer as described herein, which may include contacting a malignant growth or tumor, wherein the malignant growth or the tumor is caused by Caused by the cancers described herein. Yet other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) for treating a cancer described herein or comprising an effective amount of A pharmaceutical composition of a compound described herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may include contacting a malignant growth or tumor, wherein the malignant growth or the tumor is caused by a cancer described herein cause.

Some embodiments described herein relate to a method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid incorporation into TEAD in a cell, which may include administering to cancer cells from a cancer described herein Providing an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) salt) of pharmaceutical composition. Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof), which is used for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD.

Some embodiments described herein relate to a method for treating cancer described herein, which may include using an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g. a compound of formula (I) or a pharmaceutically acceptable salt thereof) inhibits YAP/TAZ-TEAD protein-protein interaction and/or inhibits lipid binding to TEAD . Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating the cancers described herein by inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD In the use. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of a compound of I) or a pharmaceutically acceptable salt thereof) for treating cancers described herein by inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD.

definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If a term in this article has multiple definitions, unless otherwise stated, the definition in this section prevails.

Whenever a group is described as being "optionally substituted," that group can be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" groups may be individually and independently selected from the following Group Substitution: Deuterium, Alkyl, Alkenyl, Alkynyl, Cycloalkyl, Cycloalkenyl, Aryl, Heteroaryl, Heterocyclyl, Aryl(Alkyl), Cycloalkyl(Alkyl), Hetero Aryl (alkyl), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thiamine Formyl, N-thiamine formyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, nitro, secondary Sulfonyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amine, disubstituted amine, and amine (C ₁ -C ₆ alkane base).

As used herein, "a" and "b" in "C _a to C _b " are integers which refer to the number of carbon atoms in the group. Indicated groups may be inclusive and contain "a" to "b" carbon atoms. Thus, "C ₁ to C ₄ alkyl" refers to all alkyl groups having 1 to 4 carbons, ie CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH -, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )-, and (CH ₃ ) ₃ C-. If "a" and "b" are not specified, the broadest range described in these definitions is assumed.

As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, secondary butyl, tertiary butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have from 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as "1 to 30" refers to each integer in the given range; e.g., "1 to 30 carbon atoms" means means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers the occurrence of the term "alkyl" without specifying a numerical range). The alkyl group can also be a medium size alkyl group having 1 to 12 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups can be substituted or unsubstituted.

The term "alkenyl" as used herein refers to a monovalent straight or branched chain group of two to twenty carbon atoms containing a carbon double bond(s), including but not limited to 1-propenyl, 2 -propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups can be unsubstituted or substituted.

The term "alkynyl" as used herein refers to a monovalent straight chain or branched chain group of two to twenty carbon atoms containing double carbon bond(s), including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to a fully saturated (no double or double bond) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro manner. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged cycloalkyl" refers to a compound in which the cycloalkyl contains a linkage connecting one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not connected by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-onyl, and tetrahydronaphthyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl ), and norbornyl (norbornanyl); and examples of spirocycloalkyl include spiro[3.3]heptane and spiro[4.5]decane.

As used herein, "cycloalkenyl" means a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if there is more than one double bond, the double bond cannot form A fully delocalized π-electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). For example, a cycloalkenyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro manner. Cycloalkenyl groups can be unsubstituted or substituted.

As used herein, "aryl" means a carbocyclic (full carbon) monocyclic or polycyclic aromatic ring system (including a fused ring system in which two carbocyclic rings share a bond) which is present in all All rings have fully delocalized π-electron systems. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g. 1, 2, or 3 heteroatoms), that is, elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), such as Nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atom and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms atom and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furan, thiophene, benzothiophene, thiophene, , pyrrole, Azole, benzo Azole, 1,2,3- Oxadiazole, 1,2,4- Oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, iso azoles, benziso Azole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridine , pyrimidine, pyrimidine , purine, pteridine, quinoline, isoquinoline, quinazoline, quinoline phylloline, phylloline, and three . Heteroaryl groups can be substituted or unsubstituted.

As used herein, "heterocyclyl" refers to three, four, five, six, seven, eight, nine, ten to up to 18 membered monocyclic, bicyclic, and tricyclic ring systems in which the carbon atoms are From 1 to 5 heteroatoms together form the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned in this manner, however, fully delocalized π-electron systems do not occur in all rings. Heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. The heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities such that the definition includes pendant oxygen systems as well as thio systems such as lactamides, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged heterocyclyl" refers to a compound in which the heterocyclyl contains a linkage connecting one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not connected by a bridge. A heterocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogen in the heterocyclyl group may be quaternary ammonium. A heterocyclyl group can be unsubstituted or substituted. Examples of such "heterocyclyl" include, but are not limited to, 1,3-dioxin, 1,3-di Alkane, 1,4-bis Alkane, 1,2-dioxolane (1,2-dioxolane), 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiolane Hexane (1,3-oxathiane), 1,4-oxathione (1,4-oxathiin), 1,3-oxathiolane (1,3-oxathiolane), 1,3 -Dithiolene (1,3-dithiole), 1,3-dithiolane (1,3-dithiolane), 1,4-oxathiolane, tetrahydro-1,4 - Thiothia , 2H-1,2- , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopane , hydantoin, dihydrouracil, three Alkane, hexahydro-1,3,5-tri , imidazoline, imidazolidine, iso oxazoline, iso Azolidine, oxazoline, Azolidine, Pazolidone, thiazoline, thiazolidine, morphine, oxygen , piperidine N-oxide, piperidine, piperidine , pyrrolidine, nitrogen (azepane), pyrrolidone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, sulfur phylloline, sulfur Phylinoxine, Sulfur Phenylphenone, and its benzo-fused analogues (such as benzimidazolidinone, tetrahydroquinoline, and/or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-di Azaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

As used herein, "cycloalkyl (alkyl)" refers to a cycloalkyl group as a substituent linked via a lower alkylene group. The lower alkylene and cycloalkyl of cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropyl(alkyl), cyclobutyl(alkyl), cyclopentyl(alkyl), and cyclohexyl(alkyl).

As used herein, "aryl(alkyl)" refers to an aryl group attached as a substituent through a lower alkylene group. The lower alkylene and aryl groups of aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, "heteroaryl (alkyl)" refers to a heteroaryl group attached as a substituent through a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, iso Azolylalkyl, and imidazolylalkyl, and benzofused analogs thereof.

"Heterocyclyl (alkyl)" refers to a heterocyclic group linked via a lower alkylene group as a substituent. The lower alkylene and heterocyclyl groups of heterocyclyl (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl (methyl) and 1,3-thiazinan-4-yl (methyl) (1,3-thiazinan-4-yl (methyl)).

As used herein, a "lower alkylene group" is a straight-chain _-CH2 -tethering group that forms a bond to connect molecular fragments via its terminal carbon atoms. Examples _{include ,} but _are not limited to, methylene ( _-CH2- ), ethylenyl ( _-CH2CH2- ), propylenyl ( _-CH2CH2CH2- ), and butylene ( _{-CH2CH 2CH2CH2- ) .} A lower alkylene group can be obtained by replacing one or more hydrogens of the lower alkylene group and/or by replacing two hydrogens on the same carbon with a cycloalkyl group (for example, ) to replace.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, "alkoxy" refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl as defined herein radical, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy group, tertiary butoxy, phenoxy, and benzyloxy. Alkoxy groups can be substituted or unsubstituted.

As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl) attached as a substituent through a carbonyl group , heteroaryl (alkyl), and heterocyclyl (alkyl). Examples include formyl, acetyl, propionyl, benzyl, and acryl. Acyl groups can be substituted or unsubstituted.

"cyano" refers to a "-CN" group.

The term "halogen atom" or "halogen" as used herein means any radioactive stable atom in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine, and iodine.

"thiocarbonyl" refers to a "-C(=S)R" group, where R may be the same as defined for O-carboxy. Thiocarbonyl groups can be substituted or unsubstituted.

"O-carbamyl" refers to the "-OC(=O)N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl). An O-aminoformyl group can be substituted or unsubstituted.

"N-carbamyl" refers to the "ROC(=O)N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The N-aminoformyl group can be substituted or unsubstituted.

"O-thiocarbamyl (O-thiocarbamyl)" refers to the group "-OC(=S)-N( _RA R _B )", wherein R _A and R _B can be independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heteroaryl Cyclic (alkyl). The O-thiocarbamoyl group can be substituted or unsubstituted.

"N-thiocarbamyl" refers to the group "ROC(=S)N( _RA )-", wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkyne radical, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl base). The N-thiocarbamoyl group can be substituted or unsubstituted.

"C-amido" refers to a "-C(=O)N( _RA R _B )" group, wherein R _A and R _B can be independently hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl( alkyl). A C-amido group can be substituted or unsubstituted.

"N-amido" refers to the group "RC(=O)N( _RA )-", wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) . N-amido groups can be substituted or unsubstituted.

"S-sulfonamido (S-sulfonamido)" refers to the "-SO ₂ N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The S-sulfonylamino group can be substituted or unsubstituted.

"N-sulfonamido (N-sulfonamido)" refers to the "RSO ₂ N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane radical, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-sulfonylamino group can be substituted or unsubstituted.

The "O-carboxy" group refers to the "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic radical, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

The term "C-carboxy" refers to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy. C-carboxy may be substituted or unsubstituted.

"Nitro" refers to a -NO ₂ "group.

A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, Heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A sulfenyl group can be substituted or unsubstituted.

"Sulfinyl" refers to a "-S(=O)-R" group, where R may be the same as defined for sulfenyl. A sulfinyl group can be substituted or unsubstituted.

"Sulfonyl" refers to a "SO ₂ R" group, wherein R may be the same as defined for sulfenyl. A sulfonyl group can be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups can be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) alkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

As used herein, the term "amino" refers to a -NH ₂ group.

A "mono-substituted amine" group refers to a " _-NHRA " group, where _RA can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, Heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. _RA can be substituted or unsubstituted. Examples of monosubstituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

A "di-substituted amine" group refers to a "-NR _A R _B " group, wherein RA _and R _B can be independently alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as herein defined. _RA and _RB can independently be substituted or unsubstituted. Examples of disubstituted amine groups include, but are not limited to, −N(methyl) ₂ , −N(phenyl)(methyl), −N(ethyl)(methyl), and the like.

As used herein, "hydroxyalkyl" refers to an alkyl group as described herein that includes 1, 2, or 3 hydroxyl groups (—OH) attached to the alkyl group. The alkyl portion of a hydroxyalkyl group can be straight or branched. In addition, the alkyl moiety may be lower alkyl. Examples of hydroxyalkyl groups include, but are not limited to, —CH ₂ —OH, —CH ₂ CH ₂ —OH, —CH(CH ₃ )OH, —C(CH ₃ ) ₂ OH, and —C(CH ₂ CH ₂ )OH .

As used herein, "aminoalkyl" refers to an alkyl group as described herein that includes 1, 2, or 3 amine groups (—NH ₂ ) attached to the alkyl group. The alkyl portion of the aminoalkyl group can be straight or branched. In addition, the alkyl moiety may be lower alkyl. Examples of heteroaryl rings include, but are not limited to, —CH ₂ —NH ₂ , —CH ₂ CH ₂ —NH ₂ , —CH(CH ₃ )NH ₂ , —C(CH ₃ ) ₂ NH ₂ , and —C(CH ₂ CH ₂ )NH ₂ .

When the number of substituents (eg haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl (C ₁ -C ₃ alkoxyphenyl)" may include one or more same or different alkoxy groups containing one, two, or three atoms.

As used herein, a radical refers to a species having a single unpaired electron such that the species containing the radical can be covalently bonded to another species. Therefore, radicals are not necessarily free radicals in this context. In contrast, a group denotes a specific portion of a larger molecule. The term "radical" is used interchangeably with the term "group".

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acids), sulfuric acid, nitric acid, and phosphoric acids (such as 2,3-dihydroxypropyl phosphate di hydrogen salt). Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic acid, Alkaline acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salt, alkali metal salt (such as sodium, potassium, or lithium salt), alkaline earth metal salt (such as calcium or magnesium salt), Carbonates, bicarbonates, organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, ginseng(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamines, cyclohexylamine , triethanolamine, ethylenediamine), and salts with amino acids (such as arginine and lysine). With respect to compounds of formula (I), those of ordinary skill in the art understand that when salts are formed by protonation of nitrogen-based groups (e.g., NH ₂ ), the nitrogen-based groups can be associated with a positive charge association (for example, NH ₂ can become NH ₃ ⁺ ), and this positive charge can be balanced by a negatively charged counterion such as Cl ⁻ .

It is to be understood that in any compound described herein having one or more chiral centers, unless absolute stereochemistry is expressly indicated, each center may independently have the R-configuration, or the S-configuration, or its mixture. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixture. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds yielding geometric isomers (which may be defined as E or Z), each double bond may independently be E or Z or a mixture thereof. Likewise, it is to be understood that in any such compound, all tautomeric forms are also intended to be included.

It is understood that where compounds disclosed herein have unfilled valencies, then the valences should be filled with hydrogen or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Wherever a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references herein to compounds encompass all potential isotopic forms, unless the context clearly dictates otherwise.

It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal-packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated form with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed with pharmaceutically acceptable solvents such as water, ethanol, or the like during the crystallization procedure. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Where a range of values is provided, it is understood that the upper and lower limits of the range, as well as each intervening value therebetween, are encompassed in the examples.

Unless expressly stated otherwise, the terms and phrases used in this application, and variations thereof (particularly in the appended claims), should be interpreted as open-ended and not limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation/including but not limited to" or the like; as used herein, the term "comprising )" is synonymous with "including (including), containing (containing), or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "Having" should be read as "having at least"; the term "include" should be read as "including but not limited to"; the term "example" is used to provide an illustrative examples and not an exhaustive or limiting list thereof; and the use of terms such as "preferably", "preferred", or "desired/desirable", and words of similar meaning It should not be read as implying that certain features are critical, essential, or even important to structure or function, but is merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Furthermore, the term "comprising" should be read synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

With respect to the use of substantially any plural and/or singular terms herein, one of ordinary skill in the art may switch from the plural to the singular and/or from the singular to the plural as appropriate to the context and/or application. Various singular/plural permutations may be explicitly set forth herein for clarity. The indefinite article "one (a or an)" does not exclude the plural. The mere fact that certain measures are listed in mutually different subparagraphs does not indicate that a combination of these measures cannot be used to advantage. Any element symbols in claims should not be construed as limiting the scope. compound

Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has the following structure: (I) wherein: ring A can be unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted Substituted bicyclic heteroaryl, or unsubstituted or substituted bicyclic heterocyclic group, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclic group, the bicyclic heteroaryl, or the bicyclic heteroaryl When the ring group is substituted, the phenyl group, the monocyclic heteroaryl group, the monocyclic heterocyclic group, the bicyclic heteroaryl group, or the bicyclic heterocyclic group can be selected from the following substituents by one or more Substitution: -F, -Cl, -CN, unsubstituted C ₁ - ₆ alkyl, deuterium substituted C ₁ - ₆ alkyl, hydroxyl, unsubstituted C 1 - 6 alkoxy, and unsubstituted C ₁ - ₆ alkoxy Substituted C ₁ - ₆ haloalkyl; X ¹ may be absent, –(CH ₂ ) _n –NR ^3a –, –O–, –S–, –S(O)–, –S(=O) ₂ –, –CH ₂ –, –CH(unsubstituted C ₁ -C ₆ alkyl)–, or –C(R ⁴ R ⁵ )–; X ² , X ³ , and X ⁴ can be independently N( Nitrogen), NR ^3b , O (oxygen), S (sulfur), or CR ^3c ; R ¹ can be unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted A substituted heteroaryl, or an unsubstituted or substituted heterocyclic group, wherein when the cycloalkyl, the aryl, the heteroaryl, and the heterocyclic group are substituted, the aryl, the Heteroaryl, and the heterocyclic group may be substituted by one or more substituents selected from the following: -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkyl, Unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkoxy; R ² can be unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or Substituted C ₂ -C ₁₀ heterocyclyl, ,or ; R ^3a , R ^3b , and R ^3c can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; R ⁴ and R ⁵ can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ⁴ and R ⁵ can form together unsubstituted or substituted C _3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted by substituents independently selected from the following 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; R ⁶ can be hydrogen , -F, -Cl, -CN, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ - C ₆ alkenyl, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, unsubstituted or substituted C _1-6 alkoxy, Unsubstituted or substituted hydroxyalkyl, or unsubstituted or substituted aminoalkyl; R ⁷ can be hydrogen, cyano, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted Substituted or substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ can be -CH ₂ -, -CH ₂ CH ₂ -, -O-, -OCH ₂ - , –CF ₂ –, –CHF–, or –C(CH ₃ ) ₂ –; R ⁸ can be hydrogen, –F, –CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted Substituted C ₁ -C ₆ haloalkyl; and R ⁹ may be hydrogen, -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ halo Alkyl; or R ⁸ and R ⁹ can form together an unsubstituted or substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be independently selected Substituents from the following substituents are substituted 1 to 6 times: halogen, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl and R ¹⁰ and R ¹¹ may independently be hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ¹⁰ and R ¹¹ may together form an unsubstituted or substituted 3 to 8 membered heterocyclic ring base; n can be 0 or 1; and the premise is Department of aromatic.

R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ may be substituted as described herein. base. When R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and/or R ¹¹ are substituted, R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and/or R ¹¹ can be independently selected from the group consisting of "optionally "Substituted" means that the provided group is substituted one or more times (such as 1, 2, 3, 4, or more than 4 times).

As provided herein, ^R2 can be of various structures. In some embodiments, R ² can be unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl. In other embodiments, R ² can be unsubstituted or substituted C ₂ -C ₁₀ heterocyclyl. In yet other embodiments, ^R can be a cyclic amide, such as . In yet other embodiments, ^R can be . The C ₃ -C ₁₀ cycloalkyl group for R ² may be monocyclic or polycyclic (e.g. bicyclic). Similarly, the unsubstituted or substituted C ₂ -C ₁₀ heterocyclyl for R ² may be monocyclic or polycyclic (such as bicyclic). In some embodiments, the unsubstituted or substituted C ₂ -C ₁₀ heterocyclyl for R ² may include 1, 2, 3, 4, or 5 members selected from N (nitrogen), O (oxygen), and a 4- to 12-membered heterocyclic group that is a heteroatom of S (sulfur). When R ² is unsubstituted or substituted bicyclic C ₃ -C ₁₀ cycloalkyl or unsubstituted or substituted bicyclic C ₂ -C ₁₀ heterocyclic group, C ₃ -C ₁₀ cycloalkyl and/or The two rings of the C ₂ -C ₁₀ heterocyclyl can be connected in a fused or spiro manner.

When R ² series When, the compound of formula (I) or its pharmaceutically acceptable salt can have the structure of formula (Ia): (Ia).

Ring of R ² (when R ² time) may vary. In some embodiments, Y ¹ can be -CH ₂ -, and Can be an optionally substituted pyrrolidone. In other embodiments, Y ¹ can be -CH ₂ CH ₂ -, and R ² can be an optionally substituted piperidinone. In yet other embodiments, when Y ¹ is -O-, R ² can be optionally substituted oxazolidone. In yet other embodiments, Y ¹ can be -OCH ₂ -, and R ² can be having the structure optionally replaced by Morpholinone. The ring of R ² may be substituted by one or more fluoro groups. In some embodiments, ^R is . In other embodiments, ^R2 is . The ring of ^R2 may also be substituted with an unsubstituted alkyl group. In some embodiments, Y ¹ can be -C(CH ₃ ) ₂ -, and Can be .

As provided herein, ^R2 can be , in some embodiments, R ⁶ can be hydrogen. In other embodiments, ^R6 can be halogen, such as -F or -Cl. In yet other embodiments, ^R6 can be -CN.

R ⁶ can also be a saturated or unsaturated straight-chain or branched-chain hydrogen carbon. For example, in some embodiments, R ⁶ can be unsubstituted or substituted C ₁ -C ₆ alkyl. Examples of C ¹ _{-C 6} alkyl for R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl (straight chain or branched), and hexyl (straight or branched). In other embodiments, R ⁶ can be unsubstituted or substituted C ₂ -C ₆ alkenyl or unsubstituted or substituted C _2-6 alkynyl. As an example, ^R6 can be -CH= _CH2 . R ⁶ may have a cyclic hydrocarbon. In some embodiments, ^R can be unsubstituted or substituted C _3-6 cycloalkyl, such as unsubstituted or substituted monocyclic C _3-6 cycloalkyl and unsubstituted or substituted Bicyclic C _3-6 cycloalkyl. C _3-6 cycloalkyl groups suitable for R ⁶ include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentyl.

Various other groups may be present for R ⁶ . In some embodiments, R ⁶ can be unsubstituted or substituted C ₁ -C ₆ haloalkyl. Exemplary C ₁ -C ₆ haloalkyl groups include the following: -CF ₃ , -CCl ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F , -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, and -CH ₂ CH ₂ CH ₂ Cl. In other embodiments, R can be unsubstituted or substituted C _1-6 alkoxy, such ^as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso Butoxy, secondary butoxy, tertiary butoxy, pentyloxy (straight chain or branched), and hexyloxy (straight chain or branched). In yet other embodiments, R ⁶ can be unsubstituted or substituted hydroxyalkyl. For example, R ⁶ can be unsubstituted or substituted hydroxy-C _1-6 alkyl. In yet other embodiments, R ⁶ can be unsubstituted or substituted aminoalkyl, such as unsubstituted or substituted amino-C _1-6 alkyl. The alkyl portion of the hydroxyalkyl and aminoalkyl groups can be straight or branched. In addition, a hydroxyalkyl group may have one or more hydroxyl groups (such as 1, 2, or 3), and an aminoalkyl group may have one or more amine groups (such as 1, 2, or 3). A non-limiting list of hydroxyalkyl and aminoalkyl groups includes the following: _-CH2 -OH, _{-CH2CH2 -} OH, -CH( _CH3 )OH, -C( _CH3 ) _2OH , -C( CH ₂ CH ₂ )OH, —CH ₂ —NH ₂ , —CH ₂ CH ₂ —NH ₂ , —CH(CH ₃ )NH ₂ , —C(CH ₃ ) ₂ NH ₂ , and —C(CH ₂ CH ₂ )NH ₂ .

Various ^R substituents can be unsubstituted or substituted. In some embodiments, when R ⁶ is substituted, there may be one or more moieties (such as 1, 2, 3, or more than 3). Substituted C ^3-6 cycloalkyl, substituted C ₁ -C ₆ alkyl, substituted C _{2 -C 6} alkenyl, substituted C _2-6 alkynyl, substituted C 6 alkynyl, Some moieties on substituted C ₁ -C ₆ haloalkyl, substituted C _1-6 alkoxy, substituted hydroxyalkyl, and substituted aminoalkyl are described herein. For example, the R ⁶ groups provided herein may be substituted 1, 2, 3, or more than 3 times with moieties selected from deuterium and halogen, except for substituted C ₁ -C ₆ alkyl and substituted C ₁ -C _haloalkyl , which can be substituted by deuterium 1, 2, 3, or more than 3 times. Those of ordinary skill in the art understand that the carbon to which ^R6 is attached may be a chiral center. In some embodiments, the carbon to which ^R6 is attached can be in the (R) -configuration. In other embodiments, the carbon to which ^R6 is attached can be in the (S) -configuration. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the structure . In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the structure .

Several groups can be attached to nitrogen. In some embodiments, ^R7 can be hydrogen. In other embodiments, ^R7 can be cyano. In yet other embodiments, R can be unsubstituted C ₁ -C ₆ alkyl, such as ^methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl , tertiary butyl, pentyl (straight or branched), and hexyl (straight or branched). In yet other embodiments, R ⁷ can be unsubstituted C ₁ -C ₆ haloalkyl, including those described herein. In some embodiments, ^R7 can be unsubstituted hydroxyalkyl. For example, R ⁷ can be unsubstituted hydroxy-C ₁ -C ₆ alkyl. Suitable hydroxyalkyl systems are described herein and include —CH ₂ —OH, —CH ₂ CH ₂ —OH, —CH(CH ₃ )OH, C(CH ₃ ) ₂ OH, and —C(CH ₂ CH ₂ ) OH. As provided herein, R ⁷ may be substituted, such as substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ haloalkyl, or substituted hydroxyalkyl (such as substituted hydroxy -C ₁ -C ₆ alkyl, eg -CH(OH)CF ₃ and -CH(OH)CHF ₂ ). In some embodiments, the substituted C ₁ -C ₆ alkyl can be substituted 1, 2, 3, or more than 3 times with deuterium, such as —CH ₂ D, —CHD ₂ , —CD ₃ , —CD ₂ CD ₃ , and -C(CD ₃ ) ₃ . When ^R7 is substituted, various substituents may be present, such as those described herein.

Another option for R ² . When R ² series When, the compound of formula (I) or its pharmaceutically acceptable salt can have the structure of formula (Ib): (Ib).

In some embodiments, ^R8 and ^R9 can each be hydrogen. In other embodiments, at least one of R ⁸ and R ⁹ may be a non-hydrogen group. As an example, one of ^R8 and ^R9 can be hydrogen, and the other of ^R8 and ^R9 can be -F, -CN, unsubstituted or substituted _C1 - _C6 alkyl , or unsubstituted C ₁ -C ₆ haloalkyl. As another example, one of R ^{and R} can be -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl , and the other of R ⁸ and R ⁹ may be -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl. In some embodiments, R ⁸ and R ⁹ together with the carbon to which R ⁸ and R ⁹ are attached may form an unsubstituted or substituted monocyclic cycloalkyl group, wherein the substituted monocyclic cycloalkyl group may be substituted by Substituents independently selected from the following substituents are substituted 1 to 6 times: halogen (such as F or Cl), hydroxyl, unsubstituted C _1-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl), unsubstituted C _1-4 alkoxy groups (such as methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, secondary butoxy, and tertiary butoxy), and unsubstituted C _1-4 haloalkyl (such as –CF ₃ , –CCl ₃ , –CHF ₂ , –C(CH ₃ )F ₂ , –CHCl ₂ , –CH ₂ F, –CH(CH ₃ )F, –CH ₂ CF ₃ , –CH ₂ Cl, –CH ₂ CH ₂ F, –CH ₂ CH _{2 Cl , -CH2CH2CH2F} , _{and -CH2CH2CH2Cl} ) _. The monocyclic cycloalkyl that may be formed by ^R8 and ^R9 together with the carbons to which ^R8 and ^R9 are attached may comprise three to four carbons or three to six carbons. In other embodiments, R ⁸ and R ⁹ together with the carbon to which R ⁸ and R ⁹ are attached may form an unsubstituted monocyclic heterocyclyl.

since The group from which the nitrogen leaves can be such that -NR ¹⁰ R ¹¹ can be an amine group, a mono-substituted amine, or a di-substituted amine. In some embodiments, R ¹⁰ and R ¹¹ can each be hydrogen. In other embodiments, R ¹⁰ can be hydrogen; and R ¹¹ can be unsubstituted C ₁ -C ₆ alkyl. In yet other embodiments, R ¹⁰ and R ¹¹ can each be unsubstituted C ₁ -C ₆ alkyl. Suitable C ₁ -C ₆ alkyl systems are provided herein. In yet other embodiments, R ¹⁰ can be hydrogen; and R ¹¹ can be substituted C ₁ -C ₆ alkyl. In some embodiments, R ¹⁰ and R ¹¹ can each be a substituted C ₁ -C ₆ alkyl. When R ¹⁰ and/or R ¹¹ are substituted, various moieties may replace R ¹⁰ and/or R ¹¹ . The moieties that may replace R ¹⁰ and/or R ¹¹ include those described herein. For example, R ¹⁰ and/or R ¹¹ may be substituted 1, 2, 3, or more than 3 times with moieties independently selected from deuterium, halogen, and hydroxyl. A cyclic moiety can be formed by R ¹⁰ and R ¹¹ together with the nitrogen to which R ¹⁰ and R ¹¹ are attached. In some embodiments, R ¹⁰ and R ¹¹ together with the nitrogen to which R ¹⁰ and R ¹¹ are attached form an unsubstituted or substituted 3-8 membered heterocyclyl, such as unsubstituted or substituted 3-8 member monocyclic heterocyclyl. The 3 to 8 membered heterocyclyl may also include additional heteroatoms besides the nitrogen to which R ¹⁰ and R ¹¹ are attached. Exemplary heteroatoms that may be included in the cyclic ring formed by R ¹⁰ and R ¹¹ together include second nitrogen, oxygen, and sulfur. A 3 to 8 membered heterocyclyl may be substituted. For example, a 3- to 8-membered heterocyclic group may be substituted 1, 2, 3, 4, or more than 4 times with moieties independently selected from deuterium, halogen, and hydroxyl.

Compounds of formula (I) or pharmaceutically acceptable salts thereof include those having the structure The five-member ring. Five-member ring It can be azole, and it can be aromatic. In some embodiments, can have structure . Examples of azoles include, but are not limited to, imidazole, pyrazole, Azole, 1,3,4- Oxadiazoles, triazoles, and 1,3,4-thiadiazoles. In some embodiments, X ² can be CR ^3c ; X ³ can be N; and X ⁴ can be NR ^3b . In other embodiments, X ² can be CR ^3c ; X ³ can be N; and X ⁴ can be O. In yet other embodiments, X ² can be N; X ³ can be CR ^3c ; and X ⁴ can be O. In yet other embodiments, ^X2 can be N; ^X3 can be N; and ^X4 can be O. In some embodiments, X ² can be CR ^3c ; X ³ can be N; and X ⁴ can be S. In other embodiments, ^X2 can be N; ^X3 can be N; and ^X4 can be S. In yet other embodiments, X ² can be NR ^3b ; X ³ can be N; and X ⁴ can be CR ^3c . In some embodiments of this paragraph, when ^X2 ; ^X3 and/or ^X4 can be ^NR3b , ^R3b can be hydrogen. In other embodiments of this paragraph, when X ² ; X ³ and/or X ⁴ can be NR ^3b , R ^3b can be unsubstituted C ₁ -C ₆ alkyl. In yet other embodiments of this paragraph, when X ² ; X ³ and/or X ⁴ can be NR ^3b , R ^3b can be substituted C ₁ -C ₆ alkyl.

Ring A can be attached to the rest of the molecule at two different positions (which can be two adjacent carbons in a 1,2-relationship, or a 1,3-relationship, or a 1,4-relationship). Ring A may be an aromatic monocyclic ring or a non-aromatic monocyclic or bicyclic heterocyclic group. In some embodiments, ring A can be unsubstituted phenyl. In other embodiments, Ring A can be an unsubstituted monocyclic heteroaryl. In yet other embodiments, Ring A can be an unsubstituted monocyclic heterocyclyl. In yet other embodiments, Ring A can be an unsubstituted bicyclic heterocyclyl. In some embodiments, Ring A can be a substituted phenyl group. In other embodiments, Ring A can be a substituted monocyclic heteroaryl. In yet other embodiments, Ring A can be a substituted monocyclic heterocyclyl. In yet other embodiments, Ring A can be a substituted bicyclic heterocyclyl. Heteroaryl and heterocyclyl (monocyclic and bicyclic heterocyclyl) can contain 1, 2, 3, or 4 heteroatoms. Suitable heteroatoms that may be present in heteroaryl, monocyclic heterocyclyl, and bicyclic heterocyclyl include O (oxygen), S (sulfur), and N (nitrogen). Ring A may be substituted as described herein. For example, Ring A may (including any nitrogen present in monocyclic and/or bicyclic heterocyclyls) be substituted one or more times (such as 1, 2, 3, or 4 times) with moieties independently selected from: -F , -Cl, -CN, unsubstituted C _1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl , pentyl (straight chain or branched chain), and hexyl (straight chain or branched chain)), C _1-6 alkyl substituted by deuterium (such as –CD ₃ , –CD ₂ CD ₃ , –CD ₂ CD ₂ CD _3. -CD(CD ₃ ) ₂ , -CD ₂ CD(CD ₃ ) ₂ , and -CD ₂ C(CD ₃ ) ₃ ), hydroxyl, unsubstituted C _1-6 alkoxy (such as methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy (straight chain or branched), and hexyl Oxygen (straight chain or branched)), and unsubstituted C _1-6 haloalkyl (such as –CF ₃ , –CCl ₃ , –CHF ₂ , –C(CH ₃ )F ₂ , –CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, and -CH _{2CH2CH2Cl ) .} Examples of ring A moieties that include one or more heteroatoms such as N (nitrogen), O (oxygen), and S (sulfur) include, but are not limited to, pyridine, pyrazole, triazole (such as 1,2,3 -triazole), imidazole, 1H-indazole, pyrazolo[1,5-a]pyridine, pyridin-2-one, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyridine azoles, each of which may be unsubstituted or substituted as described herein. Specific examples of what Ring A may be are as follows:

Exemplary cyclic groups for Ring A include, but are not limited to, the following: , , , , , , , , , , , , , , , , , , , , , ,and , where the asterisk indicates the point of attachment to X ¹ , and where each of these groups may be unsubstituted or substituted as described herein, including with moieties described herein (including those provided in the preceding paragraphs Those) to replace the hydrogen of the NH group.

Various rings can exist for R ¹ , wherein R ¹ can be unsubstituted or substituted. Rings that may exist for R ¹ may be non-aromatic or aromatic. In some embodiments, R ¹ can be unsubstituted or substituted cycloalkyl. Some examples of cycloalkyl groups in which R ¹ may exist include 3 to 8 membered monocyclic cycloalkyl groups and 5 to 10 membered bicyclic cycloalkyl groups. Suitable cycloalkyl for ^R may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo[1.1.1]pentyl. In other embodiments, R ¹ can be unsubstituted or substituted aryl. For example, ^R can be unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl. In some embodiments, ^R can be unsubstituted or substituted monocyclic heteroaryl. In other embodiments, ^R can be unsubstituted or substituted monocyclic heterocyclyl. In yet other embodiments, ^R can be unsubstituted or substituted monocyclic heteroaryl. In yet other embodiments, R ¹ can be unsubstituted or substituted monocyclic heterocyclyl. The heteroaryl and heterocyclyl groups in which ^R may be present may include one or more than one heteroatom (such as 1, 2, 3, or 4 heteroatoms). Suitable heteroatoms include N (nitrogen), O (oxygen), and S (sulfur). When R ¹ is substituted, various moieties can be present. In some embodiments, R ¹ may be substituted with one or more substituents (eg, 1, 2, 3, or 4 substituents) selected from: —F, —Cl, —CF ₃ , —CH ₂ CF _3. Unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkoxy (such as -OCF ₃ , -OCCl ₃ , -OCHF _2. –OC(CH ₃ )F ₂ , –OCHCl ₂ , –OCH ₂ F, –OCH(CH ₃ )F, –OCH ₂ CF ₃ , –OCH ₂ Cl, –OCH ₂ CH ₂ F, –OCH ₂ CH ₂ Cl, -OCH ₂ CH ₂ CH ₂ F, -OCH ₂ CH ₂ CH ₂ Cl, -OCF ₂ Cl, and -OCFCl ₂ ). In other embodiments, R ¹ can be unsubstituted.

An example of the ring structure of R ¹ is , wherein Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ can be independently CR ¹² or N; and each R ¹² can be hydrogen, -F, -Cl, unsubstituted C ₁ -C ₆ alkane group, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkoxy, or unsubstituted C ₁ - ₆ haloalkoxy. In some embodiments, Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ can each be CH. In some embodiments, Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ can each be CR ¹² , wherein one or more R ¹² ' (eg, 1, 2, or 3 R ¹² ') are optional From –F, –Cl, unsubstituted C ₁ -C ₆ alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl pentyl (straight chain or branched chain), and hexyl (straight chain or branched chain)), unsubstituted C ₁ - ₆ alkoxy groups (such as – methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy (straight chain or branched), and hexyloxy (straight chain or branched)) , -CF ₃ , -CH ₂ CF ₃ , or unsubstituted C ₁ - ₆ haloalkoxy (such as -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCF ₂ Cl, and –OCFCl ₂ ). In other embodiments, at least one of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ may be N (nitrogen). For example, one of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ may be N (nitrogen); and the remaining four of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ may be CR ¹² for each line. As an example, Z ¹ , Z ² , Z ³ , and Z ⁴ can each be hydrogen, and Z ⁵ can be N; or Z ¹ , Z ² , Z ³ , and Z ⁵ can each be hydrogen, and Z ⁴ can be N. In yet other embodiments, two of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ can be N (nitrogen); and among Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ The remaining three are CR ¹² .

Another example of the ring structure of ^R1 is , wherein Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , and Z ¹⁰ can be independently CHR ¹³ or N; and each R ¹³ can be hydrogen, -F, -Cl, unsubstituted C ₁ -C ₆ alkane group, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkoxy, or unsubstituted C ₁ - ₆ haloalkoxy. In some embodiments, Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , and Z ¹⁰ can each be CH ₂ . In some embodiments, Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , and Z ¹⁰ can each be CHR ¹³ , wherein one or more R ¹³ ' (eg, 1, 2, or 3 R ¹³ ') are optional From –F, –Cl, unsubstituted C ₁ -C ₆ alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl pentyl (straight chain or branched chain), and hexyl (straight chain or branched chain)), unsubstituted C ₁ - ₆ alkoxy groups (such as – methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy (straight chain or branched), and hexyloxy (straight chain or branched)) , -CF ₃ , -CH ₂ CF ₃ , or unsubstituted C ₁ - ₆ haloalkoxy (such as -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCF ₂ Cl, or –OCFCl ₂ ).

Examples of rings of ^R1 include the following: , , , , , , , , , , , , , , , , , , , , , , ,and .

^R1 can be attached directly to the carbon of ring A or through a linker. In some embodiments, ^Xi may be absent. In other embodiments, ^X can be -NH. In yet other embodiments, X ¹ can be -N(unsubstituted C ₁ -C ₆ alkyl). In yet other embodiments, X ¹ can be -N(substituted C ₁ -C ₆ alkyl). In some embodiments, X ¹ can be -(CH ₂ )-NH-*, -(CH ₂ )-N(unsubstituted C ₁ -C ₆ alkyl)-*, or -(CH ₂ )- N(substituted C ₁ -C ₆ alkyl)—*, wherein “*” indicates the point of attachment to ring A. In other embodiments, ^X can be -O- or -S-. In yet other embodiments, X ¹ can be -S(O)- or -S(=O) ₂ -. In yet other embodiments, X ¹ can be -CH ₂ -. In yet other embodiments, X ¹ can be —CH(unsubstituted C ₁ -C ₆ alkyl)—. In some embodiments, X ¹ can be -C(unsubstituted C ₁ -C ₆ alkyl) ₂ -. In other embodiments, X ¹ can be -CH(unsubstituted C ₁ -C ₆ alkyl)-. In yet other embodiments, X ¹ can be —C(substituted C ₁ -C ₆ alkyl) ₂ —. In still other embodiments, X ¹ can be -C(R ⁴ R ⁵ )-, wherein R ⁴ and R ⁵ together form an unsubstituted C _3-8 cycloalkyl. In yet other embodiments, X ¹ can be -C(R ⁴ R ⁵ )-, wherein R ⁴ and R ⁵ together form a substituted C _3-8 cycloalkyl, wherein the substituted cycloalkyl can be Substituents independently selected from the following substituents are substituted 1 to 6 times: halogen, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _{1-4 4} Haloalkyl. The cycloalkyl group that may be formed by R ^{and R} together with the carbon to which R ^{and R} are attached may be a _monocyclic C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, and cyclohexyl. In some embodiments, R ^{and R} together form a substituted C _cycloalkyl , wherein the substituted cycloalkyl can be substituted one or two times with substituents independently selected from: -F , -Cl, -OH, -CH ₃ , -OCH ₃ and -CF ₃ .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may meet the following conditions: wherein: ring A may be unsubstituted or substituted phenyl, unsubstituted or substituted Monocyclic heteroaryl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein when the phenyl, When the monocyclic heteroaryl, the monocyclic heteroaryl, the bicyclic heteroaryl, or the bicyclic heteroaryl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heteroaryl, The bicyclic heteroaryl, or the bicyclic heterocyclic group can be substituted by one or more substituents selected from the following _: -F, -Cl, -CN, unsubstituted C _1-6 alkyl, unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkyl; X ¹ may not exist, -NR ^3a -, -O-, -S-, -S(O)-, -S (=O) ₂ –, or –C(R ⁴ R ⁵ )–; X ² , X ³ , and X ⁴ can be independently N, NR ^3b , O, S, or CR ^3c ; R ¹ can be without Substituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocyclyl, wherein when the cycloalkyl, the When the aryl group, the heteroaryl group, and the heterocyclic group are substituted, the aryl group, the heteroaryl group, and the heterocyclic group may be substituted by one or more substituents selected from the group consisting of -F, -Cl, -CF ₃ , unsubstituted C ₁ - ₆ alkyl, and unsubstituted C ₁ - ₆ alkoxy; R ² can be unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl , unsubstituted or substituted C ₂ -C ₁₀ heterocyclic group, ,or ; R ^3a , R ^3b , and R ^3c can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; R ⁴ and R ⁵ can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ⁴ and R ⁵ can form together unsubstituted or substituted C _3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted by substituents independently selected from the following 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; R ⁶ can be hydrogen , -F, -Cl, -CN, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ - C ₆ alkenyl, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, unsubstituted or substituted C _1-6 alkoxy, Unsubstituted or substituted hydroxyalkyl, or unsubstituted or substituted aminoalkyl; R ⁷ can be hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted Substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ can be -CH ₂ -, -CH ₂ CH ₂ -, -O-, -OCH ₂ -, -CF ₂ –, –CHF–, or –C(CH ₃ ) ₂ –; R ⁸ can be hydrogen, –F, –CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; and R ⁹ can be hydrogen, -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; Or R ⁸ and R ⁹ can form together unsubstituted or substituted monocyclic cycloalkyl or unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be independently selected from the following The substituent is substituted 1 to 6 times: halogen, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; and R ¹⁰ and R ¹¹ may independently be hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ¹⁰ and R ¹¹ may be taken together to form an unsubstituted or substituted 3 to 8 membered heterocyclyl; and prerequisite system It is aromatic; and the premise is that the compound of formula (I) or its pharmaceutically acceptable salt cannot be selected from (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl ) phenyl) amino) pyridin-3-yl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3 -base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrrolidinyl -2-base]-[1,3,4] Oxadiazol-2-yl}-pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, and (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may meet the following conditions: wherein: ring A may be unsubstituted or substituted phenyl, unsubstituted or substituted Monocyclic heteroaryl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein when the phenyl, When the monocyclic heteroaryl, the monocyclic heteroaryl, the bicyclic heteroaryl, or the bicyclic heteroaryl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heteroaryl, The bicyclic heteroaryl, or the bicyclic heterocyclic group can be substituted by one or more substituents selected from the following _: -F, -Cl, -CN, unsubstituted C _1-6 alkyl, unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkyl; X ¹ may not exist, –(CH ₂ ) _n –NR ^3a –, –O–, –S–, –S( O)–, –S(=O) ₂ –, or –C(R ⁴ R ⁵ )–; X ² , X ³ , and X ⁴ can be independently N, NR ^3b , O, S, or CR ^3c ; ^R can be unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocyclyl, wherein when When the cycloalkyl, the aryl, the heteroaryl, and the heterocyclyl are substituted, the aryl, the heteroaryl, and the heterocyclyl can be substituted by one or more of the following Substitution: -F, -Cl, -CF ₃ , unsubstituted C ₁ - ₆ alkyl, and unsubstituted C ₁ - ₆ alkoxy; R ² can be unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ heterocyclyl, ,or ; R ^3a , R ^3b , and R ^3c can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; R ⁴ and R ⁵ can be independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ⁴ and R ⁵ can form together unsubstituted or substituted C _3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted by substituents independently selected from the following 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; R ⁶ can be hydrogen , -F, -Cl, -CN, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ - C ₆ alkenyl, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, unsubstituted or substituted C _1-6 alkoxy, Unsubstituted or substituted hydroxyalkyl, or unsubstituted or substituted aminoalkyl; R ⁷ can be hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted Substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ can be -CH ₂ -, -CH ₂ CH ₂ -, -O-, -OCH ₂ -, -CF ₂ –, –CHF–, or –C(CH ₃ ) ₂ –; R ⁸ can be hydrogen, –F, –CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; and R ⁹ can be hydrogen, -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; Or R ⁸ and R ⁹ can form together unsubstituted or substituted monocyclic cycloalkyl or unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be independently selected from the following The substituent is substituted 1 to 6 times: halogen, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; and R ¹⁰ and R ¹¹ may independently be hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ¹⁰ and R ¹¹ may together form an unsubstituted or substituted 3 to 8 membered heterocyclyl; n Can be 0 or 1; and the premise is It is aromatic; and the premise is that the compound of formula (I) or its pharmaceutically acceptable salt cannot be selected from (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl ) phenyl) amino) pyridin-3-yl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3 -base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrrolidinyl -2-base]-[1,3,4] Oxadiazol-2-yl}-pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, and (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may meet the following conditions: wherein: ring A may be unsubstituted or substituted monocyclic heteroaryl, when the monocyclic When the heteroaryl is substituted, the monocyclic heteroaryl may be substituted by one or more substituents selected from _the group consisting of -F, -Cl, -CN, unsubstituted C _1-6 alkyl, unsubstituted Substituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkyl; X ¹ can be -(CH ₂ ) _n -NR ^3a -; X ² and X ³ can each be N(nitrogen ); X ⁴ can be O (oxygen); R ¹ can be unsubstituted or substituted phenyl, wherein when the phenyl is substituted, the phenyl can be substituted by one or more selected from the following Substitution: -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkoxy; R ² can be ; R ^3a may be hydrogen; R ⁶ may be unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₂ -C ₆ alkenyl; R ⁷ may be hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ may be -CH ₂ -; n Can be 0; and the premise is Department of aromatic. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may meet the following conditions: wherein: ring A may be unsubstituted or substituted monocyclic heteroaryl, when the monocyclic When the heteroaryl is substituted, the monocyclic heteroaryl may be substituted by one or more substituents selected from _the group consisting of -F, -Cl, -CN, unsubstituted C _1-6 alkyl, unsubstituted Substituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkyl; X ¹ can be -(CH ₂ ) _n -NR ^3a -; X ² and X ³ can each be N(nitrogen ); X ⁴ can be O (oxygen); R ¹ can be unsubstituted or substituted monocyclic cycloalkyl, wherein when the monocyclic cycloalkyl is substituted, the monocyclic cycloalkyl can be One or more substituents selected from the following substituents: -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy , and unsubstituted C ₁ - ₆ haloalkoxy; R ² can be ; R ^3a may be hydrogen; R ⁶ may be unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₂ -C ₆ alkenyl; R ⁷ may be hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ may be -CH ₂ -; n Can be 0; and the premise is Department of aromatic. In some embodiments of this paragraph, R ⁶ can be unsubstituted C ₁ -C ₆ alkyl (such as methyl or ethyl). In other embodiments of this paragraph, R ⁶ can be unsubstituted or substituted C ₂ -C ₆ alkenyl (such as —CH═CH ₂ ). In some embodiments of this paragraph, Ring A can be an unsubstituted monocyclic heteroaryl that includes 1 or 2 nitrogens. In some embodiments of this paragraph, Ring A can be a substituted monocyclic heteroaryl that includes 1 or 2 nitrogens. In some embodiments of this paragraph, ^R7 can be hydrogen. In other embodiments of this paragraph, R ⁷ can be unsubstituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ haloalkyl, or unsubstituted hydroxyalkyl. In some embodiments of this paragraph, ^R can be substituted phenyl, such as monosubstituted phenyl (such as ortho monosubstituted phenyl, meta monosubstituted phenyl, or para monosubstituted phenyl) monosubstituted phenyl). In some embodiments of this paragraph, ^R can be a substituted monocyclic cycloalkyl, for example a monosubstituted monocyclic cycloalkyl, such as a monosubstituted cyclohexyl.

Examples of compounds of formula (I) and pharmaceutically acceptable salts thereof include the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and , or a pharmaceutically acceptable salt of any one of the foregoing.

Further examples of compounds of formula (I) and pharmaceutically acceptable salts thereof include the following: , , , , , , , , , , , , , , , , , , , , , , , , , , 1, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or a pharmaceutically acceptable salt of any one of the foregoing.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2021/102204 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not selected from (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl) Phenyl)amino)pyridin-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3 -base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3-(5-(2-((4-trifluoromethyl)phenyl)amino)pyridin-3-yl]-( 1,3,4) Oxadiazol-2-yl)-pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrrolidinyl -2-base]-[1,3,4] Oxadiazol-2-yl}-pyrrolidin-2-one, (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]piperidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]- 1,3,4- Oxadiazol-2-yl]piperidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]- 1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]- 1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3 -base)-1,3,4- Oxadiazol-2-yl)piperidin-2-one, and (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine- 3-base)-1,3,4- Oxadiazol-2-yl)piperidin-2-one, including any pharmaceutically acceptable salt of any of the foregoing. In some embodiments, ^R2 cannot be , wherein Y ¹ is —CH ₂ —; R ⁶ is unsubstituted C ₁ -C ₆ alkyl; and R ⁷ is hydrogen. In some embodiments, ^R2 cannot be , wherein Y ¹ is -CH ₂ CH ₂ -; R ⁶ is unsubstituted C ₁ -C ₆ alkyl; and R ⁷ is hydrogen. In some embodiments, Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when R ¹ is para-substituted phenyl (eg, trifluoromethyl para-substituted phenyl), and X ¹ is -NR ^3a (such as -NH-), then Ring A Cannot be unsubstituted monocyclic heteroaryl, such as and . In some embodiments, ^R cannot be a para-substituted phenyl, such as a para-substituted trifluoromethyl phenyl. In some embodiments, when ^R2 is (wherein Y ¹ is -CH ₂ -); R ⁶ is unsubstituted C ₁ -C ₆ alkyl; and when R ⁷ is hydrogen, ring A cannot be unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when ^R2 is (wherein Y ¹ is -CH ₂ CH ₂ -); R ⁶ is unsubstituted C ₁ -C ₆ alkyl; and when R ⁷ is hydrogen, ring A cannot be unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when ^R2 is (wherein Y ¹ is -CH ₂ -); R ⁶ is unsubstituted C ₁ -C ₆ alkyl; R ⁷ is hydrogen; and R ¹ is para-substituted phenyl (such as trifluoromethyl para substituted phenyl), ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when ^R2 is (wherein Y ¹ is -CH ₂ CH ₂ -); R ⁶ is unsubstituted C ₁ -C ₆ alkyl; R ⁷ is hydrogen; and R ¹ is para-substituted phenyl (such as trifluoromethyl (para-substituted phenyl), ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2019/222431 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not selected from: (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl ) phenyl) amino) phenyl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazol-2-yl)pyrrolidin-2-one, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopentanol, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl 4-methylbenzenesulfonate, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazol-2-yl)cyclobutanol, 3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)oxo-3-ol, 3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)tetrahydrofuran-3-ol, (1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl)carbamate, 2-(5-(1-aminocyclopropyl)-l,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, N-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino )phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl)acetamide, 1-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3, 4- Oxadiazol-2-yl)cyclopropyl)urea, 2-(5-(1-aminocyclopropyl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl )-1,3,4- Oxadiazol-2-yl)cyclopropan-1-ol, 2-(5-(1-fluorocyclopropyl)-l,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-[5-(l-methylsulfonylcyclopropyl)-1,3,4- Oxadiazol-2-yl]-N-[4-(trifluoromethyl)phenyl]aniline, 2-(5-(l-methoxycyclopropyl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(2-methyl-1,3-dioxol-2-yl)- 1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, N-(2-cyanoethyl)-2-methyl-2-(5-(2-(( 4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)acrylamide, N-(cyanomethyl)-2-methyl-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)benzene Base) -1,3,4- Oxadiazol-2-yl)acrylamide, N-(but-3-yn-l-yl)-2-methyl-2-(5-(2-((4-(trifluoromethyl)phenyl )amino)phenyl)-1,3,4- Oxadiazol-2-yl)acrylamide, 2-methyl-N-(prop-2-yn-l-yl)-2-(5-(2-((4-(trifluoromethyl)phenyl )amino)phenyl)-1,3,4- Oxadiazol-2-yl)acrylamide, N-(2-cyanoethyl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazole-2-carboxamide, N-(cyanomethyl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazole-2-carboxamide, N-(but-3-yn-l-yl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1, 3,4- Oxadiazole-2-carboxamide, N-(prop-2-yn-l-yl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1, 3,4- Oxadiazole-2-formamide, 2-(5-(oxygen -2-base)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(2-methyloxy -2-base)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(1-((methylamino)methyl)cyclopropyl)-1,3 ,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, methyl((l-(5-(2-((4-(trifluoromethyl)phenyl)amine Base) phenyl) -1,3,4- Oxadiazol-2-yl)cyclopropyl)methyl)carbamate tertiary butyl ester, N-methyl-N-((1-(5-(2-((4-(trifluoromethyl)phenyl )amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl)methyl)cyanamide, 2-(5-(1-(methylamino)cyclopropyl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, methyl(l-(5-(2-((4-(trifluoromethyl)phenyl)amino )phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl)carbamate tertiary butyl ester, N-methyl-N-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino) Phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropyl)cyanamide, 2-methyl-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazol-2-yl)acrylamide, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropane-l-carboxylic acid tertiary butyl ester, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3, 4- Oxadiazol-2-yl)cyclopropane-l-carboxylic acid, 2-(5-(2-methyltetrahydrofuran-2-yl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(2-methyloxy-2-yl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(tetrahydrofuran-2-yl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(oxygen-2-yl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(3-methyloxy-3-yl)-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl )-1,3,4- Oxadiazol-2-yl)cyclopropane-l-carbonitrile, N,N-dimethyl-1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl) -1,3,4- Oxadiazol-2-yl)cyclopropane-1-formamide, N-methyl-1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1 ,3,4- Oxadiazol-2-yl)cyclopropane-l-formamide, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)cyclopropane-1-formamide. 2,2-Dimethyl-5-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)-1,3-di Alkan-5-ol and 4-bromo-2-(5-cyclopropyl-1,3,4- Oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, together with any pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2018/231745 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2016/049586 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in US 2009/0156592 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2012/135581 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2009/094445 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2004/113330 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not the compound provided in WO 2004/056823 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot meet the following conditions: wherein ^X is -S-, -S(O)-, and/or -S(=O ) ₂ –. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot meet the following conditions: wherein ^X is -S-, -S(O)-, and/or -S(=O ) ₂ -; and ring A is phenyl. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not one that meets the following conditions: wherein X ¹ is —O—. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not one meeting the following conditions: wherein X ¹ is —O—; and ring A is phenyl. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot meet the following conditions: wherein ring A is phenyl. In some embodiments, Ring A may not be unsubstituted or substituted 1H-pyrazolo[3,4-b]pyridine, such as unsubstituted or substituted . In some embodiments, Ring A may not be unsubstituted or substituted 1H-pyrazolo[3,4-b]pyridine, such as unsubstituted or substituted ; and R ¹ is unsubstituted or substituted tetrahydropyran. In some embodiments, Ring A may not be unsubstituted or substituted 1H-pyrazolo[3,4-b]pyridine, such as unsubstituted or substituted ; When X ¹ is NR ^3a (such as NH); and R ¹ is unsubstituted or substituted tetrahydro-2H-pyran. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not one meeting the following conditions: wherein ring A is phenyl; and R ¹ is aryl, such as phenyl. In some embodiments, Can't be tied , , , and/or . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot meet the following conditions: wherein ring A is phenyl; and Tie . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot meet the following conditions: wherein ring A is phenyl; ^R is aryl (such as phenyl); and Tie . In some embodiments, R ¹ cannot be unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, for example R ¹ cannot be unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclo Butyl, and/or unsubstituted or substituted cyclopentyl. In some embodiments, ^R cannot be unsubstituted or substituted oxygen , unsubstituted or substituted oxygen, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted 1,3-dioxolane, unsubstituted or substituted tetrahydropyran, and/or unsubstituted or substituted 1,3-bis alkyl. In some embodiments, ^R cannot be unsubstituted or substituted pyrrolidine, unsubstituted or substituted piperidine, and/or unsubstituted or substituted piperidine . In some embodiments, ^R1 cannot be unsubstituted or substituted pyrimidine-2,4(1H,3H)-dione. In some embodiments, ^R1 cannot be unsubstituted or substituted bicyclic heterocyclyl. In some embodiments, ^R cannot be unsubstituted or substituted isoindoline, unsubstituted or substituted 1,2,3,4-tetrahydroisoquinoline, and/or unsubstituted or Substituted 2H-benzo[b][1,4] -3(4H)-one. In some embodiments, ^R2 cannot be unsubstituted or substituted pyrrolidine and/or unsubstituted or substituted piperidine. In some embodiments, ^R may not be unsubstituted or substituted . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not a person who meets the following conditions: wherein R ² is . In some embodiments, R ¹⁰ and/or R ¹¹ cannot be unsubstituted or substituted C ₁ -C ₆ alkyl. In some embodiments, R ¹⁰ and/or R ¹¹ cannot be substituted C ₁ -C ₆ alkyl, such as C ₁ -C ₆ alkyl substituted by alkynyl, C ₁ -C ₆ alkyl substituted by cyano alkyl. In some embodiments, R ¹⁰ and R ¹¹ cannot each be hydrogen. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not selected from: , , ,and (including its pharmaceutically acceptable salts). synthesis

Compounds of formula (I), or pharmaceutically acceptable salts thereof, can be prepared in various ways by those of ordinary skill using known techniques, as guided by the detailed techniques provided herein. General synthetic routes for the preparation of compounds of formula (I), including pharmaceutically acceptable salts, and intermediates are shown and described herein, along with some examples of starting materials used in the synthesis of the compounds described herein. The compounds and intermediates disclosed herein can be obtained using commercially available starting materials and reagents. Synthetic procedures will depend on the specific substituents present in the compounds or intermediates, and may require various protection, deprotection, or other steps of organic synthesis that are well known, but not necessarily illustrated in the general schemes. Any of the steps shown in the general schemes may be used in any combination or in a different order to obtain the desired compound or intermediate. The approaches shown and described herein are exemplary only and are not intended or construed as limiting the scope of the claimed patent scope in any way. Those of ordinary skill in the art will be able to recognize modifications to the disclosed syntheses and devise alternative routes based on the disclosure herein. plan 1:

In Scheme 1, R ¹ , X ¹ , Ring A, and R ⁶ can be as described herein. Carboxylate and reactive group (reacting group, RG) can be in various relationships (such as 1,2, 1,3-, 1,4-relationships, etc.). In Scheme 1, amines or halides of general formula (1a) can be reacted with aryl halides, heteroaryl halides, or borate esters of general formula (1b) to obtain compounds of general formula (1c) . Hydrazine formation of compounds of general formula (1c) provides compounds of general formula (1d), which can be reacted with compounds of general formula (1e) under amide coupling conditions to obtain compounds of general formula (1f). Cyclization of compounds of general formula (If) can provide compounds of general formula (Ig), which can be separated under chiral SFC or HPLC to obtain compounds of general formula (IA) and general formula (IB). Alternatively, the chiral pure acid of the compound of general formula (1e) can be used in the step of amide coupling to directly obtain the chiral pure compound of general formula IA or the compound of general formula IB. Scenario 2:

In Scheme 2, R ¹ , Ring A, and R ⁶ can be as described herein. In Scheme 2, hydrazines of general formula (2a) can be reacted with acids of general formula (2b), where PG indicates a suitable protecting group, to obtain compounds of general formula (2c). Cyclization of compounds of general formula (2c) can provide compounds of general formula (2d), which can undergo deprotection and substitution to form compounds of general formula (2e). Deprotection of compounds of general formula (2e) can provide compounds of general formula (2f), which can be separated under chiral SFC or HPLC to obtain compounds of general formula (IIA) and general formula (IIB). Option 3:

In Scheme 3, R ¹ , Ring A, and R ⁶ can be as described herein. Carboxylates and bromides can be in various relationships (such as 1,2, 1,3-, 1,4-relationships, etc.). In Scheme 3, the amide coupling of an acid of general formula (3a) and a hydrazine of general formula (3b) can provide a compound of general formula (3c). Cyclization of compounds of general formula (3c) can provide compounds of general formula (3d), which can undergo cyclization with reagents such as arylamines, heteroarylamines, aliphatic amines, arylboronic acids, or heteroarylboronic acids. Coupling reactions to provide compounds of general formula (3e). Deprotection and chiral SFC or HPLC separation provide compounds of general formula (IIIA) and general formula (IIIB). Alternatively, chiral pure hydrazides of general formula (3b) can be used in the amide coupling step to obtain chiral pure compounds of general formula (IIIA) or general formula (IIIB). Pharmaceutical composition

Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

The term "pharmaceutical composition" refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components such as diluents or carriers. Pharmaceutical compositions facilitate the administration of compounds to organisms. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid . Pharmaceutical compositions will generally be designed for a particular intended route of administration.

The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not abolish the biological activity and properties of the compound, nor does it cause significant injury or damage to the animal to which the composition is intended to be delivered .

As used herein, "carrier" refers to a compound that facilitates the incorporation of the compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a frequently utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks significant pharmacological activity but may be medically necessary or desirable. For example, diluents can be used to increase the volume of an effective drug whose mass is too small to manufacture and/or administer. It may also be a liquid used to dissolve a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, but not limited to, phosphate buffered saline that mimics the pH and isotonicity of human blood.

As used herein, "excipient" means a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity to the composition , lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition includes antioxidants and/or metal chelating agents. A "diluent" is a type of excipient.

The pharmaceutical compositions described herein may be administered to human patients by themselves, or may be pharmaceutical compositions in which they are admixed with other active ingredients (as in combination therapy), or carriers, diluents, excipients, or combinations thereof administered to human patients. Proper formulation depends upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those of ordinary skill in the art.

The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or tableting procedures. Furthermore, the active ingredient is contained in an amount effective for its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts with pharmaceutically compatible counterions.

Various techniques for administering compounds, salts, and/or compositions exist in the art, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, Intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.

Compounds, salts, and/or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound, usually in a depot or sustained release formulation, into the affected area. Additionally, the compounds can be administered in a targeted drug delivery system such as liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. For example, intranasal or pulmonary delivery may be desired to target respiratory diseases or conditions.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms (containing the active ingredient). The pack may eg comprise metal or plastic foil, eg a blister pack. The pack or dispenser unit may be accompanied by administration instructions. The package or dispenser may also be accompanied by a notice associated with the container regulating the manufacture, use, or sale of the drug in a form prescribed by a government agency reflecting the agency's approval of the drug form for human or veterinary administration. give. For example, the notification could be a label or a product leaflet approved by the Food and Drug Administration for a prescription drug. Compositions, which may include compounds described herein and/or salts formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container and labeled for treatment of the indicated condition. Therapeutic uses and methods

Some embodiments described herein relate to a method for treating a disease described herein, which may comprise administering to a subject suffering from a disease described herein an effective amount of a compound described herein (e.g., formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of the diseases described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof) for use in the treatment of the diseases described herein.

Some embodiments described herein pertain to a method for treating an autoimmune disorder described herein, which may comprise administering to a subject having an autoimmune disorder described herein an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of autoimmune disorders described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof) for use in the treatment of the autoimmune disorders described herein.

Some embodiments described herein pertain to a method for treating an inflammatory condition described herein, which may comprise administering to a subject having an inflammatory condition described herein an effective amount of a compound described herein (e.g. a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of an inflammatory condition as described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of a compound of I) or a pharmaceutically acceptable salt thereof) for use in the treatment of the inflammatory conditions described herein.

Some embodiments described herein pertain to a method for treating a cancer described herein, which may comprise administering to a subject having a cancer described herein a malignant growth or tumor with an effective amount of a compound described herein (e.g. compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer, which may include contacting a malignant growth or tumor, wherein the malignant growth or the tumor is caused by a Caused by cancer. Still other embodiments described herein relate to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein for the treatment of cancer. A pharmaceutical composition of a compound, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may include contacting a malignant growth or tumor, wherein the malignant growth or the tumor is caused by a cancer as described herein.

Some embodiments described herein relate to a method for inhibiting the replication of a malignant growth or tumor, which may comprise combining the growth or the tumor with an effective amount of a compound described herein (such as a compound of formula (I) or pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is caused by Caused by said cancer. Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of malignant growths or tumors caused by the cancers described herein. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof), for inhibiting the replication of malignant growth or tumor, wherein the malignant growth or the tumor is caused by the cancer described herein.

Some embodiments described herein relate to a method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD, which may comprise providing cancer cells from a cancer described herein with an effective amount of A compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) pharmaceutical composition. Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof), which is used for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. Some embodiments described herein relate to a method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD, which may comprise providing cancer cells from a cancer described herein with an effective amount of A compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) pharmaceutical composition. Other embodiments described herein relate to a method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD, which may comprise administering an effective amount of a cancer cell from a cancer described herein A compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) The pharmaceutical composition of the drug is contacted, thereby inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD.

Some embodiments described herein relate to a method for treating cancer described herein, which may include using an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g. a compound of formula (I) or a pharmaceutically acceptable salt thereof) inhibits YAP/TAZ-TEAD protein-protein interaction and/or inhibits lipid binding to TEAD . Other embodiments described herein pertain to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating the cancers described herein by inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD In the use. Still other embodiments described herein relate to or comprise an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula ( A pharmaceutical composition of a compound of I) or a pharmaceutically acceptable salt thereof) for treating cancers described herein by inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. Some embodiments described herein are related to a method for treating cancer described herein, which may include combining cancer cells with an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the compound inhibits YAP/TAZ-TEAD protein-protein interaction And/or inhibit lipid binding to TEAD.

Some embodiments disclosed herein relate to a method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD, which may include administering to a subject with a cancer described herein or from Cancer cells of said cancer provide an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprise an effective amount of a compound described herein (such as a compound of formula (I) compound or its pharmaceutically acceptable salt). Other embodiments disclosed herein relate to an effective amount of a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. Still other embodiments disclosed herein relate to a compound described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) or include an effective amount of a compound described herein (such as a compound of formula (I) compound or a pharmaceutically acceptable salt thereof), which is used for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD.

Examples of suitable cancers include, but are not limited to: mesothelioma, renal cell carcinoma, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, oral squamous cell carcinoma, squamous cell carcinoma of the lung , lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, uveal melanoma, pancreatic adenocarcinoma, kidney Renal papillary cell carcinoma, rectal adenocarcinoma, urothelial bladder cancer, esophageal cancer, head and neck squamous cell carcinoma, squamous cell carcinoma (including head and neck squamous cell carcinoma), cancers resistant to EGFR inhibitors, and MEK Inhibitor-resistant cancers. In addition, the compound of formula (I), together with its pharmaceutically acceptable salts, can be used to treat cancers with one or more of the following characteristics: hippo pathway alteration, YAP and/or TAZ amplification, mutation, acquisition of functional fusion, second Neurofibromatosis (NF2) mutation or deletion, and/or LATS1/2 mutation.

As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a person. In some embodiments, the subject may be a child and/or an infant, such as a child or infant with a fever. In other embodiments, the subject can be an adult.

As used herein, the terms "treat, treating, treatment, therapeutic" and "therapy" do not necessarily mean complete cure or elimination of a disease or condition. Any alleviation to any degree of any undesirable sign or symptom of a disease or condition may be considered treatment and/or therapy. Additionally, treatment can include actions that can worsen a subject's overall sense of well-being or appearance.

The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of an active compound or pharmaceutical agent that elicits an indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound, salt, or composition may be that amount required to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or prolong the survival of the subject being treated. The response can occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. In view of the disclosure provided herein, determination of an effective amount is well within the ability of one of ordinary skill in the art. The therapeutically effective amount of a compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant drugs, and other factors as will be recognized by those of ordinary skill in the medical art.

The amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, required for treatment will vary not only with the particular compound or salt selected, but also with the route of administration, the disease or condition being treated. nature and/or symptoms, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. Those of ordinary skill in the art will appreciate that in certain instances it may be desirable to administer the compounds disclosed herein in amounts exceeding or even far exceeding the dosage ranges described herein to effectively and aggressively treat, in particular, the aggressive disease or condition.

In general, however, a suitable dosage will often be in the range of about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may be in the range of about 0.10 mg/kg to about 7.5 mg/kg body weight/day, such as about 0.15 mg/kg to about 5.0 mg/kg/recipient body weight/day, about 0.2 mg/kg to about 4.0 mg /kg/recipient body weight/day, or any amount in between. The compounds may be administered in unit dosage form; for example, each unit dosage form contains 1 to 500 mg, 10 to 100 mg, 5 to 50 mg, or any amount therebetween of the active ingredient.

The desired dose may conveniently be presented in a single dose, or in divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-doses themselves may be further divided, for example, into discrete, loosely spaced administrations.

As will be apparent to those of ordinary skill in the art, useful in vivo doses to be administered and the particular mode of administration will vary depending on the age, body weight, severity of affliction, and the species of mammal being treated, the particular compound employed, and The particular use for which these compounds are employed will vary. Determination of effective dosage levels (ie, dosage levels required to achieve the desired effect) can be achieved by those of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, a useful dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing its in vitro activity with its in vivo activity in animal models. This comparison can be done by comparison with established drugs such as cisplatin and/or gemcitabine

Dosage and intervals may be adjusted individually to provide plasma levels or minimum effective concentration (MEC) of the active moiety sufficient to maintain a modulating effect. The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10 to 90% of the time, preferably between 30 to 90% of the time, and optimally between 50 to 90% of the time . In cases of local administration or selective uptake, the local effective concentration of the drug may not be related to plasma concentration.

It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or abnormal organ function. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is insufficient (excluding toxicity). The magnitude of the dosage administered in the management of the condition of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of a disease or condition can be assessed, for example, based in part on standard prognostic assessment methods. In addition, the dosage and possibly the frequency of administration will also vary according to the age, weight and response of the individual patient. Programs similar to those discussed above are available in veterinary medicine.

The efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subgroup of compounds sharing certain chemical moieties can be established by determining in vitro toxicity on cell lines, such as mammalian and preferably human cell lines. The results of such studies are generally predictive of toxicity in animals (eg, mammals) or, more specifically, humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models such as mice, rats, rabbits, dogs, or monkeys. The therapeutic effect of a particular compound can be established using several recognized methods such as in vitro methods, animal models or human clinical trials. When selecting a model to determine efficacy, one skilled in the art can be guided by the best current techniques to select the appropriate model, dose, route of administration and/or regimen. example

Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. Example 1 ( S )-3-(hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 1A ) and ( R )-3-(hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl) Amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 1B )

To a stirred degassed solution of methyl 2-aminobenzoate (2.50 g, 16.5 mmol) in PhMe (50 mL) was added 1-iodo-4-(trifluoromethyl)benzene (5.40 g, 19.9 mmol ), Cs ₂ CO ₃ (8.06 g, 24.8 mmol), Pd ₂ (dba) ₃ (1.50 g, 1.65 mmol), and BINAP (0.31 g, 0.50 mmol). After stirring at 100 °C for 16 h, the mixture was cooled to room temperature (rt), filtered through a pad of celite. The filter cake was washed with PhMe (3x). The combined filtrates were concentrated and the residue was purified by silica gel chromatography eluting with 7 to 10% EtOAc in petroleum ether to provide 2-((4-(trifluoromethyl)phenyl) amino) methyl benzoate (2.7 g, 9.1 mmol, 55%). MS (LCMS): m/z 296.50 [M+H] ⁺ .

To a stirred solution of methyl 2-((4-(trifluoromethyl)phenyl)amino)benzoate (3.50 g, 11.9 mmol) in _MeOH (7 mL) at rt was added _NH2NH2 (7.70 g, 15.4 mmol), and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated, triturated with water, filtered, and dried under reduced pressure to afford 2-((4-(trifluoromethyl)phenyl)amino)benzoylhydrazine (3.4 g, 97%), which was used directly in the next step. MS (LCMS): m/z 296.50 [M+H] ⁺ .

To a stirred solution of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (1.10 g, 4.41 mmol) in DMF (11 ml) at 0°C was added HOBt (1.70 g, 8.82 mmol), EDC·HCl (1.10 g, 8.83 mmol), and Et ₃ N (2.45 mL, 17.6 mmol). After 10 min, 2-((4-(trifluoromethyl)phenyl)amino)benzohydrazine (1.04 g, 3.53 mmol) was added. After stirring at rt for 16 h, water (40 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over _Na2SO4 , filtered, and evaporated under reduced pressure _. The residue was purified by silica gel chromatography using 5% MeOH:DCM to provide 1-(4-methoxybenzyl)-2-oxo- N '-(2-((4-(trifluoro Methyl)phenyl)amino)benzoyl)pyrrolidine-3-carbazide (1.2 g, 52%). MS (LCMS): m/z 525.42 [MH] ^- .

To 1-(4-methoxybenzyl)-2-oxo- N '-(2-((4-(trifluoromethyl)phenyl)amino)benzoyl)pyrrolidine-3 - To a stirred solution of carbazide (1.20 g, 2.28 mmol) in DCM (24 mL), TEA (0.95 mL, 6.8 mmol) and p-TsCl (521 mg, 2.73 mmol) were added. After stirring at rt for 16 h, water (30 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced _pressure . The residue was purified by silica gel chromatography using 80% EtOAc in petroleum ether to provide 1-(4-methoxybenzyl)-3-(5-(2-((4-(trifluoromethyl Base) phenyl) amino) phenyl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one (800 mg, 68%).

To 1-(4-methoxybenzyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4 at 0°C - To a solution of oxazol-2-yl)pyrrolidin-2-one (1.5 g, 2.9 mmol) in CH ₃ CN (30 mL) was added TEA (0.82 mL, 5.9 mmol), DMAP (72 mg, 0.59 mmol ), and (Boc) ₂ O (1.30 g, 5.90 mmol). The mixture was allowed to warm to rt, then stirred for 16 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex:EtOAc, 1:2) to provide (2-(5-(2-((tertiary butoxycarbonyl)oxy)-1-(4-methano Oxybenzyl)-4,5-dihydro-1 H -pyrrol-3-yl)-1,3,4- Oxadiazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (1.7 g, 81%). MS (LCMS): m/z 653.59 [M-56] ⁺ .

To (2-(5-(2-((tertiary butoxycarbonyl)oxy)-1-(4-methoxybenzyl)-4,5-dihydro-1 H - Pyrrol-3-yl)-1,3,4- A solution of tert-butyl oxazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (1.50 g, 1.41 mmol) in THF (20 mL) was added dropwise to 2.5 N n -BuLi in hexane (0.98 mL). The mixture was allowed to stir for 10 min. A solution of paraformaldehyde (634 mg, 21.1 mmol) in THF (5 mL) was added dropwise at -78 °C. The mixture was stirred for 1 h, whereupon it was warmed to 0 °C over the course of 2 h. The reaction was quenched with water (20 mL) followed by extraction with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex/EtOAc 1:3) to provide (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)-2- Pendant oxypyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (500 mg, 55%). MS (LCMS): m/z 583.56 [M-56] ⁺ .

To (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4 - To a stirred solution of oxadiazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (500 mg, 54.0 mmol) in DCM (5 mL) was added dropwise TEA (0.30 mL, 2.3 mmol), DMAP (19.0 mg, 0.156 mmol), and Ac ₂ O (0.20 mL, 2.0 mmol), then continued stirring at rt for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex:EtOAc, 1:1) to provide (3-(5-(2-((tertiary butoxycarbonyl)(4-(trifluoromethyl)benzene Base) amino) phenyl) -1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)methyl acetate (450 mg, 84%). MS (LCMS): m/z 625.63 [M-56] ⁺ .

To (3-(5-(2-((tertiary butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)methyl acetate (0.600 g, 0.882 mmol) in DCM (3 mL) To the stirred solution in , TFA (18 mL) and trifluoromethanesulfonic acid (0.70 mL, 4.4 mmol) were added. The mixture was allowed to warm to rt, then stirring was continued for 16 h. The mixture was concentrated, and saturated NaHCO ₃ solution (20 ml) was added to the residue. The mixture was extracted with DCM (3 x 30 mL). _The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH:DCM, 1:20) to provide 3-(hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl )amino)phenyl)-1,3,4- (S)-3-(hydroxymethyl)-3-(5 -(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 1A ) (40 mg; 8%) and ( R )-3-(hydroxymethyl)-3-(5-(2-((4-(tri Fluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 1B ) (32 mg; 10%). The stereochemistry of 1A and 1B is arbitrarily assigned. Preparative Chiral SFC Conditions String/Size : YMC-Pack Diol-120 (4.6 × 250 mm), 5 µ CO ₂ % : 80% Co-solvent % : 20% (MeOH) total flow : 60g/min back pressure : 100 bar temperature : 30°C Solubility : MeOH UV : 220nm

Compound 1A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.16 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.64-7.52 (m, 4H ), 7.32 (d, J = 8.4 Hz, 2H), 7.19-7.14 (m, 1H), 5.34 (t, J = 11.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.36-3.31 (m, 2H), 2.69-2.62 (m, 1H), 2.57-2.50 (m, 1H); MS (LCMS): m/z 419.2 [M+H] ⁺ . HPLC: 98.30%; Chiral HPLC: 99.89% (RT: 4.69 min).

Compound 1B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.16 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.64-7.52 (m, 4H ), 7.32 (d, J = 8.4 Hz, 2H), 7.19-7.14 (m, 1H), 5.34 (t, J = 11.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.36-3.31 (m, 2H), 2.69-2.62 (m, 1H), 2.57-2.50 (m, 1H); MS (LCMS): m/z 419.2 [M+H] ⁺ . HPLC: 97.49%; Chiral HPLC: 98.92% (RT: 6.54 min). Example 2 ( S )-3-(methyl-d3)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3, 4- Oxadiazol-2-yl)pyrrolidin-2-one ( 2A ) and ( R )-3-(methyl-d3)-3-(5-(3-((4-(trifluoromethyl)phenyl )amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 2B )

To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (10.0 g, 34.3 mmol) in MeOH (100 mL) was added NH ₂ NH _{2 · H2O} (17.2 g, 343 mmol). After heating at 70 °C for 16 h, the mixture was concentrated. The residue was triturated with n-pentane, filtered, and dried under reduced pressure to provide 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbazide (10.0 g, 98% ). MS (LCMS): m/z 264.13 [M+H] ⁺ .

3-bromo-2-pyridinecarboxylic acid (10.0 g, 49.5 mmol) and 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbazide (12.9 g, 49.5 mmol) were prepared at rt To a solution in DCM (100 mL) and DMF (30 mL), DIPEA (19.0 g, 147 mmol) and HATU (22.3 g, 58.8 mmol) were added. The mixture was stirred for 16 h. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 5 to 10% MeOH in DCM to afford 3-bromo- N' -(1-(4-methoxybenzyl)-2-pentan oxypyrrolidine-3-carbonyl) 2-pyridine hydrazide (picolinohydrazide) (10.0 g, 46%). MS (LCMS): m/z 445.46 [MH] ^- .

3-Bromo- N' -(1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonyl)2-pyridinecarbohydrazine (3.00 g, 6.71 mmol) at 0°C To a stirred solution in DCM (30 mL) was added _Et3N (2.00 g, 20.0 mmol) followed by pTsCl (1.36 g, 7.20 mmol). After stirring at rt for 16 h, the mixture was diluted with water (50 mL) and extracted with DCM (2 x 30 mL). _The combined organic layers were dried over _Na2SO4 and concentrated. The residue was purified by silica gel chromatography using 70 to 80% ethyl acetate in petroleum ether to provide 3-(5-(3-bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (1.00 g, 34%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.74-8.73 (m, 1H), 8.12 (dd, J= 8.4 Hz, J = 1.2 Hz, 1H), 7.35-7.32 (m, 1H), 7.21 (d, J = 8.4, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.51-4.41 (m, 2H), 4.20 (t, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.53-3.47 (m, 1H), 3.40-3.34 (m, 1H), 2.68-2.61 (m, 1H), 2.58-2.52 (m, 1H). MS (LCMS): m/z 429.32 [M+H] ⁺ .

Ethyl 3-(5-(3-bromopyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (1.00 g, 2.33 mmol) in THF (10 ml) was added to THF (4.67 mL , 4.67 mmol) of 1 M LiHMDS. After stirring for 30 min, CD ₃ I (0.672 g, 4.67 mmol) was added at -78°C. The mixture was allowed to warm to 0 °C, then stirred for 30 min. The reaction was quenched with saturated _NH4Cl (10 mL) and extracted with EtOAc (3 x 15 ml). _The combined organic layers were dried over _Na2SO4 and concentrated. The residue was purified by silica gel chromatography using EtOAc in hexanes to provide 3-(5-(3-bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-(methyl- _d3 )pyrrolidin-2-one (0.75 g, 72%). MS (LCMS): m/z 446.5 [M+H] ⁺ .

To 3-(5-(3-bromopyridin-2-yl)-1,3,4- Diazol-2-yl)-1-(4-methoxybenzyl)-3-(methyl- d ₃ )pyrrolidin-2-one (0.750 g, 1.68 mmol) in toluene (10 mL) To the stirred solution, 4-(trifluoromethyl)aniline (0.326 g, 2.02 mmol) and Cs ₂ CO ₃ (1.09 g, 3.36 mmol) were added. The mixture was degassed with nitrogen for 15 min, and _Pd2 (dba) ₃ (0.153 g, 0.168 mmol) and DPEphos (0.090 g, 0.168 mmol) were added. The mixture was heated at 100 °C for 16 h, cooled to rt, and filtered through a pad of celite. The filter cake was washed with toluene (3x). The combined filtrates were concentrated. The residue was purified by silica gel chromatography using EtOAc in petroleum ether to provide 1-(4-methoxybenzyl)-3-(methyl- d ₃ )-3-(5-(3- ((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one (0.52 g, 59%).

To 1-(4-methoxybenzyl)-3-(methyl-d3)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino) at 0°C Pyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)pyrrolidin-2-one (0.600 g, 1.14 mmol) in DCM (6 mL), trifluoromethanesulfonic acid (1.0 mL, 11 mmol) and TFA were added. After stirring at rt for 24 h, the reaction was quenched with saturated NaHCO ₃ (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by preparative HPLC to give a racemic mixture, which was further separated by chiral SFC to obtain ( S )-3-(methyl- d ₃ )-3-(5-(3 -((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 2A ) (55 mg, 9%) and ( R )-3-(methyl- d ₃ )-3-(5-(3-((4- (Trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 2B ) (45 mg, 8%). The stereochemistry of 2A and 2B is arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALPAK-IG (30 × 250) mm, 5 µm CO ₂ % : 75% Co-solvent % : 35% (0.2% 7N ammonia in MeOH in ACN:MeOH) (1:1) total flow : 110g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility : ACN + MeOH

Compound 2A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35-8.34 (m, 1H), 8.19 (s, 1H), 8.00-7.98 (m, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.42-3.37 (m, 2H), 2.72-2.67 (m, 1H) , 2.25-2.21 (m, 1H). MS (LCMS): m/z 407.50 [M+H] ⁺ . HPLC: 98.78%; chiral purity: 98.77% (RT: 2.61 min).

Compound 2B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35-8.34 (m, 1H), 8.19 (s, 1H), 8.00-7.98 (m, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.42-3.35 (m, 2H), 2.74-2.67 (m, 1H) , 2.27-2.20 (m, 1H). MS (LCMS): m/z 407.50 [M+H] ⁺ . HPLC: 99.36%; chiral purity: 96.76% (RT: 3.52 min). Example 3 ( S )-3-(aminomethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 3A ) and ( R )-3-(aminomethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl )amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 3B )

To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (5.00 g, 18.0 mmol) in DCM (125 mL) was added _{Cs2CO 3} (17.6 g, 54.1 mmol), followed by the addition of tert-butyl ((phenylsulfonyl)methyl)carbamate (8.80 g, 32.5 mmol). After stirring at rt for 16 h, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by silica gel column chromatography using 20% EtOAc:petroleum ether to provide 3-(((tertiary butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl yl)-2-oxopyrrolidine-3-carboxylic acid ethyl ester (3.6 g, 49%). MS (LCMS): m/z 351.41 [M-56] ⁺ .

To 3-(((tertiary butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid ethyl ester (3.60 g, 8.86 mmol) in THF:EtOH: _H2O (2:2:1, 36 mL) was added LiOH· _H2O (1.12 g, 26.6 mmol). The mixture was stirred at rt for 24 h, then concentrated under reduced pressure. Water (20 mL) was added. The mixture was acidified with 2N HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure to afford 3-(((tertiary-butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl ₎ - 2-oxopyrrolidine-3-carboxylic acid (2.9 g, 87%), which was used directly in the next step without further purification. MS (LCMS): m/z 323.37 [M-56] ⁺ .

3-(((tertiary butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (1.7 g, 4.49 mmol) in DMF (34 mL), were added EDC·HCl (2.24 g, 8.99 mmol), HOBT (1.21 g, 8.99 mmol), Et ₃ N (2.50 mL, 18.0 mmol), and 2-((4-(Trifluoromethyl)phenyl)amino)benzohydrazine (1.59 g, 5.39 mmol). After stirring at rt for 16 h, water (40 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by silica gel chromatography using 45% EtOAc:petroleum ether to provide ((1-(4-methoxybenzyl)-2-oxo-3-(2-(2-(( tert-butyl 4-(trifluoromethyl)phenyl)amino)benzoyl)hydrazine-1-carbonyl)pyrrolidin-3-yl)methyl)carbamate (2.0 g, 68%). MS (LCMS): m/z 654.44 [MH] ⁺ .

To ((1-(4-methoxybenzyl)-2-oxo-3-(2-(2-((4-(trifluoromethyl)phenyl)amino)benzene To a stirred solution of tert-butyl formyl)hydrazine-1-carbonyl)pyrrolidin-3-yl)methyl)carbamate (3.00 g, 4.58 mmol) in DCM (30 mL) was added DIPEA (1.50 mL , 9.16 mmol), followed by the addition of Burgess reagent (2.20 g, 9.16 mmol). After stirring at rt for 16 h, the reaction was quenched with water (30 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 40% EtOAc:petroleum ether to provide ((1-(4-methoxybenzyl)-2-oxo-3-(5-(2-(( 4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- (oxadiazol-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester (2.2 g, 75%). MS (LCMS): m/z 638.46 [M+H] ⁺ .

((1-(4-methoxybenzyl)-2-oxo-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)benzene Base) -1,3,4- To a stirred solution of tert-butyl (oxadiazol-2-yl)pyrrolidin-3-yl)methyl)carbamate (1.00 g, 1.57 mmol) in DCM (30 mL) was added TFA (30 mL), followed by Add trifluoromethanesulfonic acid (0.48 mL, 5.5 mmol). After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL), basified with saturated aqueous NaHCO ₃ , and extracted with EtOAc (3×30 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. The residue was purified by preparative HPLC to provide a racemic mixture, which was separated by chiral SFC to provide ( S )-3-(aminomethyl)-3-(5-(2-( (4-(Trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 3A ) (95 mg, 14%) and ( R )-3-(aminomethyl)-3-(5-(2-((4-( Trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 3B ) (96 mg, 15%). The stereochemistry of 3A and 3B is arbitrarily assigned.

Preparative HPLC method: column/dimensions: GEMINI NX C-18 (21.2 × 250 mm × 5 µ); mobile phase A: 10 Mm ABC in water; mobile phase B: acetonitrile (ORG); gradient (time/B %): 0.01/25, 1/25, 10/50, 17/50, 17.1/100, 24/100, 24.1/25, 26/25. Flow rate: 18 mL/min; Solubility: THF. Preparative SFC conditions String/Size : DCPAK-P4VP (30 × 250 mm), 5µ CO ₂ % : 60% Co-solvent % : 40% (MeOH) total flow : 110g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility : MeOH

Compound 3A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.45 (s, 1H), 7.90 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.49 (d, J =8.4 Hz, 1H), 7.41-7.37 (m, 3H), 6.98-6.94 (m, 1H), 5.83 (s, 1H), 3.67-3.61 (m, 1H), 3.57 -3.48 (m, 2H), 3.36 (d, J = 13.2 Hz, 1H), 2.89-2.83 (m, 1H), 2.67-2.60 (m, 1H), 1.25 (s, 2H). LC-MS: m/z 418.38 [M+H] ⁺ . HPLC: 98.88%; chiral purity: 99.90% (RT: 2.11 min).

Compound 3B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.45 (s, 1H), 7.90 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.49 (d, J =8.4 Hz, 1H), 7.41-7.37 (m, 3H), 6.98-6.94 (m, 1H), 5.83 (s, 1H), 3.67-3.61 (m, 1H), 3.57 -3.48 (m, 2H), 3.36 (d, J = 13.2 Hz, 1H), 2.89-2.83 (m, 1H), 2.67-2.60 (m, 1H), 1.25 (s, 2H). LC-MS: m/z 418.38 [M+H] ⁺ . HPLC: 98.92%; chiral purity: 99.58% (RT: 3.13 min). Example 4 ( R )-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 4A ) and ( S )-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 4B )

To 2-(methoxycarbonyl)phenyl)boronic acid (1.00 g, 5.56 mmol) in 1,4-bis To a stirred degassed solution in alkanes:H ₂ O (4:1, 10 mL), add 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.59 g, 6.67 mmol), K ₂ CO ₃ (1.54 g, 11.1 mmol), and Pd(dppf)Cl ₂ .DCM (453 mg, 0.556 mmol). After heating at 100 °C for 16 h, the mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography (5% EtOAc:petroleum ether) to provide methyl 2-(4-(trifluoromethyl)benzyl)benzoate (800 mg, 49%). MS (LCMS): 295.22 m/z [M+H] ⁺ .

To a stirred solution of methyl 2-(4-(trifluoromethyl)benzyl)benzoate (0.800 g, 2.72 mmol) in MeOH (8 mL) at rt was added _NH2NH2 ( _2.72 g, 54.4 mmol). After heating at 80 °C for 16 h, the mixture was concentrated under reduced pressure, washed with water (35 mL), and dried under reduced pressure to afford 2-(4-(trifluoromethyl)benzyl)benzoyl Hydrazine (600 mg, 75%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.49 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.40-7.24 (m , 4H), 4.44 (s, 2H), 4.18 (s, 2H). MS (LCMS): m/z 295.23 [M+H] ⁺ .

To a stirred solution of 2-(4-(trifluoromethyl)benzyl)benzoylhydrazine (800 mg, 2.72 mmol) in DMF (8 mL) at 0°C was added 3-methyl-2- Pyrrolidine-3-carboxylic acid (467 mg, 3.26 mmol), HOBt (735 mg, 5.44 mmol), EDC·HCl (1.00 g, 5.44 mmol), and TEA (1.50 mL, 10.9 mmol). After stirring at rt for 16 h, the reaction was quenched with water (15 mL) and extracted with EtOAc (2 x 30 mL). _The combined organic layers were dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 80% EtOAc in petroleum ether to provide 3-methyl-2-oxo- N' -(2-(4-(trifluoromethyl)benzyl ) benzoyl) pyrrolidine-3-carbazide (360 mg, 32% yield). MS (LCMS): m/z 420.39 [M+H] ⁺ .

3-Methyl-2-oxo- N' -(2-(4-(trifluoromethyl)benzyl)benzoyl)pyrrolidine-3-carbazide (0.150 g, 0.357 mmol) in DCM (4 mL), TEA (0.15 mL, 1.1 mmol) and pTsCl (0.147 g, 0.77 mmol) were added. After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 80% EtOAc in petroleum ether to provide a racemic mixture, which was separated by chiral SFC to provide ( R )-3-methyl-3-( 5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 4A ) (15.4 mg, 11%) and ( S )-3-methyl-3-(5-(2-(4-(trifluoromethyl) Benzyl)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one (4B) (9 mg, 6%). The stereochemistry of 4A and 4B was arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALPAK ADH (30 × 250 mm), 5 µ CO ₂ % : 70% Co-solvent% : 30% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility : MeOH

Compound 4A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.15 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.63-7.57 (m, 3H), 7.52-7.45 (m , 2H), 7.33 (d, J = 7.6 Hz, 2H), 4.51 (s, 2H), 3.37-3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.21-2.14 (m, 1H), 1.55 (s, 3H); MS (LCMS): m/z 400.28 [MH] ^- . LCMS purity: 99.79%; HPLC purity: 99.15%; chiral purity: 97.92% (RT: 2.05 min).

Compound 4B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.15 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.63-7.57 (m, 3H), 7.52-7.45 (m , 2H), 7.33 (d, J = 7.6 Hz, 2H), 4.51 (s, 2H), 3.37-3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.21-2.14 (m, 1H), 1.55 (s, 3H); MS (LCMS): m/z 400.28 [MH] ^- . LCMS purity: 98.52%; HPLC purity: 97.09%; chiral purity: 99.79% (RT: 3.68 min). Example 5 ( R )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 5A ) and ( S )-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 5B )

A stirred solution of methyl 3-bromo2-picolinate (1.0 g, 6.3 mmol) in PhMe (10 mL) was degassed and 4-(trifluoromethyl)aniline (1.75 g, 8.07 mmol) was added at rt. ), K ₂ CO ₃ (1.7 g, 12.6 mmol), Xantphos (364 mg, 0.63 mmol), and Pd(OAc) ₂ (141 mg, 0.63 mmol). The mixture was heated at 100 °C for 16 h. The mixture was filtered through a pad of celite, and the filter cake was washed with PhMe (3x). The combined filtrates were concentrated. The residue was purified by silica gel chromatography using 20% EtOAc in petroleum ether as eluent to afford methyl 3-((4-(trifluoromethyl)phenyl)amino)2-picolinate (1.02 g, 74%). MS (LCMS): 297.30 m/z [M+H] ⁺ .

To a stirred solution of methyl 3-((4-(trifluoromethyl)phenyl)amino)2-picolinate (1.00 g, 3.33 mmol) in MeOH (3 mL) was added _NH at rt _NH2 (2.0 mL, 33 mmol). After stirring at 80 °C for 16 h, the mixture was concentrated under reduced pressure. The mixture was filtered, washed with water (35 mL), and dried under reduced pressure to provide 3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbohydrazine (960 mg, 96% ). MS (LCMS): m/z 297.123 [M+H] ⁺ .

To a stirred solution of 3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbohydrazine (500 mg, 1.69 mmol) in DMF (8 mL) at 0°C was added 3 -Methyl-2-oxopyrrolidine-3-carboxylic acid (600 mg, 4.22 mmol), HOBt (456 mg, 3.37 mmol), EDC·HCl (648 mg, 3.37 mmol), and TEA (0.70 mL, 6.7 mmol). After stirring at rt for 16 h, the reaction was quenched with water (15 mL) followed by extraction with EtOAc (2 x 30 mL). _The combined organic layers were dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 80% EtOAc in petroleum ether to provide N '-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl)phenyl)amino)2-pyridinylhydrazine (400 mg, 57% yield). MS (LCMS): m/z 422.39 [M+H] ⁺ .

Towards N '-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbohydrazine at rt (800 mg, 1.90 mmol) in DCM (2 mL) was added TEA (0.60 mL, 5.7 mmol) and pTsCl (435 mg, 2.28 mmol). After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 80% EtOAc in petroleum ether to give a racemic mixture, which was further separated by chiral SFC to provide ( R )-3-methyl-3- (5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 5A ) (80 mg, 10%) and (S)-3-methyl-3-(5-(2-(4-(trifluoromethyl) Benzyl)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 5B ) (100 mg, 13%). The stereochemistry of 5A and 5B was arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALPAK-IC (30 × 250 mm), 5 µ CO ₂ % : 60% Co-solvent % : 40% (ACN:IPA) (1:1) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility :ACN

Compound 5A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.43-3.36 (m, 2H), 2.75-2.66 (m, 1H), 2.27-2.20 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 404.33 [M+H] ⁺ ; LCMS purity: 98.35%; HPLC purity: 95.03%; chiral purity: 99.97% (RT: 2.17 min).

Compound 5B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.43-3.36 (m, 2H), 2.75-2.66 (m, 1H), 2.27-2.20 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 404.33 [M+H] ⁺ ; LCMS purity: 95.54%; HPLC purity: 95.08%; chiral purity: 99.82% (RT: 2.98 min). Example 6 ( R )-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 6A ) and ( S )-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino) Pyridin-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 6B )

Example 6 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 6A and 6B was arbitrarily assigned. Preparative SFC conditions String/Size : LUX-CELLULOSE-4 (21 × 250 mm), 5 µ CO ₂ % : 70% Co-solvent% : 30% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility : MeOH+ACN

Compound 6A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 7.6, 1.6 Hz, 1H ), 8.21 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 8.0, 5.2 Hz, 1H), 3.49-3.39 (m, 2H), 2.83-2.75 (m, 1H), 2.29-2.21 (m, 1H), 1.64 (s, 3H). MS (LCMS): m/z 404.33 [M+H] ⁺ ; LCMS purity: 99.67%; HPLC purity: 99.41%; chiral purity: 99.94% (RT: 1.88 min).

Compound 6B : ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.24 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 7.6, 1.6 Hz, 1H ), 8.21 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 8.0, 5.2 Hz, 1H), 3.49-3.39 (m, 2H), 2.83-2.75 (m, 1H), 2.29-2.21 (m, 1H), 1.64 (s, 3H). MS (LCMS): m/z 404.33 [M+H] ⁺ ; LCMS purity: 99.22%; HPLC purity: 99.74%; chiral purity: 99.67% (RT: 2.95 min). Example 7 ( S )-3-methyl-3-(5-(2-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)-1,3,4 - Oxadiazol-2-yl)pyrrolidin-2-one ( 7A ) and ( R )-3-methyl-3-(5-(2-((5-(trifluoromethyl)pyridin-2-yl) Amino)pyridin-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 7B )

Example 7 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 7A and 7B is arbitrarily assigned. Preparative Chiral SFC Conditions String/Size : CHIRALPAK-IC (30 × 250 mm), 5 µm CO ₂ % : 60% Co-solvent % : 40% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C Solubility : MeOH UV : 215nm

Compound 7A : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (br s, 1H), 8.72-8.67 (m, 2H), 8.58-8.57 (m, 1H), 8.36 (dd, J =7.6 Hz , J =1.6 Hz, 1H), 8.21-8.19 (m, 2H), 7.26-7.23 (m, 1H), 3.48-3.36 (m, 2H), 2.80-2.74 (m, 1H), 2.27-2.21 (m , 1H), 1.63 (s, 3H); MS (LCMS): m/z 403.24 [MH] ^- ; HPLC: 99.15%; Chiral HPLC: 99.9% (RT: 3.36 min).

Compound 7B : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (br s, 1H), 8.72-8.7 (m, 2H), 8.56-8.57 (m, 1H), 8.36 (dd, J =7.6 Hz , J =1.6 Hz, 1H), 8.21-8.19 (m, 2H), 7.26-7.23 (m, 1H), 3.48-3.39 (m, 2H), 2.81-2.74 (m, 1H), 2.27-2.21 (m , 1H), 1.63 (s, 3H). MS (LCMS): m/z 403.24 [MH] ^- . HPLC: 98.64%. Chiral HPLC: 99.86% (RT: 4.64 min). Example 8 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridine -2-base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 8A ) and ( R )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino) Pyril -2-base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 8B )

Example 8 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 8A and 8B was arbitrarily assigned.

Preparative HPLC conditions: column/size: X SELECT C18-CSH filled with C8 (19 × 250 mm), 5 µ; mobile phase A: 10MM AMM-bicarbonate in water; mobile phase B: acetonitrile; gradient (time /B%): 0/30, 1/30, 7/60, 12.9/60, 13.0/100, 17/100, 17.1/30, 20/30; flow rate: 18 ml/min; solubility: THF + acetonitrile + water. Preparative Chiral SFC Conditions String/Size : CHIRALCEL-OX-H (30 × 250 mm), 5 µm CO ₂ % : 60% Co-solvent% : 40% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C Solubility : MeOH UV : 295nm

Compound 8A : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.23 (s , 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.75 (d, J =8.4 Hz, 2H), 3.48-3.38 (m, 2H), 2.76-2.72 (m, 1H), 2.31-2.24 ( m, 1H), 1.65 (s, 3H); MS (LCMS): m/z 403.20 [MH] ^- ; HPLC: 99.83%; Chiral HPLC: 99.90% (RT: 3.60 min).

Compound 8B : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.23 (s , 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.75 (d, J =8.4 Hz, 2H), 3.45-3.38 (m, 2H), 2.79-2.72 (m, 1H), 2.31-2.24 ( m, 1H), 1.65 (s, 3H); MS (LCMS): m/z 403.20 [MH] ^- ; HPLC: 99.51%; Chiral HPLC: 99.85% (RT: 5.42 min). Example 9 ( S )-3-(5-(1,5-dimethyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazol-4-yl)- 1,3,4- Oxadiazol-2-yl)-3-methylpyrrolidin-2-one ( 9A ) and ( R )-3-(5-(1,5-dimethyl-3-((4-(trifluoromethyl Base) phenyl) amino) -1 H - pyrazol-4-yl) - 1,3,4- Oxadiazol-2-yl)-3-methylpyrrolidin-2-one ( 9B )

Example 9 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 9A and 9B was arbitrarily assigned.

Preparative HPLC method: column/size: X BRIDGE C18 (19 × 250, 5 µm); mobile phase A: 20 mM ABC in water pH; mobile phase B: 100% acetonitrile; gradient (time/B%): 0.01 /35, 1/35, 10/65, 13/65, 13.1/100, 17/100, 17.1/35, 19/35. Flow rate: 18 ml/min; diluent: acetonitrile + water + THF. Preparative Chiral SFC Conditions String/Size : CHIRALCEL-OX-H (30 × 250 mm), 5 µ CO ₂ % : 60% Co-solvent % : 40% (ACN:IPA (1:1)) total flow : 110g/min back pressure : 100 bar temperature : 30°C Solubility : MeOH UV : 293nm

Compound 9A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.60 (s, 1H), 8.12 (s, 1H), 7.61-7.56 (m, 4H), 3.78 (s, 3H), 3.36-3.31 (m, 2H), 2.67-2.59 (m, 1H), 2.52-2.51 (m, 3H), 2.20-2.14 (m, 1H), 1.54 (s, 3H); MS (LCMS): m/z 419.25 [ MH] ^- ; HPLC: 99.55%; chiral HPLC: 99.85% (RT: 2.16 min).

Compound 9B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.60 (s, 1H), 8.12 (s, 1H), 7.61-7.56 (m, 4H), 3.79 (s, 3H), 3.36-3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.52-2.51 (m, 3H), 2.20-2.14 (m, 1H), 1.54 (s, 3H); MS (LCMS): m/z 419.25 [ MH] ^- ; HPLC: 99.56%; Chiral HPLC: 97.9% (RT: 4.01 min). Example 10 ( R )-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 10A ) and ( S )-3-(5-(3-((4-(trifluoromethyl)phenyl)amino) Pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 10B )

To a solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (10.0 g, 36.1 mmol) in DMF (30 mL) at 0°C, add NaH (2.16 g, 54.09 mmol). The mixture was stirred for 30 min, then 1,2-dibromoethane (6.2 mL, 72.12 mmol) was added. Stirring was continued for 6 h at rt. The reaction was quenched with saturated _NH4Cl (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography using 40% EtOAc in petroleum ether as eluent to provide 3-(2-bromoethyl)-1-(4-methoxybenzyl)-2- Oxypyrrolidine-3-carboxylic acid ethyl ester (12 g, 65%). MS (LCMS): m/z 384.25 [M+H] ⁺ .

Add 3-(2-bromoethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid ethyl ester (10.0 g, 26.0 mmol) in toluene at 0°C (10 mL), DBU (7.7 mL, 52 mmol) was added. After heating at 80 °C for 16 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography using 50% EtOAc in petroleum ether to provide 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxy ethyl acetate (4.0 g, 44%). MS (LCMS): m/z 304.37 [M+H] ⁺ .

Add 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid ethyl ester (1.00 g, 3.30 mmol) in THF:EtOH:H ₂ at 0°C To a stirred solution in O (1:1:1, 10 mL), LiOH·H ₂ O (270 mg, 6.60 mmol) was added. After stirring for 1 h at rt, the organic solvent was removed. The residue was acidified with 2 N HCl, then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine _, dried over _Na2SO4 , filtered, concentrated, and dried under reduced pressure to afford 1-(4-methoxybenzyl)-2-oxo-3-ethene 1-pyrrolidine-3-carboxylic acid (1.0 g), which was used in the next step without further purification. MS (LCMS): m/z 276.25 [M+H] ⁺ .

1-(4-Methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (1.00 g, 3.63 mmol) was stirred in DMF (10 mL) at 0°C To the solution, add DIPEA (2.50 mL, 14.5 mmol), HATU (2.76 g, 7.28 mmol), and 3-((4-(trifluoromethyl)phenyl)amino) 2-pyridylhydrazine (650 mg , 2.19 mmol). After stirring at rt for 16 h, the reaction was quenched with water (15 mL) followed by extraction with EtOAc (3 x 30 mL). The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by silica gel chromatography using EtOAc in petroleum ether to provide N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3 -carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbohydrazine (1.0 g, 61%). MS (LCMS): m/z 554.60 [M+H] ⁺ .

N' -(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl) )phenyl)amino)2-pyridinecarbohydrazine (1.00 g, 1.81 mmol) in DCM (10 mL) was added DIPEA (0.62 mL, 3.6 mmol) and Burgess reagent (0.86 g, 3.6 mmol ). After stirring at rt for 16 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography using EtOAc in petroleum ether to provide 1-(4-methoxybenzyl)-3-(5-(3-((4-(trifluoromethyl) Phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.15 g, 13%). MS (LCMS): m/z 536.59 [M+H] ⁺ .

To 1-(4-methoxybenzyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1 at 0°C, 3,4- To a stirred solution of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.40 g, 0.75 mmol) in DCM (6 mL) was added trifluoromethanesulfonic acid (0.35 mL, 3.7 mmol) and TFA (12 mL). After stirring at rt for 16 h, the reaction was quenched with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography using EtOAc in hexanes to give a racemic mixture which was further separated by chiral SFC to provide ( R )-3-(5-(3-( (4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 10A ) (30 mg, 9.6%) and ( S )-3-(5-(3-((4-(trifluoromethyl ) phenyl) amino) pyridin-2-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 10B ) (25 mg, 8%). The stereochemistry of 10A and 10B was arbitrarily assigned. Preparative Chiral SFC Conditions String/Size : YMC PACK DIOL-120 (20 × 250 mm), 5 µ CO ₂ % : 70% Co-solvent % : 30% (MeOH) total flow : 60g/min back pressure : 100 bar temperature : 30°C Solubility : MeOH + ACN UV : 298nm

Compound 10A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.27 (br s, 1H), 8.35-8.32 (m, 2H), 7.99 (d, J= 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.30-6.23 (m, 1H), 5.47-5.41 (m, 2H), 3.44- 3.39 (m, 1H), 3.281 (m, 1H), 2.83- 2.76 (m, 1H), 2.57- 2.54 (m, 1H); MS (LCMS): m/z 414.22 [MH] ^- ; HPLC purity: 99.25% ; Chiral purity: 99.96% (RT: 2.37 min).

Compound 10B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.27 (s, 1H), 8.35-8.32 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.4 Hz, J = 4.4 Hz, 1H), 7.43-7.41 (m, 2H), 6.30-6.23 (m, 1H), 5.47-5.41(m, 2H) , 3.44-3.32 (m, 1H), 3.28-3.27 (m, 1H), 2.79-2.77 (m, 1H), 2.58-2.56 (m, 1H); MS (LCMS): m/z 414.22 [MH] ^- ; HPLC purity: 99.%; chiral purity: 98.78% (RT: 3.40 min). Example 11 ( S )-1-(hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 11 )

To (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- To a solution of oxadiazol-2-yl)pyrrolidin-2-one (41.3 mg, 0.103 mmol) in THF (5 mL), potassium carbonate (284 mg, 2.053 mmol) and 37% aqueous formaldehyde (0.167 mL, 2.05 mmol). After stirring overnight at rt, water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide (S)-1-(hydroxymethyl)-3-methyl-3-(5-(2 -((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 11) (13 mg, 29%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.13 (s, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 1.0 Hz, 2H), 7.58-7.53 (m , 2H), 7.31 (d, J = 1.0 Hz, 2H), 7.19-7.13 (m, 1H), 6.02 (t, J = 1.0 Hz, 1H), 4.70-4.56 (m, 2H), 3.63-3.49 ( m, 2H), 2.72-2.57 (m, 1H), 2.20-2.10 (m, 1H), 1.58 (s, 3H). MS (LCMS): m/z 415.1 [M+H-18] ⁺ . Example 12 ( R )-1-(hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3 ,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 12 )

Example 12 was synthesized similarly to Example 11. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.15 (s, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 1.0 Hz, 2H), 7.57-7.54 (m , 2H), 7.31 (d, J = 1.0 Hz, 2H), 7.20-7.13 (m, 1H), 6.02 (t, J = 1.0 Hz, 1H), 4.71-4.57 (m, 2H), 3.63-3.47 ( m, 2H), 2.72-2.58 (m, 1H), 2.23-2.09 (m, 1H), 1.58 (s, 3H). MS (LCMS): m/z 415.1 [M+H-18] ⁺ . Example 13 ( S )-1-(hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 13 )

Example 13 was synthesized similarly to Example 11. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.29 (s, 1H), 8.34 (dd, J = 4.4, 1.3 Hz, 1H), 7.99 (dd, J = 8.6, 1.2 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.53 (dd, J = 8.7, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.04 (t, J = 7.1 Hz, 1H), 4.71 -4.60 (m, 2H), 3.62-3.54 (m, 2H), 2.76-2.64 (m, 1H), 2.25-2.16 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 416.1 [M+H-18] ⁺ . Example 14 ( R )-1-(hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 14 )

Example 14 was synthesized similarly to Example 11. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35 (dd, J = 4.3, 1.3 Hz, 1H), 8.00 (dd, J = 8.6, 1.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.6, 4.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.05 (t, J = 7.2 Hz, 1H), 4.73 -4.59 (m, 2H), 3.66-3.55 (m, 2H), 2.74-2.64 (m, 1H), 2.26-2.16 (m, 1H), 1.63 (s, 3H). MS (LCMS): m/z 416.1 [M+H-18] ⁺ . Example 15 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1, 2-b]pyrazol-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 15 )

To a solution of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (568 mg, 3.15 mmol) in DMF (2 mL) was added NBS (673 mg, 3.78 mmol). After stirring overnight at rt, water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography to provide ethyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (806 mg, 99%). MS (LCMS): m/z 259, 261 [M+2] ⁺ .

3-Bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (263 mg, 1.01 mmol), 4-(trifluoromethyl)aniline ( 196 mg, 1.22 mmol), and cesium carbonate (992 mg, 3.05 mmol) in two The mixture in alkanes (8 mL) was degassed by bubbling nitrogen for 1 min before adding Pd(dba) ₃ (93 mg, 0.102 mmol) and Xantphos (117 mg, 0.203 mmol). The mixture was heated at 95 °C for 4 h, then cooled to rt. Water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to provide 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b] Ethyl pyrazole-2-carboxylate (160 mg, 46%). MS (LCMS): 340.1 m/z [M+H] ⁺ .

To ethyl 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (167 mg , 0.492 mmol) in anhydrous MeOH (2 mL), hydrazine monohydrate (1 mL, 19.98 mmol) was added. After heating at 80 °C overnight, the mixture was concentrated, and the residue was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 3-((4-(trifluoromethyl)phenyl)amino)-5,6-di Hydrogen-4H-pyrrolo[1,2-b]pyrazole-2-carbazide (90 mg, 56%). MS (LCMS): m/z 326.1 [M+H] ⁺ .

To 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbazide (90 mg, 0.277 mmol) in DMF (6 mL), add (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (39.6 mg, 0.277 mmol), HATU (210 mg, 0.553 mmol ), DMAP (33.8 mg, 0.277 mmol), and DIPEA (0.15 mL, 0.83 mmol). After stirring overnight at rt, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide (R)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl )-3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbazide (59 mg, 47%). MS (LCMS): m/z 451.1 [M+H] ⁺ .

To (R)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)-5,6- To a solution of dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbazide (59 mg, 0.13 mmol) in DCM (5 mL) was added tosyl-Cl (30 mg, 0.157 mmol) and TEA (0.050 mL, 0.359 mmol). After stirring overnight at rt, the mixture was treated with EtOAc (20 mL) and saturated NaHCO ₃ (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide the crude product. The residue was further purified by HPLC eluting with 0 to 100% MeCN:H ₂ O containing 0.1% formic acid. The product fractions were combined, neutralized with saturated aqueous NaHCO ₃ , and extracted with EtOAc (2×20 mL). _The combined organic phases were dried over _Na2SO4 , filtered and concentrated. Dissolve the residue in 1,4-bis (1 mL), refrigerated, and lyophilized overnight to provide ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)- 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 15 ) (9.4 mg, 16%). ¹ H NMR (400 MHz, CD ₃ OD): δ 7.40 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.29-4.21 (m, 2H), 3.44-3.37 ( m, 2H), 2.91-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.63-2.54 (m, 1H), 2.26-2.15 (m, 1H), 1.61 (s, 3H). MS (LCMS): m/z 433.1 [M+H] ⁺ . Example 16 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 16 )

Example 16 was synthesized similarly to Example 15. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.36 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.23 (t, J = 6.1 Hz, 2H), 3.41 -3.32 (m, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.52-2.41 (m, 1H), 2.20-2.08 (m, 3H), 1.95-1.86 (m, 2H), 1.56 (s , 3H). MS (LCMS): m/z 447.2 [M+H] ⁺ . Example 17 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-2-yl )-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 17 )

Example 17 was synthesized similarly to Example 15. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.86 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.58-7.51 (m, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.38-7.32 (m, 1H), 7.14 (dt, J = 6.9, 1.3 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.32-3.24 ( m, 2H), 2.49-2.44 (m, 1H), 2.20-2.09 (m, 1H), 1.51 (s, 3H). MS (LCMS): m/z 443.2 [M+H] ⁺ . Example 18 ( S )-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl )-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 18 )

Example 18 was synthesized similarly to Example 15. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.93 (s, 1H), 8.77 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H ), 7.79-7.75 (m, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.60-7.53 (m, 1H), 7.07-7.01 (m, 1H), 3.40-3.31 (m, 2H), 2.78-2.66 (m, 1H), 2.22-2.12 (m, 1H), 1.56 (s, 3H). MS (LCMS): m/z 443.1 [M+H] ⁺ . Example 19 3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1, 3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 19 )

Example 19 was synthesized similarly to Example 15. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.62-8.60 (m, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.89-7.85 (m, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.56-7.49 (m, 1H), 7.05-6.98 (m, 1H), 3.64-3.50 (m, 2H), 2.98-2.89 (m, 1H), 2.41-2.33 (m, 1H), 1.76 (s, 3H). MS (LCMS): m/z 443.1 [M+H] ⁺ . Example 20 ( S )-3-methyl-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazol-3-yl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 20 )

To a solution of methyl 4-bromo-lH-indazole-3-carboxylate ₍ 1.06 g, 4.14 mmol) in DMF (6 mL) was added _K2CO3 (1.72 g, 12.4 mmol). The mixture was stirred at rt for 1 h, then iodomethane (0.881 g, 6.21 mmol) in DMF (1 mL) was added. After stirring overnight at rt, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to provide methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (755 mg, 68%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.83 (dd, J = 8.5, 0.7 Hz, 1H), 7.56 (dd, J = 7.4, 0.7 Hz, 1H), 7.44-7.37 (m, 1H) , 4.14 (s, 3H), 3.91 (s, 3H). MS (LCMS): m/z 270.0 [M+2] ⁺ .

Methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (755 mg, 2.81 mmol), 4-(trifluoromethyl)aniline (542 mg, 3.37 mmol), and cesium carbonate ( 2.74 g, 8.42 mmol) in di The mixture in alkanes (8 mL) was degassed by bubbling nitrogen for 1 min, after which _Pd2 (dba) ₃ (257 mg, 0.281 mmol) and Xantphos (162 mg, 0.281 mmol) were added. After heating at 95 °C for 4 h, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to provide methyl 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3-carboxylate (620 mg, 63%). MS (LCMS): m/z 350.1 [M+H] ⁺ .

To 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3-carboxylic acid methyl ester (620 mg, 1.77 mmol) in anhydrous MeOH (3 mL) To the solution in , was added hydrazine monohydrate (1.0 mL, 20 mmol). After heating at 80 °C overnight, the mixture was concentrated, and the residue was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)- 1H-Indazole-3-carbazide (534 mg, 86%). MS (LCMS): m/z 350.1 [M+H] ⁺ .

To a solution of 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3-carbazide (78.0 mg, 0.223 mmol) in DMF (6 mL) In, add (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (32.0 mg, 0.223 mmol), DMAP (27.3 mg, 0.223 mmol), HATU (127 mg, 0.335 mmol), and DIPEA (0.12 mL, 0.68 mmol). After stirring overnight at rt, the mixture was treated with EtOAc (20 mL) and saturated NaHCO ₃ (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide (R)-1-methyl-N'-(3-methyl-2-oxopyrrole Pyridine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3-carbazide (96 mg, 91%). MS (LCMS): m/z 475.2 [M+H] ⁺ .

To ( R )-1-methyl-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino) To a solution of -1H-indazole-3-carbazide (96.0 mg, 0.202 mmol) in DCM (5 mL), add tosyl-Cl (46.3 mg, 0.243 mmol) and TEA (0.10 mL, 0.72 mmol ). After stirring overnight at rt, the mixture was treated with EtOAc (20 mL) and saturated NaHCO ₃ (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The crude product was purified by HPLC eluting with 0 to 100% MeCN:H ₂ O containing 0.1% formic acid. The product fractions were combined and concentrated. The residue was extracted with saturated NaHCO ₃ /EtOAc. The combined organic layers were dried over _Na2SO4 , concentrated, and dried under reduced pressure to provide ( S )-3-methyl-3-(5-(1 _- methyl-4-((4-( Trifluoromethyl)phenyl)amino)-1H-indazol-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 20 ) (35.0 mg, 36.4%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.32 (s, 1H), 8.22 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.51-7.39 (m, 3H), 7.31 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 4.18 (s, 3H), 3.46-3.37 (m, 2H), 2.80-2.69 (m, 1H), 2.25 ( ddd, J = 5.3, 7.4, 12.9 Hz, 1H), 1.63 (s, 3H). MS (LCMS): m/z 457.2 [M+H] ⁺ . Example 21 ( S )-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1, 2-b]pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 21 )

To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (0.85 g, 5.6 mmol) in MeOH (12 mL) was added diethyl ether (10 mL, 20 mmol) of 2M (diazomethyl)trimethylsilane. After stirring overnight at rt, the reaction was quenched with brine. The mixture was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, concentrated, and dried under reduced pressure to provide 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxy methyl ester (0.70 g, 75%). MS (LCMS): m/z 167.1 [M+H] ⁺ .

To a solution of methyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (1.40 g, 8.42 mmol) in MeCN (5 mL) at rt was added Br ₂ (0.65 mL, 13 mmol) and acetic acid (3.0 mL, 13 mmol). After heating at 80 °C for 16 h, the mixture was treated with EtOAc (20 mL) and 1M NaOH (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). _The combined organic layers were dried ( _Na2SO4 ) and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 2-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole - Methyl 3-carboxylate (1.39 g, 67%). MS (LCMS): m/z 245.0 [M], 247.0 [M+2].

To 2-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid methyl ester (175 mg, 0.714 mmol) and 4-(trifluoromethyl)aniline ( 138 mg, 0.857 mmol) in two To a solution in alkanes (8 mL), _Cs2CO3 (698 mg, 2.14 mmol) was added _. The mixture was degassed by bubbling nitrogen for 1 min before BrettPhos Pd G3 (64.7 mg, 0.07 mmol) and BrettPhos (77 mg, 0.143 mmol) were added. After heating at 95 °C for 4 h, the mixture was cooled to rt, and brine (20 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). _The combined organic layers were dried over _Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 2-((4-(trifluoromethyl)phenyl)amino)-5,6-di Hydrogen-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid methyl ester (182 mg, 78%). MS (LCMS): m/z 326.1 [M+H] ⁺ .

To 2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid methyl ester (182 mg , 0.56 mmol) in anhydrous MeOH (2 mL), hydrazine monohydrate (1 mL) was added. After heating at 80 °C for 16 h, the mixture was concentrated, and the residue was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc:hexanes to provide 2-((4-(trifluoromethyl)phenyl)amino)-5,6 - Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbazide (63 mg, 35%). MS (LCMS): m/z 326.1 [M+H] ⁺ .

To 2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbazide (63 mg, 0.19 mmol) in DMF (2 mL), add ( R )-3-methyl-2-oxopyrrolidine-3-carboxylic acid (27.7 mg, 0.194 mmol), DMAP (24 mg, 0.19 mmol ), HATU (147 mg, 0.387 mmol), and DIPEA (0.10 mL, 0.58 mmol). After stirring at rt for 16 h, the mixture was treated with brine (20 mL) and EtOAc (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide ( R )-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl )-2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbazide (70.5 mg, 81%). MS (LCMS): m/z 451.2 [M+H] ⁺ .

To ( R )-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-(trifluoromethyl)phenyl)amino)-5,6- To a solution of dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbazide (70 mg, 0.15 mmol) in DCM (1 mL) was added tosyl-Cl (44.4 mg, 0.233 mmol) and TEA (0.043 mL, 0.31 mmol). After stirring at rt for 16 h, the mixture was diluted with saturated NaHCO ₃ (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide ( S )-3-methyl-3-(5-(2-((4-(trifluoro Methyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 21 ) (23 mg, 34%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.55 (m, 4H), 4.17 (t, J = 7.2 Hz, 2H), 3.40 -3.35 (m, 2H), 3.14-3.04 (m, 2H), 2.66-2.55 (m, 3H), 2.22-2.12 (m, 1H), 1.55 (s, 3H). MS (LCMS): m/z 433.1 [M+H] ⁺ . Example 22 ( S )-3-methyl-3-(5-(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 22 )

Example 22 was synthesized similarly to Example 21. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.29 (s, 1H), 8.46 (dd, J = 1.6, 0.9 Hz, 1H), 8.09 (s, 1H), 8.04 (dd, J = 8.9, 2.4 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 4.19 (t, J = 7.3 Hz, 2H), 3.31-3.25 (m, 2H), 3.15-3.05 (m, 2H), 2.66- 2.56 (m, 2H), 2.48-2.43 (m, 1H), 2.17-2.05 (m, 1H), 1.48 (s, 3H). MS (LCMS): m/z 434.1 [M+H] ⁺ . Example 23 ( S )-3-methyl-3-(5-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 23 )

Example 23 was synthesized similarly to Example 21. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.73 (s, 1H), 8.68 (d, J = 2.6 Hz, 1H), 8.09 (dd, J = 2.4, 8.6 Hz, 1H), 8.05 (s , 1H), 7.70 (d, J = 8.8 Hz, 1H), 4.11 (t, J = 7.3 Hz, 2H), 3.32-3.27 (m, 2H), 3.07-2.99 (m, 2H), 2.58-2.48 ( m, 3H), 2.16-2.07 (m, 1H), 1.48 (s, 3H). MS (LCMS): m/z 434.1 [M+H] ⁺ . Example 24 and 25 ( R )-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4 - Oxadiazol-2-yl)pyrrolidin-2-one ( 24 ) and ( S )-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino )pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 25 )

1-(4-methoxybenzyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3 ,4- To a stirred solution of oxazol-2-yl)-3-vinylpyrrolidin-2-one (1.00 g, 1.87 mmol) in ACN (10 mL) was added triethylamine (0.78 mL, 5.6 mmol) at rt. ), DMAP (114 mg, 0.93 mmol), and Boc-anhydride (1.30 mL, 5.61 mmol). After stirring for 16 h, the mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give (2-(5-(1-(4 _- methoxybenzyl)-2-oxo-3-ethene Pyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (860 mg, 72%). LC-MS: m / z 636.37 [M+H] ⁺ .

To an ice-cold aqueous solution of 50% KOH (180 mL) was added diethyl ether (360 mL) with stirring. N -Methyl- N -nitrosourea (9.0 g, 87 mmol) was added portionwise over 10 min while maintaining the reaction temperature at approximately 0°C. The mixture was stirred at 0 °C for 2 h. Transfer the mixture to a separatory funnel. The organic layer was separated and dried over solid KOH (9 g). The ether layer containing diazomethane was transferred to a round bottom flask and cooled to -5°C. Add (2-(5-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (900 mg, 1.41 mmol) and Pd(OAc) ₂ (31.8 mg, 0.141 mmol ). The mixture was stirred at -5 °C for 1 h, then allowed to warm gradually to rt. The mixture was stirred at rt for 4 h, then filtered through a pad of celite. The filter cake was washed with diethyl ether (60 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 30% EtOAc in petroleum ether to provide (2-(5-(3-cyclopropyl-1-(4-methoxybenzyl)- 2-oxopyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (720 mg, 78%). LC-MS: m/z 650.66 [M+H] ⁺ .

To tertiary butyl (2-(5-(e-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl) 1,3, 4- To a stirred solution of oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl) (700 mg, 1.08 mmol) in DCM (21 mL) was added TFA (21 mL) and trifluoro Methanesulfonic acid (0.47 mL, 5.4 mmol). After the mixture was slowly warmed to rt, the mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure. Water (20 mL) was added to the resulting residue The mixture was basified with saturated aqueous NaHCO ₃ and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC purification followed by chiral SFC to provide ( R )-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl )-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 24 ) (12.4 mg, 39%) and ( S )-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl Base) phenyl) amino) pyridin-2-yl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 25 ) (12.2 mg, 38%). The stereochemistry of 24 and 25 was arbitrarily assigned. Preparative HPLC conditions: String/Size : X-bridge C18 (19 × 150 × 5 µm) mobile phase A : 10 mm ammonium bicarbonate in water mobile phase B :ACN Gradient (T%B) : 0.01/25, 1/25, 8/45, 15.5/45, 15.6/100, 22/100, 22.1/25, 24/25. flow rate : 17ml/min sample diluent : Acetonitrile + THF + water. Preparative SFC conditions String/Size : Chiralcel OD-H (30 × 250)mm, 5µ CO ₂ % : 70% Co-solvent% : 30% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 298nm Solubility : MeOH

Compound 24 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.32 (s, 1H), 8.35 (dd, J = 4.0, 0.8 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.4, 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.35-3.28 (m, 2H), 2.64-2.57 (m,1H), 2.14-2.08 (m, 1H), 1.58-1.54 (m, 1H), 0.69-0.54 (m, 3H), 0.35-0.31 (m, 1H) . LC-MS (ESI): 428.24 [MH] ^- . LCMS purity: 98.70. HPLC purity: 98.13%. Chiral purity: 99.92% (RT: 1.88 min).

Compound 25 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.32 (s, 1H), 8.35 (dd, J = 4.0, 0.8 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.4, 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.35-3.28 (m, 2H), 2.64-2.57 (m, 1H), 2.14-2.08 (m, 1H), 1.58-1.54 (m, 1H), 0.69-0.54 (m, 3H), 0.35-0.31 (m, 1H) . LC-MS (ESI): 428.39 [MH] ^- _. LCMS purity: 98.56. HPLC purity: 97.70%. Chiral purity: 99.59% (RT: 2.97 min). Examples 26 and 27 ( R )-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazol-4-yl)-1 ,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 26 ) and ( S )-3-(5-(1-methyl-3-((4-(trifluoromethyl)benzene Base) amino) -1 H -pyrazol-4-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 27 )

To 3-amino-1-methyl-1 H -pyrazole-4-carboxylic acid ethyl ester (4.00 g, 23.6 mmol) in 1,4-di To a stirred solution in alkanes (80 mL), 1-bromo-4-(trifluoromethyl)benzene (6.38 g, 28.4 mmol) and cesium carbonate (15.4 g, 47.3 mmol) were added. The mixture was degassed by nitrogen flow for 10 min, then Pd(OAc) ₂ (0.531 g, 2.36 mmol) and Xantphos (1.37 g, 2.36 mmol) were added. After stirring at 100 °C for 16 h, the mixture was diluted with EtOAc (100 mL) and filtered through a pad of Celite. The filter cake was washed with EtOAc (2 x 30 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 20% EtOAc in petroleum ether to give 1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1 H -Pyrazole-4-carboxylic acid ethyl ester (5.8 g, 78%). LC-MS: m/z 314.23 [M+H] ⁺ .

1-Methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carboxylic acid ethyl ester (4.00 g, 12.8 mmol) was dissolved in methanol ( To the stirred solution in 40 mL), hydrazine hydrate (6.14 mL, 192 mmol) was added. After stirring at 80 °C for 16 h, the mixture was concentrated under reduced pressure. The residue was triturated with toluene (2 x 20 mL). The residue was dissolved in EtOAc (30 mL) and cooled to 0 °C. Petroleum ether was added dropwise until a precipitate formed. The precipitate was filtered, washed with petroleum ether (30 mL), and dried under reduced pressure to give 1-methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H - Pyrazole-4-carbazide. LC-MS: m/z 300.28 [M+H] ⁺ .

To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (1.20 g, 4.36 mmol) in THF (12 mL) at rt , T3P (2.08 g, 6.54 mmol, 50% solution in EtOAc) and DIPEA (2.28 mL, 13.07 mmol) were added. After 10 min, 1-methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carbazide (1.04 g, 3.49 mmol) was added. After stirring at rt for 16 h, the mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine, separated, dried over potassium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 70% EtOAc in petroleum ether to provide N' -(1-(4-methoxybenzyl)-5-oxo-3-ethene Pyrrolidine-3-carbonyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carbazide (1.32 g, 54%) . LC-MS: m/z 557.62 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (s, 1H), 9.86 (s, 1H), 9.08 (br s, 1H), 8.82 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.43-5.31 (m, 2H), 4.60 (d, J = 14.4 Hz, 1H), 4.32 (d, J = 14.8 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 3.26-3.20 (m, 2H), 2.66-2.58 (m, 1H), 2.27-2.22 (m, 1H).

Towards N' -(1-(4-methoxybenzyl)-5-oxo-3-vinylpyrrolidine-3-carbonyl)-1-methyl-3-((4-( To a stirred solution of trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carbazide (1.30 g, 2.34 mmol) in DCM (26 mL) was added DIPEA (0.368 mL, 9.34 mmol) and Burgess reagent (2.22 g, 9.34 mmol). After stirring for 24 h, the mixture was diluted with DCM (30 mL), washed with water (50 mL), separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 70% EtOAc in petroleum ether to give 1-(4-methoxybenzyl)-3-(5-(1-methyl-3 -((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (1.23 g, 98%). LC-MS: m/z 539.60 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.37 (br s, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H) , 7.15 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.40 Hz, 2H), 6.31 (dd, J = 17.6, 10.8 Hz, 1H), 5.44-5.33 (m, 2H), 4.51 ( d, J = 14.8 Hz, 1H), 4.36 (d, J = 14.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.46-3.40 (m, 1H), 3.33-3.27 (m , 1H), 3.00-2.95 (m, 1H), 2.45-2.38 (m, 1H).

1-(4-methoxybenzyl)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyridine Azol-4-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (1.20 g, 2.87 mmol) in DCM (36 mL) was added TFA (36 mL) and trifluoromethanesulfonic acid ( 12 mL). After stirring for 16 h, the mixture was diluted with water (20 mL) and basified with saturated aqueous NaHCO ₃ . The mixture was extracted with DCM (2 x 100 mL). The organic layer was dried over _Na2SO4 , filtered, and concentrated under reduced _pressure . The residue was purified by flash column chromatography on silica gel using 8% methanol in dichloromethane to give a racemic mixture which was further separated by chiral SFC to provide ( R )-3 -(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 26 ) (150 mg, 16%) and ( S )-3-(5-(1-methyl-3-((4- (Trifluoromethyl)phenyl)amino) -1H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 27 ) (150 mg, 16%). The stereochemistry of 26 and 27 was arbitrarily assigned. Preparative SFC conditions String/Size : Chiralpak AS-H (30 × 250 × 5µ) CO ₂ % : 70% Co-solvent % : 30% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 274nm Solubility : MeOH

Compound 26 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.54 (br s, 1H), 8.42 (br s, 1H), 8.26 (s, 1H), 7.66-7.59 (m, 4H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.42-5.36 (m, 2H), 3.88 (s, 3H), 3.40-3.35 (m, 1H), 3.32-3.26 (m, 1H), 2.77-2.70 (m, 1H), 2.49-2.46 (m, 1H). LC-MS: m/z 417.28 [MH] ⁺ . LCMS purity: 99.75. HPLC purity: 99.34%. Chiral purity: 99.99% (RT: 1.86 min).

Compound 27 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.54 (br s, 1H), 8.42 (br s, 1H), 8.26 (s, 1H), 7.66-7.59 (m, 4H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.42-5.36 (m, 2H), 3.88 (s, 3H), 3.40-3.35 (m, 1H), 3.32-3.26 (m, 1H), 2.77-2.70 (m, 1H), 2.50-2.46 (m, 1H). LC-MS: m/z 417.25 [MH] ⁺ . LCMS purity: 99.89. HPLC purity: 99.37%. Chiral purity: 99.19% (RT: 2.59 min). Example 28 ( S )-1-methyl-3-(5-(3-methyl-2-side oxypyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)pyridin-2( 1H )-one ( 28 )

A suspension of 2-fluoro-4-iodonicotinic acid (3.0 g, 11 mmol) in 6M hydrochloric acid (60 mL) was heated at 100 °C for 1 h. After cooling the mixture to rt, the precipitate was filtered, washed with cold water (2 x 20 mL), and dried under reduced pressure to give 2-hydroxy-4-iodonicotinic acid (2 g, crude). The residue was dissolved in DMF (20 mL) and cooled to 0 °C. Potassium carbonate (2.0 g, 15 mmol) was added. After stirring for 30 min, iodomethane (2.3 mL, 38 mmol) was added at 0 °C. The mixture was allowed to warm to rt. The mixture was stirred for 16 h, then poured into ice-cold water (200 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was triturated in pentane to afford methyl 4-iodo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (1.1 g, 33%) which Used directly in the next step without further purification. MS (LCMS): 294.1 m/z [M+H] ⁺ .

To 4-iodo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (1.10 g, 3.76 mmol) in 1,4 di To a stirred solution in alkanes (10 mL), 4-(trifluoromethyl)aniline (0.73 g, 4.5 mmol) and _K2CO3 (1.0 g, 7.5 mol) _were added. After the mixture was degassed with argon for 15 min, Pd(OAc) ₂ (0.084 g, 0.37 mmol) and Xantphos (0.217 g, 0.37 mmol) were added. The mixture was stirred at 100 °C for 16 h. After cooling to rt, the mixture was diluted with EtOAc (50 mL), then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 5% MeOH in DCM as eluent to afford 1-methyl-2-oxo-4-((4-(trifluoromethyl)benzene (yl)amino)-1,2-dihydropyridine-3-carboxylic acid methyl ester (0.98 g, 80%). MS (LCMS): 327.3 m/z [M+H] ⁺ .

Methyl 1-methyl-2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine (0.98 g, 3.0 mmol) at rt To a stirred solution in MeOH (10 mL) was added hydrazine hydrate (5 mL). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure and co-evaporated with toluene (2 x 20 mL) to give 1-methyl-2-oxo-4-((4-(trifluoromethyl)phenyl)amino )-1,2-dihydropyridine-3-carbazide (0.87 g, 88%), which was used in the next step without further purification. MS (LCMS): m/z 327.3 [M+H] ⁺ .

1-methyl-2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine-3-carbazide (0.87 g , 2.6 mmol) in DMF (8.7 mL), add (R-3-methyl-2-side oxypyrrolidine-3-carboxylic acid (0.57 g, 3.9 mmol), HOBt (0.7 g, 5.3 mmol), EDC·HCl (1 g, 5.3 mmol), and TEA (1.1 mL, 8 mmol). After stirring at rt for 16 h, water (30 mL) was added. The mixture was washed with EtOAc (3 × 50 mL) Extraction. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 80% EtOAc in petroleum ether as eluent , to provide ( R )-1-methyl- N '-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-oxo-4-((4-(trifluoromethyl yl)phenyl)amino)-1,2-dihydropyridine-3-carbazide (0.84 g, 70%). MS (LCMS): m/z 452.7 [M+H] ⁺ .

To ( R )-1-methyl- N '-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-oxo-4-((4-(tri To a stirred solution of fluoromethyl)phenyl)amino)-1,2-dihydropyridine-3-carbazide (0.200 g, 0.462 mmol) in DCM (8 mL) was added DIPEA (0.3 mL, 1.38 mmol ) and Burgess reagent (660 g, 2.76 mmol). After the mixture was allowed to warm to rt, the mixture was stirred for 16 h. Water (10 mL) was added, and the mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by non-chiral preparative SFC (Chiralpak-IG, 30 × 250 mm, 5 u; 60% CO ₂ , 40% iPrOH, total flow rate 100 g/min, back pressure 100 bar, temperature 30°C) to Provides (S)-1-methyl-3-(5-(3-methyl-2-oxopyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)pyridin-2(1H)-one ( 28 ) (50 mg, 25%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.24 (s, 1H), 8.12 (s, 1H), 7.77-7.73 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 6.21 (d, J = 7.6 Hz, 1H), 3.49-3.34 (m, 5H), 2.64-2.58 (m, 1H), 2.23 – 2.16 (m, 1H), 1.57 (s, 3H). MS (LCMS): 434.43 m/z [M+H] ⁺ _. LCMS purity: 98.9%. HPLC purity: 98.7%. Chiral purity: 99.43% (RT: 3.95 min). Example 29 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-thiadi Azol-2-yl)pyrrolidin-2-one ( 29A ) and ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridine -2-yl)-1,3,4-thiadiazol-2-yl)pyrrolidine-2-thione ( 29B )

To a stirred solution of ( R )-3-methyl-2-oxopyrrolidine-3-carboxylic acid (348 mg, 2.43 mmol) in DMF (6 mL) was added HOBt (546 mg , 4.05 mmol), EDC·HCl (778 mg, 4.05 mmol), TEA (1.1 mL, 8.1 mmol), and 3-((4-(trifluoromethyl)phenyl)amino) 2-picolylhydrazine (600 mg, 2.03 mmol). After the resulting suspension was stirred at rt for 16 h, water (15 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 3% methanol in DCM as eluent to provide ( S ) -N '-(3-methyl-2-oxopyrrolidine -3-Carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)-2-pyridinecarbohydrazine (650 mg, 76%). MS (LCMS): 422.43 m/z [M+H] ⁺ .

To ( S ) -N' -(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)-2 at rt - To a stirred solution of picolylhydrazine (600 mg, 1.43 mmol) in THF (12 mL) was added Lawesson's reagent (693 mg, 1.71 mmol). After stirring the resulting suspension at 60 °C for 3 h, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge C18, 19x150 mm, 5 µ; mobile phase A: 10 mM ammonium bicarbonate in water; mobile phase B: acetonitrile; flow rate: 18 mL/min) to provide ( R )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-thiadiazole-2- yl)pyrrolidin-2-one ( 29A ) (5.7 mg, 0.72%) and ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amine yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-2-thione ( 29B ) (14.5 mg, 2.06%).

Compound 29A : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.05 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.55-7.39 (m, 3H), 3.46-3.32 (m, 2H), 2.89-2.82 (m, 1H), 2.37-2.30 (m, 1H), 1.58 (s, 3H); MS (LCMS): m/z 418.23 [MH] ^- . HPLC purity: 96.84%. Chiral purity: 99.63% (RT: 2.75 min).

Compound 29B : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.67 (br s, 1H), 10.04 (s, 1H), 8.25 (dd, J =4.0, 1.2 Hz, 1H), 7.99 (dd, J = 8.8, 1.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.55-7.39 (m, 3H), 3.64 (t, J = 6.8 Hz, 2H), 3.06-3.00 (m, 1H ), 2.41-2.33 (m, 1H), 1.71 (s, 3H). MS (LCMS) m/z 434.21 [MH] ^- . HPLC purity: 99.23%; chiral purity: 99.86% (RT: 3.67 min). Example 30 ( S )-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,2,4- Oxadiazol-5-yl)pyrrolidin-2-one ( 30 )

3-bromo-2-pyridinecarbonitrile (444 mg, 2.43 mmol), 4-(trifluoromethyl)aniline (469 mg, 2.91 mmol), and cesium carbonate (2.37 g, 7.28 mmol) were dissolved in The mixture in alkanes (20 mL) was bubbled with nitrogen for 1 min, after which Pd(dppf) _2Cl2 ( ₃₅₅ mg, 0.485 mmol) and Xantphos (281 mg, 0.485 mmol) were added. After stirring at 95 °C overnight, brine (50 mL) was added. The mixture was extracted with EtOAc (50 mL). After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by flash column chromatography on silica gel, eluting with 0 to 70% EtOAc, to provide 3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbonitrile ( 404 mg, 63%). LC-MS exact mass calculated: 263.07, found: MS (APCI) m/z 264.1 [M+H] ⁺ .

To 3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbonitrile (404 mg, 1.54 mmol), hydroxylamine hydrochloride (1.07 g, 15.4 mmol) in di To a mixture in alkanes:water (30:20 mL), sodium bicarbonate (1.29 g, 15.35 mmol) was added portionwise. After stirring overnight at rt, the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered, and concentrated _. The residue was purified by flash chromatography on silica gel, eluting with EtOAc:hexanes, to provide (Z)-N'-hydroxy-3-((4-(trifluoromethyl)phenyl)amino) 2-picolinimidamide. LC-MS exact mass calculated: 296.09, found: MS (APCI) m/z 297.1 [M+H] ⁺ .

(Z)-N'-hydroxy-3-((4-(trifluoromethyl)phenyl)amino) 2-pyridinecarboxamidine (113 mg, 0.38 mmol), (R)-3-methyl- 2-oxopyrrolidine-3-carboxylic acid (54.6 mg, 0.38 mmol), EDCI (110 mg, 0.57 mmol), and HOBt (88 mg, 0.57 mmol) in 1,4-bis The mixture in alkanes (6 mL) was stirred overnight at 70 °C. After cooling to rt, the mixture was diluted with saturated aqueous NaHCO ₃ , then extracted with EtOAc (3×20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography to give ( S )-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridine-2 -base)-1,2,4- Oxadiazol-5-yl)pyrrolidin-2-one ( 30 ) (12.2 mg, 7.9%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.46 (s, 1H), 8.28-8.17 (m, 1H), 8.06 (s, 1H), 8.00-7.93 (m, 1H), 7.68 (d, J = 1.0 Hz, 2H), 7.55-7.41 (m, 1H), 7.32 (d, J = 1.0 Hz, 2H), 3.44-3.21 (m, 2H), 2.74 (ddd, J = 5.9, 8.3, 13.0 Hz , 1H), 2.05-2.00 (m, 1H), 1.43 (s, 3H). LC-MS exact mass calculated: 403.13, found: MS (APCI) m/z 404.1 [M+H] ⁺ . Example 31 ( S )-3-methyl-3-(3-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl) -1,2,4- Oxadiazol-5-yl)pyrrolidin-2-one ( 31 )

5-Bromo-1,2-dimethyl-1H-imidazole-4-carboxylic acid methyl ester (263 mg, 2.15 mmol), 4-(trifluoromethyl)aniline (581 mg, 2.58 mmol), and carbonic acid Cesium (2.1 g, 6.46 mmol) in di The mixture in alkanes (20 mL) was bubbled with nitrogen for 1 min, after which BrettPhos Pd G3 (195 mg, 0.22 mmol) and BrettPhos (116 mg, 0.22 mmol) were added. After stirring at 90 °C overnight, brine (50 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography to give 1,2-dimethyl-5-((4-(trifluoromethyl)phenyl)amino)-1H-imidazole-4-carboxylic acid methyl ester. LC-MS exact mass calculated: 266.08, found: MS (APCI) m/z 267.1 [M+H] ⁺ .

To 1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbonitrile (108 mg, 0.406 mmol) and hydroxylamine hydrochloride (282 mg, 4.06 mmol) in two To a mixture in alkanes:water (30:20 mL), sodium bicarbonate (341 mg, 4.06 mmol) was added portionwise. After stirring overnight at rt, the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel flash chromatography eluting with EtOAc:hexanes (20% 7N NH ₃ in MeOH) to provide (Z)-N'-hydroxy-1-methyl-3 -((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxamidine (41 mg, 34%). LC-MS exact mass calculated: 299.1, found: MS (APCI) m/z 300.1 [M+H] ⁺ .

( Z )-N'-hydroxyl-1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxamidine (41 mg, 0.137 mmol) , ( R )-3-methyl-2-oxopyrrolidine-3-carboxylic acid (19.6 mg, 0.137 mmol), EDCI (39.4 mg, 0.206 mmol), and HOBt (31.5 mg, 0.206 mmol) in 1 ,4-two The mixture in alkanes (2 mL) was stirred overnight at 70 °C. After cooling to rt, the mixture was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (3×20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by flash chromatography on silica gel to give ( S )-3-methyl-3-(3-(1-methyl-3-((4-(trifluoromethyl)phenyl) Amino)-1H-pyrazol-4-yl)-1,2,4- Oxadiazol-5-yl)pyrrolidin-2-one ( 31 ) (3.1 mg, 5.6%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.80-8.70 (m, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.33 (s, 48H), 3.31-3.26 (m, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.19-2.03 ( m, 1H), 1.49 (s, 3H). LC-MS exact mass calculated: 406.14, found: MS (APCI) m/z 407.1 [M+H] ⁺ .

Examples 32 to 47 were prepared using procedures similar to those shown for Examples 1, 2, 5, and 15, and using appropriate starting materials either readily commercially available or prepared by known and published procedures. [Table A] compound structure IUPAC name ¹ H NMR (400 Hz): δ ppm LCMS (m/z) 32* ( S )-3-methyl-3-(5-(3-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)amino)pyridin-2-yl)-1 ,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 8.19 (s, 1H), 8.14 (dd, J = 4.0, 1.2 Hz, 1H), 7.99 (s, 1H), 7.70 (dd, J = 8.8, 1.2 Hz, 1H), 7.44 ( dd, J = 8.4, 4.4 Hz, 1H), 3.43-3.37 (m, 2H), 2.74-2.67 (m, 1H), 2.47 (s, 6H), 2.26-2.20 (m, 1H), 1.60 (s, 3H). 394.41 [M+H] ⁺ 33* ( R )-3-methyl-3-(5-(3-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)amino)pyridin-2-yl)-1 ,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ ): δ 8.19 (s, 1H), 8.14 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (s, 1H), 7.70 (dd, J = 8.8, 1.2 Hz, 1H), 7.44 (dd, J = 8.4, 4.4 Hz, 1H), 3.44-3.37 (m, 2H), 2.74-2.67 (m, 1H), 2.47 (m, 6H), 2.26-2.20 (m, 1H), 1.61 (s , 3H). 394.41 [M+H] ⁺ 34* ( R )-3-(difluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ δ 9.20 (s, 1H), 8.67 (s, 1H), 8.37 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d , J = 8.8, 2H), 7.57-7.54 (m, 1H), 7.40 (d, J = 8.4, 2H), 6.77 (t, J = 54.4 Hz, 1H), 3.49-3.40 (m, 2H), 2.79 -2.69 (m, 2H). 440.71 [M+H] ⁺ 35* ( S )-3-(difluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ δ 9.20 (s, 1H), 8.67 (s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d , J = 8.8, 2H), 7.57-7.54 (m, 1H), 7.40 (d, J = 8.4, 2H), 6.77 (t, J = 54.4 Hz, 1H), 3.49-3.40 (m, 2H), 2.78 -2.71 (m, 1H). 440.71 [M+H] ⁺ 36 ( S )-3-methyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 8.55 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.61(q, J = 19.6, 8.8 Hz, 4H), 3.88 (s, 3H), 3.38- 3.32 (m, 2H), 2.67-2.60 (m, 1H), 2.21-2.15 (m, 1H), 1.55 (s, 3H). 407.3 [M+H] ⁺ 37* ( S )-3-allyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 9.29 (s, 1H), 8.35 (dd, J = 4.4, 1.2 Hz, 1H), 8.23 (s, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 ( d, J = 8.8 Hz, 2H), 7.55-7.51 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 5.77-5.74 (m, 1H), 5.26-2.13 (m, 2H), 3.40 -3.34 (m, 2H), 2.87-2.86 (m, 1H), 2.72-2.67 (m, 2H), 2.36-2.33 (m, 1H). 428.16 [MH] ^- 38* ( R )-3-allyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 9.29 (s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 8.24 (s, 1H), 8.00 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 ( d, J = 8.8 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 5.79-5.75 (m, 1H), 5.26-2.13 (m, 2H), 3.42 -3.34 (m, 2H), 2.91-2.86 (m, 1H), 2.68-2.51 (m, 2H), 2.37-2.32 (m, 1H). 428.16 [MH] ^- 39 ( R )-1-(hydroxymethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO-d ₆ : δ 9.28 (s, 1H), 8.45-8.25 (m, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.81-7.63 (m, 1H), 7.61-7.47 (m, 1H ), 7.47-7.29 (m, 1H), 6.33 (s, 1H), 6.15-6.02 (m, 1H), 5.52-5.35 (m, 2H), 4.81-4.68 (m, 1H), 4.68-4.56 (m , 1H), 3.66-3.55 (m, 1H), 3.54-3.45 (m, 1H), 2.85-2.72 (m, 1H), 2.54 (d, J = 3.8 Hz, 1H). 446.1 [M+H] ⁺ 40 ( S )-3-methyl-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1 ,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 8.12-8.08 (m, 3H), 7.45 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 3.38-3.25 ( m, 2H), 2.58-2.50 (m, 1H), 2.21-2.10 (m, 1H), 1.51 (s, 3H). 405.28 [MH] ^- 41* ( S )-3-fluoro-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 9.19 (s, 1H), 8.88 (s, 1H), 8.36 (dd, J = 4.4, 0.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.8, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.54-3.38 (m, 2H), 3.17-2.82 (m, 1H), 2.82-2.73 (m, 1H). 406.23 [MH] ^- 42* ( R )-3-fluoro-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 9.19 (s, 1H), 8.88 (s, 1H), 8.36 (dd, J = 4.4, 0.8 Hz, 1H), 8.00 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 ( d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.8, 4.4 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 3.52-3.38 (m, 2H), 3.17-2.82 ( m, 1H), 2.82-2.73 (m, 1H). 406.23 [MH] ^- 43* ( R )-3-ethynyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ δ 9.22 (s, 1H), 8.58 (s, 1H), 8.35 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.8, 1.2 Hz, 1H), 7.68 (d , J = 8.8 Hz, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.72 (s, 1H), 3.46 (t, J = 6.0 Hz, 2H), 2.95 -2.88 (m, 1H), 2.67-2.61 (m, 1H). 412.25 [MH] ^- 44* ( S )-3-ethynyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ δ 9.23 (s, 1H), 8.58 (s, 1H), 8.35 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d , J = 8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.72 (s, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.95 -2.88 (m, 1H), 2.67-2.62 (m, 1H). 412.25 [MH] ^- 45 ( S )-3-methyl-3-(5-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)-2H-1,2,3-triazole- 4-base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 8.76 (s, 1H), 8.18 (s, 1H), 7.64 (s, 4H), 4.25 (s, 3H), 3.45-3.35 (m, 2H), 2.76-2.59 (m, 1H ), 2.30-2.16 (m, 1H), 1.67-1.52 (m, 3H) 408.1 [M+H] ⁺ 46 ( S )-3-methyl-3-(5-(3-((4-(2,2,2-trifluoroethyl)phenyl)amino)pyridin-2-yl)-1,3, 4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 9.19 (s, 1H), 8.22-8.20 (m, 2H), 7.78 (dd, J = 8.4, 1.2 Hz, 1H), 7.45 (dd, J = 8.4, 4.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 3.64 (q, J = 11.6 Hz, 2 H), 3.44-3.36 (m, 2 H), 2.76-2.69 (m, 1H), 2.28-2.21 (m, 1H), 1.62 (s, 3H). 416.26 [MH] ^- 47 ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)benzyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : δ 8.19 (s, 1H), 8.05-8.02 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.36-7.32 ( m, 1H), 7.23-7.21 (m, 1H), 4.76 (d, 2H), 3.45-3.38 (m, 2H), 2.76-2.69 (m, 1H), 2.28-2.21 (m, 1H), 1.62 ( s, 3H). 418.78 [M+H] ⁺ Compounds with * are stereoisomers. Both stereoisomers were obtained and stereochemistry was arbitrarily assigned. Examples 48 and 49 ( R )-2-(2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1, 3,4- Oxadiazol-2-yl)pyrrolidin-3-yl)acetonitrile ( 48 ) and ( S )-2-(2-oxo-3-(5-(3-((4-(trifluoromethyl) Phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-3-yl)acetonitrile ( 49 )

To a stirred solution of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (841 mg, 3.38 mmol) in DMF (8 mL) at 0°C was added 3 -((4-(trifluoromethyl)phenyl)amino)2-pyridylhydrazine (500 mg, 1.69 mmol), HOBt (456 mg, 3.37 mmol), EDC·HCl (648 mg, 3.37 mmol) , and TEA (0.7 mL, 6.756 mmol). After stirring at rt for 16 h, the mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 80% EtOAc in petroleum ether to provide N '-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3 -carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)2-pyridinecarbohydrazine (582 mg, 65%). MS (LCMS) m/z 528.58 [M+H] ⁺ .

To N '-(1-(4-methoxybenzyl)-2-side oxypyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl)phenyl)amino) 2- To a stirred solution of picolylhydrazine (10.0 g, 189 mmol) in DCM (80 mL), Burgess reagent (180 g, 759 mmol) and DIPEA (10.0 mL, 569 mmol) were added. After stirring at rt for 16 h, the mixture was concentrated and the residue was purified by flash column chromatography on silica gel using 80% EtOAc in petroleum ether to provide 1-(4-methoxybenzyl)- 3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one (6.3 g, 65% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), , 7.99 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.49-4.35 (m, 3H), 3.75 (s, 3H), 3.45-3.34 (m, 2H), 2.58-2.54 (m, 1H), 2.50-2.34 (m, 1H); MS (LCMS) m/z 510.60 [M+H] ⁺ .

To 1-(4-methoxybenzyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1 at 0°C, 3,4- To a solution of oxadiazol-2-yl)pyrrolidin-2-one (2.40 g, 4.71 mmol) in CH ₃ CN (48 mL) was added TEA (1.97 mL, 14.1 mmol), DMAP (0.288 g, 2.36 mmol ), and (Boc) ₂ O (5.14 g, 23.6 mmol). After stirring at rt for 16 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with Hex:EtOAc (1:2) to provide (2-(5-(2-((tertiary butoxycarbonyl)oxy)- 1-(4-methoxybenzyl)-4,5-dihydro-1 H -pyrrol-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (2.4 g, 72%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.76 (d, J = 3.2 Hz, 1H), 7.99 (dd, J = 8.0,.2 Hz, 1H), 7.53-7.44 (m, 5H), 7.19 ( d, J = 8.8, 2H), 6.84 (d, J = 8.8, 2H), 4.62 (d, J = 14.4 Hz, 1H), 4.27 ( _d , J = 14.8 Hz, 1H), 3.79 (s, 3H), 3.40-3.35 (m, 1H), 3.34-3.23 (m, 1H), 3.02-2.95 (m, 1H), 2.80-2.74 (m, 1H), 1.42 (s, 9H), 1.34 (s, 9H). MS (LCMS) m/z 710.86 [M+H] ⁺ .

To (2-(5-(2-((tertiary butoxycarbonyl)oxy)-1-(4-methoxybenzyl)-4,5-dihydro-1 H -pyrrole -3-base)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)-tert-butylcarbamate (5.00 g, 7.04 mmol) in MeOH:THF:H ₂ O (2 :2:1) (50 mL), LiOH·H ₂ O (0.889 g, 21.2 mmol) was added in portions. After stirring at rt for 2 h, the mixture was evaporated under reduced pressure and the pH was adjusted to ~pH 4 with 1 N HCl. The aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography to provide (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3 ,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (4.0 g, 93%). MS (LCMS) m/z 554.60 [M-56] ^- .

To (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4- In a stirred solution of oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (1.50 g, 2.46 mmol) in THF (15 mL), 1M LiHMDS (7 mL, 7.38 mmol) in THF was added dropwise. The mixture was stirred at -78°C for 30 min, and ethyl 2-bromoacetate (0.60 mL, 49 mmol) was added. After stirring at rt for 10 h, the reaction was quenched with sat. NH ₄ Cl followed by extraction with EtOAc (100 mL). The organic layer was washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether:EtOAc (1:3) to provide 2-(3-(5-(3-((tertiary butoxycarbonyl)(4(trifluoro Methyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxypyrrolidin-3-yl)ethyl acetate (1.2 g, 70%). MS (LCMS) m/z 596.58 [M+H] ⁺ [De Boc adduct].

To 2-(3-(5-(3-((tertiary butoxycarbonyl)(4(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3 at 0°C, 4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)ethyl acetate (1.00 g, 1.44 mmol) in EtOH:THF:H ₂ O (2:2:1, 10 mL), LiOH.H ₂ O (0.910 g, 2.15 mmol) was added in portions. After stirring at rt for 16 h, the mixture was concentrated and the pH was adjusted to ~pH 4 with 1 N HCl. The solution was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to provide 2-(3-(5-(3-((tertiary butoxycarbonyl)(4-(trifluoromethane Base) phenyl) amino) pyridin-2-yl) -1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)acetic acid (0.90 g, 94%) was used directly in the next step . MS (LCMS) m/z 666.31 [MH] ^- .

2-(3-(5-(3-((tertiary butoxycarbonyl)(4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3 ,4- A stirred solution of oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)acetic acid (500 mg, 0.749 mmol) in DCM (16 mL) , NH ₄ Cl (80 mg, 1.5 mmol), HATU (426 mg, 1.12 mmol), and DIPEA (1.5 ml, 8.6 mmol) were added. After stirring at rt for 16 h, the mixture was diluted with DCM (50 mL), washed with brine, dried over _MgSO4 , and concentrated. The residue was purified by silica gel column chromatography using 5 to 10% MeOH in DCM to provide (2-(5-(3-(2-amino-2-oxoethyl)-1 -(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (350 mg, 70%). MS (LCMS) m/z 665.42 [MH] ^- .

To (2-(5-(3-(2-amino-2-oxoethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3 -base)-1,3,4- In a stirred solution of oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)-tert-butylcarbamate (350 mg, 0.525 mmol) in DCM (3.5 mL) , TFA (10.5 mL) and trifluoromethanesulfonic acid (10.5 mL) were added dropwise sequentially. After stirring at rt for 16 h, the mixture was diluted with DCM (300 mL) and ice water (50 mL), then neutralized with saturated aqueous NaHCO ₃ . The organic layer was washed with brine, dried over _MgSO4 , and concentrated. The residue was triturated with pentane (2 x 10 mL) to afford 2-(2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridine -2-base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-3-yl)acetamide (180 mg, 66%). MS (LCMS) m/z 447.37 [M+H] ⁺ .

To 2-(2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3 at -50°C, 4- To a stirred solution of oxazol-2-yl)pyrrolidin-3-yl)acetamide (100 mg, 0.220 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (1.0 mL) and _Et3N (1.0 mL). After stirring at rt for 16 h, the mixture was diluted with DCM (10 mL), washed with brine, dried over _MgSO4 , and concentrated. The residue was purified by preparative HPLC followed by chiral SFC to provide ( R )-3-(cyanomethyl)-2-oxo-3-(5-(3-((4-( Trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-1-ium ( 48 ) (3.0 mg, 3%) and ( S )-3-(cyanomethyl)-2-oxo-3-(5-(3 -((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-1-ium ( 49 ) (3.0 mg, 3%). The stereochemistry of 48 and 49 was arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALCEL-OX (30 × 250) mm, 5 µ _CO2 %: : 60% Co-solvent %: : 40% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 298nm Solubility : MeOH

Compound 48 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.24 (s, 1H), 8.56 (s, 1H), 8.35 (dd, J = 4.4, 1.2 Hz, 1H), 7.98 (dd, J = 8.8, 1.2 Hz, 1H), 7.66 (d, J = 8.4, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4, 2H), 3.46 (t, J = 6.8, 2H) , 3.39 (s, 2H), 2.82-2.76 (m, 1H), 2.46-2.44 (m, 1H); MS (LCMS) m/z 429.39 [M+H] ⁺ .

Compound 49 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.24 (s, 1H), 8.57-8.55 (br s, 1H), 8.36-8.35 (m, 1H), 7.99 (dd, J = 8.8 ,1.2 Hz, 1H), 7.66 (d, J = 8.4, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4, 2H), 3.46 (t, J = 6.4, 2H), 3.39 (s, 2H), 2.82-2.76 (m, 1H), 2.50-2.49 (m, 1H); MS (LCMS) m/z 429.39 [M+H] ⁺ . Example 50 ( R )-2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidine-1-carbonitrile ( 50 )

To ( R )-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 10B ) (150 mg, 0.361 mmol) in acetonitrile (3 mL) was added Cs ₂ CO ₃ (294 mg, 0.904 mmol). The mixture was stirred for 1 h, cooled to 0 °C, and cyanogen bromide (96 mg, 0.90 mmol) was added. After stirring at rt for 16 h, the mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated. The residue was purified by silica gel column chromatography using 55% ethyl acetate in petroleum ether as eluent, followed by chiral SFC to provide ( R )-2-oxo-3-(5 -(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidine-1-carbonitrile ( 50 ) (10 mg, 6%). Preparative SFC conditions String/Size : Chiralcel OX-H (30 × 250) mm, 5 µ CO ₂ % : 50% Co-solvent % : 50% (ACN) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 295nm Solubility :ACN

Compound 50 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.25 (br s, 1H), 8.34 (dd, J = 4.4, 1.2 Hz, 1H), 8.34 (dd, J = 8.8, 1.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57-7.54 (m, 1H), 7.42 (d, J = 8.8 Hz, 2H), 6.27-6.20 (m, 1H), 5.56 (d, J = 10.8 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 4.03-3.93 (m, 2H), 3.03-2.97 (m, 1H), 2.78-2.72 (m, 1H). MS (LCMS) m/z 439.24 [MH] ^- . Examples 51 and 52 ( R )-3-(5-(3-((( 1S , 3R )-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3 ,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 51 ) and ( R )-3-(5-(3-(((1 R ,3 S )-3-(trifluoromethyl Base) cyclohexyl) amino) pyridin-2-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 52 )

To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (241 g, 0.869 mol) in MeOH (1.5 L) at 20 °C, Add NH ₂ NH ₂ ·H ₂ O (435 g, 8.69 mol). After stirring at 90 °C for 2 h, the mixture was concentrated. The residue was triturated with 1.0 L of n-heptane for 30 min at rt, followed by filtration to provide 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbazide (223 g, 97%). ¹ H NMR (400 MHz, D ₂ O): δ 7.15 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.31 (dd, J = 23.4, 14.8 Hz, 2H) , 3.71 (s, 3H), 3.42 (m, 1H), 3.36-3.22 (m, 2H), 2.22-2.04 (m, 2H).

1-(4-Methoxybenzyl)-2-oxopyrrolidine-3-carbazide (201 g, 763 mmol) and 3-bromo-2-pyridinecarboxylic acid (140 g, 694 mmol) were prepared at 20°C ) in MeCN (2.8 L), EDCI (200 g, 1.04 mol), HOBT (141 g, 1.04 mol), and TEA (140 g, 1.39 mol) were added. After stirring at 20 °C for 16 h, the mixture was concentrated and water (2 L) was added. The resulting precipitate was collected by filtration. The solid was suspended in EtOAc (2.0 L), followed by the addition of 1N HCl (300 mL). The mixture was stirred for 45 min and filtered. The filter cake was washed with 1M aqueous HCl (2X) and dried to provide A as a solid. The combined filtrates were saturated with solid NaCl and extracted with EtOAc (4x). The combined organic layers were washed with 1N HCl (3x), dried over MgSO ₄ , filtered, and concentrated to give B as a solid. The combined solids (solid A and solid B) were triturated with n-heptane (1.0 L) at rt for 30 min, filtered, and dried to provide 3-bromo-N'-(1-(4-methoxybenzyl yl)-2-oxopyrrolidine-3-carbonyl)2-pyridinecarbohydrazine (268 g, 86%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.11-10.01 (m, 2H), 8.55-8.54 (m, 1H), 8.07-8.05 (m, 1H), 7.34-7.28 (m, 1H), 7.20- 7.17 (m, 2H), 6.89-6.86 (m, 2H), 4.43 (dd, J = 26.8, 14.5 Hz, 2H), 3.81 (s, 3H), 3.64-3.59 (m, 1H), 3.35-3.24 ( m, 2H), 2.49-2.32 (m, 2H).

3-Bromo-N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonyl) 2-pyridinecarbohydrazine (268 g, 598 mmol) at 0°C To a stirred solution in DCM (2.6 L), TEA (182 g, 1.80 mol) and TsCl (137 g, 718 mmol) were added portionwise. After stirring at 20 °C for 16 h, the reaction was quenched with water (1.0 L). The mixture was extracted with DCM (3x), and the combined org. layers were washed with brine, dried over MgSO ₄ , filtered, and concentrated. The resulting concentrate was triturated with n-heptane:EtOAc (2:1, 1.0 L), filtered, and dried to provide 3-(5-(3-bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (241 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.75 (dd , J = 4.5, 1.4 Hz, 1H), 8.13 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (dd, J = 8.2, 4.6 Hz , 1H), 7.22 (d, J = 7.8 Hz, 2H), 6.90-6.87 (d, J = 7.8 Hz, 2H), 4.52-4.42 (dd, J = 24.0, 14.5 Hz, ,2H), 4.22 (t , J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.53-3.48 (m, 1H), 3.41-3.35 (m, 1H), 2.67-2.54 (m, 2H).

3-(5-(3-bromopyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (119 g, 278 mmol) in DMF (1.2 L), NaH (22.2 g, 555 mmol, 60% by weight). The mixture was stirred for 30 min, then 1,2-dibromoethane (104 g, 554 mmol) was added. After stirring at 20 °C for 16 h, the reaction was quenched with water (1.2 L) and extracted with EtOAc (6 x 500 mL). The combined organic layers were washed with brine (3x), dried over _MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (heptane:EA=3:1 to 1:3) to provide 3-(2-bromoethyl)-3-(5-(3-bromopyridine- 2-base)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (94.8 g, 64%). This material was used directly in subsequent steps.

3-(2-bromoethyl)-3-(5-(3-bromopyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (94.8 g, 177 mmol) in toluene (900 mL), DBU (53.8 g, 353 mmol). After stirring at 80 °C for 16 h, the mixture was diluted with water (500 mL), followed by extraction with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2x), dried over _MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (heptane:EtOAc=3:1 to 1:3) to provide 3-(5-(3-bromopyridin-2-yl)-1,3,4 - Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (44.6 g, 55%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.74 (d, J = 4.6, 1.4 Hz, 1H), 8.11 (d, J = 8.2, 1.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.19 (d, J = 6.7 Hz, 2H), 6.86 (d, J = 6.6 Hz, 2H), 6.42 (dd, J = 17.4, 10.6 Hz, 1H), 5.46 (d, J = 10.6 Hz, 1H), 5.43 (d, J = 17.4 Hz, 1H), 4.54 (d, J = 14.6 Hz, 1H), 4.38 (d, J = 14.6 Hz, 1H), 3.81 (s, 3H), 3.45-3.44 (m, 1H) , 3.33-3.31 (m, 1H), 3.00-2.98 (m, 1H), 2.48 (m, 1H). MS (LCMS) m/z 454.8 [M+H] ⁺ .

Make 3-(5-(3-bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (40 g) was subjected to chiral SFC to provide (S)-3-(5- (3-Bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (18 g, 98% ee, 99.7% chemical purity) and (R)-3- (5-(3-Bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (17 g, 97% ee, 97.2% chemical purity). Preparative SFC conditions instrument : Waters 200 preparative SFC String/Size : CHIRALCEL OD (50 × 250) mm, 10 µm mobile phase : A for CO ₂ and B for MeOH (0.1% NH ₃ •H ₂ O gradient B 50% flow rate 160 mL/min back pressure : 100 bar Column temperature : 40°C wavelength : 210nm period time : ~ 5 min sample preparation Compounds were dissolved in 1000 mL of MeOH injection : 2.5 mL per injection analytical chiral condition instrument : Agilent 1260 with DAD or equivalent String/Size : CHIRLPAK OD (4.6 × 250) mm, 5 µm mobile phase : A: Hexane, B: EtOH isocratic elution A:B = 60:40 (v/v) stop time 20 minutes flow rate 1.0 mL/min Column temperature : 37°C wavelength : 254nm injection : 2 mL

To ( R )-3-(5-(3-bromopyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (0.300 g, 0.659 mmol), racemic (1 R ,3 S )-3 -(Trifluoromethyl)cyclohex-1-amine hydrochloride (0.161 g, 0.791 mmol) in PhMe (3 mL) was stirred solution (degassed with nitrogen for 15 min), added Cs ₂ CO ₃ (0.664 g, 1.98 mmol), DPEPhos (0.070 g, 0.13 mmol), and Pd ₂ (dba) ₃ (0.033 g, 0.065 mmol). The mixture was then degassed again for 10 min. After stirring at 100 °C for 16 h, the mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using 45% ethyl acetate in petroleum ether to provide rac ( R )-1-(4-methoxybenzyl)-3-(5- (3-(((1 S ,3 R )-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.26 g, 99%).

Racemic ( R )-1-(4-methoxybenzyl)-3-(5-(3-(((1 S ,3 R )-3-(trifluoromethyl) Cyclohexyl)amino)pyridin-2-yl)-1,3,4- To a stirred solution of oxazol-2-yl)-3-vinylpyrrolidin-2-one (0.260 g, 0.480 mmol) in DCM (2.6 ml) was added TFA (7.8 ml) and trifluoromethanesulfonic acid ( 2.6 mL). After stirring at rt for 16 h, the mixture was concentrated, neutralized with saturated NaHCO ₃ and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography using 100% ethyl acetate as eluent, followed by chiral SFC to provide (( R )-3-(5-(3-((( 1S , 3 R )-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 51 ) (0.050 g, 25%) and ( R )-3-(5-(3-(((1 R ,3 S ) -3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 52 ) (0.052 g, 26%). The stereochemistry of 51 and 52 was arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALCEL-OX-H (30 × 250) mm, 5µ CO ₂ % : 60% Co-solvent% : 40% (ACN:MeOH, 1:1) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 215nm Solubility : ACN + MeOH

Compound 51 : ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (br s, 1H), 8.01 (dd, J = 4.2, 1.0 Hz, 1H), 7.50-7.37 (m, 3H), 6.30 -6.23 (m, 1H), 5.46-5.40 (m, 2H), 3.67-3.69 (m, 1H), 3.43-3.40 (m, 1H), 3.29-3.28 (m, 1H), 2.81-2.67 (m, 1H), 2.57-2.51 (m, 2H), 2.20-2.18 (m, 1H), 2.09-2.01 (m, 1H), 1.89-1.80 (m, 2H), 1.52-1.48 (m, 1H), 1.30- 1.19 (m, 3H). LC-MS: m/z 422.38 [M+H] ⁺ .

Compound 52 : ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (br s, 1H), 8.01 (dd, J = 4.4, 1.2 Hz, 1H), 7.49 (d, 8.0 Hz, 1H), 7.43-7.37 (m, 2H), 6.30-6.23 (m, 1H), 5.46-5.40 (m, 2H), 3.69-3.67 (m, 1H), 3.43-3.39 (m, 1H), 3.32-3.31 (m , 1H), 2.81-2.76 (m, 1H), 2.57-2.51 (m, 2H), 2.22-2.20 (m, 1H), 2.07-2.04 (m, 1H), 1.88-1.86 (m, 2H), 1.51 -1.47 (m, 1H), 1.32-1.20 (m, 3H). LC-MS: m/z 422.38 [M+H] ⁺ . Example 53 ( R )-3-(5-(3-((trans-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 53 )

Compound 53 was prepared in a similar manner to Compound 51 and Compound 52 . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (br s, 1H), 7.99 (d, J= 4.0, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.40-7.33 (m , 2H), 6.26-6.22 (m, 1H), 5.46-5.39 (m, 2H), 3.59-3.57 (m, 1H), 3.42-3.39 (m, 1H), 3.29-3.27 (m, 1H), 2.80 -2.75 (m, 1H), 2.56-2.53 (m, 1H), 2.50-2.49 (m, 1H), 2.15-2.12 (m, 2H), 1.95-1.92 (m, 2H), 1.51-1.44 (m, 2H), 1.38- 1.32 (m, 2H). LCMS m/z 422.46 [M+H] ⁺ . Example 54 ( R )-3-(5-(3-(((1s, 4s )-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 54 )

Compound 54 was produced in a manner similar to Compound 51 and Compound 52 . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (br s, 1H), 8.01 (t, J = 2.0, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.43-7.38 (m , 2H), 6.31-6.28 (m, 1H), 5.47-5.41 (m, 2H), 4.08-4.09 (m, 1H), 3.45-3.38 (m, 1H), 3.28-3.26 (m, 1H), 2.85 -2.77 (m, 1H), 2.50-2.42 (m, 2H), 1.90-1.79 (m, 6H), 1.76-1.70 (m, 2H). LC-MS: m/z 422.50 [M+H] ⁺ . Examples 55 and 56 ( S )-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazol-3-yl)-1 ,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 55 ) and ( R )-3-(5-(1-methyl-4-((4-(trifluoromethyl)benzene Base) amino) -1 H -pyrazol-3-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 56 )

To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (3.00 g, 10.9 mmol) in DCM (30 mL) at rt , tert-butylhydrazinecarboxylate (2.16 g, 16.3 mmol), DIPEA (10.0 mL, 54.5 mmol), and HATU (4.97 g, 13.1 mmol) were added. After stirring at rt for 16 h, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate in petroleum ether as eluent to afford 2-(1-(4-methoxybenzyl)-2-oxo - tert-butyl 3-vinylpyrrolidine-3-carbonyl)hydrazine-1-carboxylate (3.0 g, 70%). MS (LCMS): m/z 388.32 [MH] ^- .

2-(1-(4-Methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester (0.90 g, To a stirred solution of 3.1 mmol) in TFA (27 mL), trifluoromethanesulfonic acid (4.5 mL, 2.6 mmol) was added. After stirring at 80 °C for 2 h, the mixture was concentrated. The residue was triturated with pentane (2 x 10 mL) to provide 2-oxo-3-vinylpyrrolidine-3-carbazide (1.2 g, crude), which was used in the next step without further purification step. MS (LCMS): m/z 170.18 [M+H] ⁺ .

1-Methyl-4-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazole-3-carboxylic acid (0.300 g, 1.05 mmol) and 2- To a stirred solution of oxy-3-vinylpyrrolidine-3-carbazide (1.2 g crude) in DMF (3 mL) was added DIPEA (3.88 mL, 21.0 mmol) and HATU (0.480 g, 1.26 mmol) . After stirring at rt for 16 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 10% methanol in DCM as eluent to yield 1-methyl- N' -(5-oxo-3-vinylpyrrolidine -3-Carbonyl)-4-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-3-carbazide (0.40 g, 36% over two steps). MS (LCMS): m/z 435.45 [MH] ^- .

To 1-methyl- N' -(5-oxo-3-vinylpyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)- To a stirred solution of 1 H -pyrazole-3-carbazide (0.400 g, 0.917 mmol) in DCM (4 mL), DIPEA (0.676 g, 3.67 mmol) and Burgess reagent (0.874 g, 3.67 mmol) were added. After stirring at rt for 16 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using (5 to 10)% methanol in DCM, followed by chiral SFC to provide ( S )-3-(5-(1-methyl- 4-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 55 ) (0.04 g, 10%) and ( R )-3-(5-(1-methyl-4-((4- (Trifluoromethyl)phenyl)amino) -1H -pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 56 ) (0.038 g, 9%). The stereochemistry of 55 and 56 was arbitrarily assigned. Preparative SFC conditions String/Size : CHIRALPAK-IC (30 × 250) mm, 5 µ CO ₂ % : 55% Co-solvent % : 45% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 247nm Solubility : MeOH + ACN

Compound 55 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.24 (br s, 1H), 8.12-8.08 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.20-6.13 (m, 1H), 5.39-5.32 (m, 2H), 3.97 (s, 3H), 3.29-3.22 (m, 2H), 2.67-2.59 (m, 1H) , 2.49-2.46 (m, 1H); MS (LCMS) m/z 417.25 [MH] ^- .

Compound 56 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.24 (br s, 1H), 8.12-8.08 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.20-6.13 (m, 1H), 5.39-5.33 (m, 2H), 3.97 (s, 3H), 3.29-3.22 (m, 2H), 2.67-2.59 (m, 1H) , 2.49-2.42 (m, 1H); MS (LCMS) m/z 417.21 [MH] ^- .

1-Methyl-4-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-3-carboxylic acid methyl ester (0.360 g, 1.20 mmol) was dissolved in THF ( 2.2 mL), ethanol (2.2 mL), and H ₂ O (2.2 mL), was added LiOH·H ₂ O (0.151 g, 3.60 mmol). After stirring at 80 °C for 3 h, the mixture was concentrated, diluted with water (10 mL), acidified with 2N HCl (~1.5 mL), and extracted with DCM (3 x 20 mL). _The combined organic layers were dried over _Na2SO4 , filtered, and concentrated to provide 1-methyl-4-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-3 - Carboxylic acid (0.34 g, 99%) which was used directly in the next step without further purification. MS (LCMS): m/z 284.22 [MH] ^- . Example 57 ( S )-3-(5-(5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)- 1,3,4- Oxadiazol-2-yl)-3-methylpyrrolidin-2-one ( 57 )

To a stirred solution of methyl 5-fluoro-1-methyl-1H-pyrazole-3-carboxylate (990 mg, 6.26 mmol) in DMF (5 mL) was added NBS (1.34 g, 7.51 mmol). After stirring at rt temperature, the reaction was quenched with brine (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 4-bromo-5-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (1.4 g, 94%). MS (APCI) m/z 238.0 [M+H] ⁺ .

4-Bromo-5-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (211 mg, 0.890 mmol), 4-(trifluoromethyl)aniline (172 mg, 1.07 mmol) in two To a stirred mixture in alkanes (5 mL), add Cs ₂ CO ₃ (870 mg, 2.67 mmol) (degassed with nitrogen for 1 min), BrettPhos Pd G3 (81 mg, 0.089 mmol), and BrettPhos (47.8 mg, 0.089 mmol). After stirring overnight at 90 °C, the reaction was quenched with brine and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl) Amino)-1H-pyrazole-3-carboxylic acid methyl ester (133 mg, 47%). MS (APCI) m/z 318.1 [M+H] ⁺ .

To 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carboxylic acid methyl ester (133 mg, 0.420 mmol) in anhydrous MeOH (5 mL), hydrazine hydrate (1 mL, 20 mmol) was added. After stirring at 60 °C overnight, the mixture was concentrated, diluted with saturated _NaHCO3 (10 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl) Amino)-1H-pyrazole-3-carbazide (126 mg, 95%). MS (APCI) m/z 318.1 [M+H] ⁺ .

To 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carbazide (56.0 mg, 0.177 mmol) in DMF (2 mL ), add (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (25.3 mg, 0.177 mmol), DMAP (21.5 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), and DIPEA (0.10 mL, 0.57 mmol). After stirring overnight at rt, the mixture was diluted with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide (R)-5-fluoro-1-methyl-N'-(3-methyl-2- Oxypyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carbazide (36 mg, 46%). MS (APCI) m/z 443.1 [M+H] ⁺ .

To (R)-5-fluoro-1-methyl-N'-(3-methyl-2-side oxypyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl )amino)-1H-pyrazole-3-carbazide (36.2 mg, 0.082 mmol) in DCM (2 mL) was added to a stirred solution of 4-toluene-1-sulfonyl chloride (18.7 mg, 0.10 mmol) and TEA (0.034 mL, 0.245 mmol). After stirring overnight at rt, the reaction was quenched with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc:hexanes to provide ( S )-3-(5-(5-fluoro-1-methyl-4-((4 -(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4- Oxadiazol-2-yl)-3-methylpyrrolidin-2-one ( 57 ) (17.4 mg, 50%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.13-8.08 (m, 1H), 8.08 (s, 1H), 7.48-7.38 (m, 2H), 6.77 (d, J = 8.6 Hz, 2H) , 3.90 (s, 3H), 3.31-3.26 (m, 2H), 2.48-2.40 (m, 1H), 2.23-2.01 (m, 1H), 1.49 (s, 3H). MS (APCI) m/z 425.1 [M+H] ⁺ . Example 58 and 59 ( S )-3-methyl-1-(( S )-2,2,2-trifluoro-1-hydroxyethyl)-3-(5-(3-((4-(three Fluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 58 ) and ( S )-3-methyl-1-(( R )-2,2,2-trifluoro-1-hydroxyethyl)-3 -(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 59 )

To ( S )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- To a stirred solution of oxadiazol-2-yl)pyrrolidin-2-one ( 5B ) (20.9 mg, 0.052 mmol) in THF (0.76 mL) was added K ₂ CO ₃ (101 mg, 0.73 mmol) and 2, 2,2-Trifluoro-1,1-ethanediol (0.58 mL, 5.12 mmol). After stirring at rt for 16 h, the mixture was extracted with EtOAc (3 x 15 mL), washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by preparative HPLC (ACCQ, ACN/H ₂ O/0.1% FA) to provide ( S )-3-methyl-1-(( S )-2,2,2-trifluoro- 1-Hydroxyethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 58 ) (8.0 mg, 31%) and ( S )-3-methyl-1-(( R )-2,2,2-trifluoro-1 -Hydroxyethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 59 ) (9.5 mg, 36%). Compound 58 and Compound 59 are stereoisomers and the stereochemistry shown is relative. The stereochemistry of 58 and 59 was arbitrarily assigned.

Compound 58 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.26 (br s, 1H), 8.41-8.30 (m, 1H), 8.04-7.97 (m, 1H), 7.97-7.88 (m, 1H ), 7.75-7.61 (m, J = 8.1 Hz, 2H), 7.60-7.48 (m, 1H), 7.47-7.35 (m, 2H), 5.77-5.65 (m, 1H), 3.73-3.58 (m, 2H ), 2.79-2.68 (m, 1H), 2.33-2.23 (m, 1H), 1.65 (br s, 3H). MS (APCI) m/z 502.10 [M+H] ⁺ .

Compound 59 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.29 (s, 1H), 8.38-8.32 (m, 1H), 8.02-7.97 (m, 1H), 7.92 (br d, J = 5.7 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.6, 4.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 5.75-5.68 (m, 1H ), 3.81-3.73 (m, 1H), 3.51-3.43 (m, 1H), 2.82-2.64 (m, 1H), 2.35-2.26 (m, 1H), 1.66 (s, 3H). MS (APCI) m/z 502.10 [M+H] ⁺ . Examples 60 and 61 (R)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1, 3,4- Oxadiazol-2-yl)-1-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3-vinylpyrrolidin-2-one ( 60 ) and (R)-3 -(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3-vinylpyrrolidin-2-one ( 61 )

Compound 60 and Compound 61 were prepared in a manner similar to Compound 58 and Compound 59 using Example 26 instead. Compound 60 and Compound 61 are stereoisomers and the stereochemistry shown is relative. The stereochemistry of 60 and 61 was arbitrarily assigned.

Compound 60 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.54 (s, 1H), 8.38 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.66-7.57 (m, 4H ), 6.22 (dd, J = 17.5, 10.7 Hz, 1H), 5.75-5.69 (m, 1H), 5.49-5.37 (m, 2H), 3.89 (s, 3H), 3.63-3.56 (m, J = 9.7 Hz, 1H), 3.46-3.43 (m, 1H), 2.76-2.65 (m, 2H). MS (APCI) m/z 517.10 [M+H] ⁺ .

Compound 61 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.47 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.62-7.51 (m, 4H ), 6.14 (dd, J = 17.5, 10.6 Hz, 1H), 5.71-5.63 (m, 1H), 5.42-5.37 (m, 1H), 5.32-5.24 (m, 1H), 3.81 (s, 3H), 3.70-3.62 (m, 1H), 3.32-3.31 (m, 1H), 2.80-2.62 (m, 1H), 2.51-2.45 (m, 1H). MS (APCI) m/z 517.10 [M+H] ⁺ . Examples 62 and 63 ( R )-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl) -1H- pyrazole- 5-yl)pyrrolidin-2-one ( 62 ) and ( S )-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridine-2 -yl)-1H - pyrazol-5-yl)pyrrolidin-2-one ( 63 )

Add 1-(4-methoxybenzyl)-3-methyl-2-oxopyrrolidine-3-carboxylic acid ethyl ester (10.0 g, 34.3 mmol) and tertiary butyl acetate at -40°C (9.272 mL, 68.647 mmol) in anhydrous PhMe (50 mL) was added dropwise to 1M LiHMDS in THF (103 mL, 103 mmol). After stirring at rt for 4 h, the mixture was cooled to 0 °C. The reaction was quenched with saturated _NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, and concentrated to provide 3-(1-(4-methoxybenzyl)-3-methyl-2-oxopyrrolidine-3 -yl)-3-oxopropanoic acid tert-butyl ester (12.0 g), which was used in the next step without further purification. MS (LCMS) m/z 360.27 [MH] ^- .

To tertiary butyl 3-(1-(4-methoxybenzyl)-3-methyl-2-oxopyrrolidin-3-yl)-3-oxopropionate (16.0 g, 44.3 mmol) in PhMe (80 mL) was added p -TSA (7.61 g, 44.3 mmol). After stirring at 90 °C for 16 h, the mixture was concentrated, neutralized with saturated NaHCO ₃ , and extracted with EtOAc (3×100 mL). The combined organic layers were dried over _Na2SO4 , concentrated, and the residue was purified by silica gel flash column chromatography using 48% ethyl acetate in petroleum ether as eluent to provide 3 _- acetyl methoxybenzyl-1-(4-methoxybenzyl)pyrrolidin-2-one (6.0 g, 51%). MS (LCMS) m/z 262.26 [M+H] ⁺ .

Add 3-acetyl-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (5.00 g, 19.1 mmol) in anhydrous THF (50 mL) at -78°C To the solution, 1M LiHMDS (57 mL, 57 mmol) in THF was added. The mixture was stirred at -78 °C for 20 min. Methyl 3-bromo2-picolinate (8.00 g, 38.3 mol) was added, and the mixture was stirred at the same temperature for 30 min. After stirring at 0 °C for 2.5 h, the reaction was quenched with saturated _NH4Cl (100 mL), and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over _Na2SO4 , filtered, and concentrated to afford 1-(3-bromopyridin-2-yl)-3-(1-(4-methoxybenzyl ₎ -3-Methyl-2-oxopyrrolidin-3-yl)propane-1,3-dione (10.0 g), which was used in the next step without further purification. MS (LCMS) m/z 447.39 [M+2+H] ⁺ .

To 1-(3-bromopyridin-2-yl)-3-(1-(4-methoxybenzyl)-3-methyl-2-oxopyrrolidin-3-yl) at 0°C To a stirred solution of propane-1,3-dione (2.00 g, 4.50 mmol) in methanol (30 mL), hydrazine monohydrate (10 mL) and acetic acid (1 mL) were added. After stirring at 70 °C for 16 h, the mixture was concentrated, diluted with ice water (50 mL), and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over _MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography using 55% ethyl acetate in petroleum ether to provide 3-(3-(3-bromopyridin-2-yl)-1 H- pyrazole-5- yl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (1.00 g, 50%). MS (LCMS) m/z 443.41 [M+H] ⁺ .

To 3-(3-(3-bromopyridin-2-yl)-1 H -pyrazol-5-yl)-1-(4-methoxybenzyl)-3-methylpyrrolidine at 0°C To a stirred solution of -2-one (550 mg, 1.24 mmol) in THF (11 mL) was added 60% sodium hydride (74.0 mg, 3.12 mmol). The mixture was allowed to warm to rt, stirred for 40 min, cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (0.57 ml, 3.1 mmol) was added. After stirring at rt for 2 h, the reaction was quenched with ice water (30 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over _MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography using 45% ethyl acetate in petroleum ether to provide 3-(3-(3-bromopyridin-2-yl)-1-((2-(tri Methylsilyl)ethoxy)methyl) -1H -pyrazol-5-yl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one and 3-( 5-(3-Bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)-1-(4- Mixture of methoxybenzyl)-3-methylpyrrolidin-2-one (0.25 g). MS (LCMS) m/z 571.86 [M+H] ⁺ .

To 3-(3-(3-bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-5-yl)-1 -(4-methoxybenzyl)-3-methylpyrrolidin-2-one (1.20 g, 2.10 mmol) and 4-(trifluoromethyl)aniline (0.338 g, 2.10 mmol) in 1,4- two Cs ₂ CO ₃ (2.05 g, 6.29 mmol), Xantphos (0.243 g, 0.420 mmol), and Pd ₂ (dba) ₃ (0.192 g, 0.210 mmol), degas again for 10 min. After stirring at 100 °C for 16 h, the mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate (2 x 40 mL). The combined filtrates were dried over MgSO ₄ , concentrated, and the residue was purified by silica gel column chromatography using 40% ethyl acetate in petroleum ether to provide 1-(4-methoxybenzyl)- 3-Methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethyl Oxy)methyl) -1H -pyrazol-5-yl)pyrrolidin-2-one and 1-(4-methoxybenzyl)-3-methyl-3-(5-(3-( (4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3 -yl) a mixture of pyrrolidin-2-ones (0.8 g). MS (LCMS) m/z 650.29 [MH] ^- .

1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl at rt )-1-((2-(trimethylsilyl)ethoxy)methyl) -1H -pyrazol-5-yl)pyrrolidin-2-one and 1-(4-methoxybenzyl )-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl )ethoxy)methyl) -1H -pyrazol-3-yl)pyrrolidin-2-one] (0.130 g, 0.200 mmol) to a stirred mixture in THF (1.3 ml) was added tetrabutyl fluoride Ammonium chloride (1M solution in THF) (2.6 mL). After stirring at 80 °C for 16 h, the mixture was concentrated, diluted with water (20 mL), and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over _MgSO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography using 40% ethyl acetate in petroleum ether to provide 1-(4-methoxybenzyl)-3-methyl-3-(3-(3 -((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl) -1H -pyrazol-5-yl)pyrrolidin-2-one (0.050 g, 48%). MS (LCMS) m/z 522.07 [M+H] ⁺ .

1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridine-2- To a stirred solution of -1 H -pyrazol-5-yl (0.0700 g, 0.134 mmol) in toluene (1.14 ml), p -TSA (0.300 g, 2.01 mmol) was added. Stirred at 100°C for 5 h Afterwards, the mixture was concentrated, neutralized with 10% aqueous NaHCO ₃ , and extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, and concentrated. The residue was dried over silica gel Purification by column chromatography using 7% methanol in dichloromethane followed by chiral SFC provided ( R )-3-methyl-3-(3-(3-((4-(trifluoromethane yl)phenyl)amino)pyridin-2-yl) -1H -pyrazol-5-yl)pyrrolidin-2-one (62) (9.4 mg, 17%) and ( S )-3-methyl -3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1 H -pyrazol-5-yl)pyrrolidin-2-one (63 ) (11.3 mg, 21%). Compound 62 and Compound 63 are enantiomers, and the stereochemistry shown is relative. The stereochemistry of 62 and 63 is arbitrarily assigned. Preparative Chiral SFC Conditions String/Size : CHIRALPAK-AD-H (30 × 250) mm, 5 µ CO ₂ % : 70% Co-solvent % : 30% (0.2% isopropylamine in isopropanol) total flow : 100g/min back pressure : 100 bar temperature : 30°C Solubility :ACN UV : 308nm

Compound 62 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.12 (br s, 1H), 10.05 (br s, 1H), 8.22 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.22 – 7.30 (m, 3H), 6.80 (s, 1H), 3.28-3.26 (m, 2H), 2.52-2.51 (m, 1H), 2.17-2.13 (m , 1H), 1.45 (s, 3H). MS (LCMS): m/z 402.73 [M+H] ⁺ .

Compound 63 : ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.15 (br s, 1H), 10.13 (br s, 1H) 8.20 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H) , 7.62-760 (m, 2H), 7.29-7.20 (m, 2H), 6.83 (s, 1H), 3.28-3.26 (m, 2H), 2.54-2.51 (m, 1H), 2.17-2.05 (m, 1H), 1.46 (s, 3H). MS (LCMS): m/z 402.73 [M+H] ⁺ .

Examples 64 to 70 were prepared using procedures similar to those shown for Examples 1, 2, 5, and 15, and by modifying starting materials that were readily commercially available or prepared by known and published procedures. [Form B] compound structure IUPAC name ¹ H NMR (400 Hz): δ ppm LCMS (m/z) 64 ( S )-3-methyl-3-(5-(3-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)pyridin-2-yl)-1,3 ,4- Oxadiazol-2-yl)pyrrolidin-2-one DMSO- d ₆ : 8.97 (br s, 1H), 8.26-8.17 (m, 3H), 8.03 (d, J = 3.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.4, 4.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.86 (d, J = 5.6 Hz, 2H), 3.45-3.39 (m, 2H), 2.74-2.71 (m, 1H ), 2.26-2.25 (m, 1H), 1.63 (s, 3H). 417.25 [MH] ^- 65 ( R )-1-(hydroxymethyl)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl )-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 8.53 (s, 1H), 8.41 (s, 1H), 7.64 (d, J= 8.8 Hz, 2H), 7.60 (d, J= 8.8 Hz, 2H), 6.25-6.18 (m, 1H ), 6.06 (t, J= 7.2 Hz, 1H), 5.43-5.36 (m, 2H), 4.74-4.71 (m, 1H), 4.32-4.57 (m, 1H), 3.88 (s, 3H), 3.57- 3.46 (m, 2H), 2.73-2.66 (m, 1H), 2.46-2.42 (m, 1H). 449.50 [M+H] ⁺ 66 ( R )-3-(5-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)-2H-1,2,3-triazol-4-yl)- 1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 8.75 (s, 1H), 8.32 (s, 1H), 7.64 (s, 4H), 6.28-6.20 (m, 1H), 5.47-5.39 (m, 2H), 4.25 (s, 3H) , 3.31-3.24 (m, 2H), 2.82-2.74 (m, 1H), 2.57-2.53 (m, 1H). 419.9 [M+H] ⁺ 67 ( R )-1-(hydroxymethyl)-3-(5-(3-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1 ,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 8.02-8.00 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.45-7.36 (m, 2H), 6.27 (dd, J = 17.5, 10.6 Hz, 1H), 6.10 (t, J = 7.0 Hz, 1H), 5.48-5.40 (m, 2H), 4.77-4.71 (m, 1H), 4.65-4.59 (m, 1H), 4.05-3.98 (m, 1H), 3.63-3.57 (m, 1H), 3.55-3.49 (m, 1H), 3.32-3.28 (m, 1H), 2.82-2.74 (m, 1H), 2.49-2.45 (m, 1H), 1.90-1.84 (m, 2H) , 1.83-1.72 (m, 4H), 1.62-1.46 (m, 2H). 452.20 [M+H] ⁺ 68 ( R )-1-(hydroxymethyl)-3-(5-(3-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1 ,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 8.01-7.99 (m, 1H), 7.51-7.47 (m, 1H), 7.42-7.38 (m, 1H), 7.35 (d, J = 7.7 Hz, 1H), 6.26 (dd, J = 17.5, 10.6 Hz, 1H), 6.09 (t, J = 7.0 Hz, 1H), 5.47-5.39 (m, 2H), 4.76-4.70 (m, 1H), 4.65-4.59 (m, 1H), 3.63-3.59 (m, 1H), 3.58-3.57 (m, 1H), 3.55-3.48 (m, 1H), 3.32-3.26 (m, 1H), 2.79-2.72 (m, 1H), 2.47-2.41 (m, 1H) , 2.21-2.05 (m, 2H), 2.01-1.87 (m, 2H), 1.56-1.43 (m, 2H), 1.41-1.31 (m, 2H). 452.20 [M+H] ⁺ 69 ( R )-3-(5-(3-((5-(trifluoromethoxy)pyridin-2-yl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 10.10 (br s, 1H), 8.91 (dd, J = 8.4, 1.2 Hz, 1H), 8.39-8.30 (m, 3H), 7.62-7.59 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.30-6.23 (m, 2H), 5.47-5.41 (m, 1H), 3.45-3.36 (m, 1H), 3.29-3.28 (m, 1H), 2.84-2.77 (m,1H ), 2.58-2.56 (m,1H). 431.19 [MH] ^- 70 ( R )-3-(5-(3-((5-(chlorodifluoromethoxy)pyridin-2-yl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one DMSO- d ₆ : 9.16 (s, 1H), 8.32 (s, 1H), 8.25 (dd, J = 4.4, 1.2 Hz, 1H), 7.79 (dd, J = 8.8, 1.2 Hz, 1H), 7.49-7.36 (m, 4H), 6.31-6.24 (m, 1H), 5.47-5.41 (m, 2H), 3.46-3.40 (m, 1H), 2.99-2.91 (m, 1H), 2.85-2.78 (m, 1H) , 2.58-2.56 (m, 1H). 447.25 [MH] ^- Examples 71 and 72 ( R )-3-(fluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3 ,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 71 ) and ( S )-3-(fluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl) Amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 72 )

To (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4- In a stirred solution of oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (2.00 g, 3.28 mmol) in THF (20 mL), 1.4M LiHMDS in THF (3.51 mL, 4.92 mmol) was added dropwise. The mixture was stirred at -78 °C for 30 min, then a solution of paraformaldehyde (1.477 g, 49.26 mmol) in THF (5 mL) was added. The mixture was warmed to 0 °C, then stirred at 0 °C for 2 h. The reaction was quenched with saturated _NH4Cl (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (Hex:EtOAc 1:3) to provide (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)- 2-oxopyrrolidin-3-yl)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (1.7 g, 81%). MS (LCMS) m/z 584.62 [M-56] ^- .

To (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4 - In a stirred solution of tert-butyl (oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (1.00 g, 1.56 mmol) in DCM (10 mL), DAST (1.27 g, 7.82 mmol) was added in portions. The mixture was warmed to rt, then stirred at rt for 16 h. The reaction was quenched with ice-cold water (50 mL), followed by extraction with DCM (3 x 40 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography to provide (2-(5-(3-(fluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine- 3-base)-1,3,4- Oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate tert-butyl ester (0.53 g, 53%). MS (LCMS) m/z 642.76 [M+H] ⁺ .

To (2-(5-(3-(fluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4 - In a stirred solution of tert-butyl (oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (0.530 g, 0.826 mmol) in DCM (5.3 mL), TFA (15.9 mL) and triflic acid (0.36 mL, 4.13 mmol) were added. The mixture was warmed to rt, then stirred at rt for 24 h. The mixture was concentrated and neutralized with saturated NaHCO ₃ , then extracted with DCM (3×30 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel column chromatography (MeOH:DCM, 1:20), followed by chiral SFC to provide ( R )-3-(fluoromethyl)-3-(5-(3- ((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 71 ) (40 mg; 28%), and ( S )-3-(fluoromethyl)-3-(5-(3-((4-( Trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 72 ) (40 mg; 28%). The stereochemistry of 71 and 72 was arbitrarily assigned. Preparative SFC conditions: String/Size : CHIRALPACK-IJ (30 × 250 mm), 5 µ CO ₂ % : 60% Co-solvent% : 40% (MeOH) total flow : 100g/min back pressure : 100 bar temperature : 30°C UV : 220nm Solubility : ACN

Compound 71 : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.24 (br s, 1H), 8.47 (br s, 1H), 8.36 (dd, J = 5.6, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.4, 2H), 7.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.41 (d, J = 8.4, 2H), 5.08-4.90 ( m, 2H), 3.49-3.38 (m, 2H), 2.80-2.74 (m, 1H), 2.62-2.57 (m, 1H). MS (LCMS) m/z 422.21 [M+H] ⁺ . HPLC: 98.87%. Chiral HPLC: 99.94% (RT: 5.88 min).

Compound 72 : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.24 (br s, 1H), 8.47 (br s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.4, 2H), 7.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.41 (d, J = 8.4, 2H), 5.09-4.91 ( m, 2H), 3.47-3.38 (m, 2H), 2.80-2.74 (m, 1H), 2.67-2.54 (m, 1H). MS (LCMS) m/z 422.39 [M+H] ⁺ . HPLC: 98.18%. Chiral HPLC: 99.86% (RT: 8.19 min). Example 73 ( R )-3-(5-(1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazol-4-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 73 )

To a stirred mixture of ethyl 3-iodo- 1H -pyrazole-4-carboxylate (2.00 g, 7.52 mol) in DMF (20 mL) was added NaH (1.00 g, 45.1 mmol) at -10 °C and _CF2Br3 ( _4.0 mL, 45 mmol). The mixture was warmed to rt, then stirred at rt for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine solution (2 x 100 mL). After separation, the organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 10% EtOAc in petroleum ether to provide the two positional isomers [1-(bromodifluoromethyl)-3-iodo- 1H -pyridine A mixture of ethyl azole-4-carboxylate and ethyl 1-(bromodifluoromethyl)-5-iodo- 1H -pyrazole-4-carboxylate] (2.1 g, 71%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.22 (s, 0.62H), 8.11 (s, 0.38H), 4.38-4.33 (m, 2H), 1.41-1.36 (m, 3H). MS (LCMS): m/z 394.85 [M+H] ⁺ _.

[1-(bromodifluoromethyl)-5-iodo-1 H -pyrazole-4-carboxylic acid ethyl ester and 1-(bromodifluoromethyl)-3-iodo-1 H -Pyrazole-4-carboxylic acid ethyl ester] (2.00 g, 5.08 mmol) in DCM (20 mL) was added to a stirred solution of AgBF ₄ (5.90 g, 30.5 mmol). The mixture was warmed to rt, then stirred at rt for 16 h. The mixture was diluted with DCM (100 mL) and washed with brine (2 x 50 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 5 to 10% EtOAc in petroleum ether to provide [3-iodo-1-(trifluoromethyl) -1H -pyrazole-4-carboxy A mixture of ethyl 5-iodo-1-(trifluoromethyl)-1H - pyrazole-4-carboxylate] (1.2 g, 71%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.21-8.09 (s & s, 1H), 4.39-4.33 (m, 2H), 1.41-1.36 (m, 3H). MS (LCMS): m/z 334.05 [M+H] ⁺ _.

To [3-iodo-1-(trifluoromethyl)-1 H -pyrazole-4-carboxylic acid ethyl ester and 5-iodo-1-(trifluoromethyl)-1 H -pyrazole-4-carboxylate Acetate ethyl ester] (1.20 g, 3.60 mmol) in di To a stirred mixture in alkanes (10 mL), 4-(trifluoromethyl)aniline ( _1.16 g, 7.21 mmol) and _Cs2CO3 (3.50 g, 10.8 mmol) were added. The mixture was degassed with N ₂ for 5 min, followed by Xantphos (416 mg, 0.720 mmol) and Pd(OAc) ₂ (81 mg, 0.36 mmol). After the mixture was stirred at 130 °C for 16 h, it was cooled to rt, diluted with EtOAc (100 mL), and washed with brine. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 5 to 10% EtOAc in petroleum ether to provide 1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl )amino) -1H -pyrazole-4-carboxylic acid ethyl ester (650 mg, 49%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.44 (s, 1H), 8.31 (s, 1H), 7.66 (d, J = 8.4, 2H), 7.57 (d, J = 8.4, 2H), 4.40-4.33 ( m, 2H), 1.41-1.34 (m, 3H). MS (LCMS): m/z 368.27 [M+H] ⁺ _.

To ethyl 1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carboxylate (650 mg, 1.77 mmol) in MeOH To the stirred mixture in (6.5 mL), hydrazine hydrate (3.3 mL) was added. After the mixture was stirred at 60 °C for 2 h, it was concentrated and azeotropically dried with toluene (3x). The resulting crude was washed with pentane (3x) and dried under reduced pressure to afford 1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino) -1H - Pyrazole-4-carbazide (580 mg, 92%). MS (LCMS): m/z 354.41 [M+H] ⁺

To 1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazole-4-carbazide (500 mg, 1.42 mmol) in THF (10 mL), add ( S )-1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (584 mg, 2.12 mmol), 50% _T3P (0.70 mL, 2.1 mmol), and DIPEA (0.80 mL, 4.2 mmol) in EtOAc. After the mixture was stirred at rt for 16 h, it was diluted with EtOAc (50 mL) and washed with brine. After separation, the organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 30 to 74% EtOAc in petroleum ether to provide ( S ) -N' -(1-(4-methoxybenzyl)-2-pentan Oxy-3-vinylpyrrolidine-3-carbonyl)-1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazole-4 - Carboxazide (750 mg, 87%). MS (LCMS): m/z 611.62 [M+H] ⁺ .

To ( S )-N ' -(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)-1-(trifluoromethyl)-3- To a stirred mixture of ((4-(trifluoromethyl)phenyl)amino)-1H - pyrazole-4-carbazide (500 mg, 0.819 mmol) in DCM (5.0 mL) was added DIEA (0.50 mL, 2.4 mmol) and Burgess reagent (780 mg, 3.28 mmol). After the mixture was stirred at rt for 16 h, it was diluted with brine (20 mL) and extracted with DCM (50 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 20 to 30% EtOAc in petroleum ether to provide ( R )-1-(4-methoxybenzyl)-3-(5-(1 -(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (320 mg, 66%). MS (LCMS): m/z 593.78 [M+H] ⁺ _.

To ( R )-1-(4-methoxybenzyl)-3-(5-(1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl) )amino)-1 H -pyrazol-4-yl)-1,3,4- To a stirred mixture of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (400 mg, 0.675 mmol) in DCM (8.0 mL), TFA (2.0 mL) and trifluoromethanesulfonic acid ( 2.0 mL). The mixture was warmed to rt, then stirred at rt for 16 h. The mixture was diluted with DCM and ice water, then neutralized with saturated NaHCO ₃ . After extraction and separation, the organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated. The residue was purified by preparative HPLC to provide ( R )-3-(5-(1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)- 1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 73 ) (120 mg, 37%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.31 (s, 1H), 8.90 (s, 1H), 8.31 (s, 1H), 7.76-7.69 (m, 4H), 6.30-6.23 (m, 1H ), 5.45-5.41 (m, 2H), 3.43-3.31 (m, 1H), 3.29-3.28 (m, 1H), 2.84-2.77 (m, 1H), 2.56-2.53 (m, 1H). MS (LCMS): m/z 473.26 [M+H] ⁺ _. Example 74 ( R )-3-(5-(1-(methyl- d ₃ )-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl )-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 74 )

Add ( S )-1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid ethyl ester (500 mg, 2.73 mmol) in THF ( 2.5 mL), EtOH (2.5 mL), and water (2.5 mL), was added NaOH (109 mg, 2.73 mmol). After stirring the mixture at 0 °C for 2 h, it was concentrated and lyophilized for 12 h to afford ( S )-1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrole Sodium pyridine-3-carboxylate (450 mg, 85% yield). ¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) δ 7.19 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.34 (dd, J = 17.6, 10.8 Hz, 1H), 5.06-5.20 (m, 2H), 4.43-4.55 (m, 1H), 4.22-4.39 (m, 1H), 3.77 (s, 3H), 3.31-3.36 (m, 1 H), 3.12-3.15 (m, 1 H), 2.54-2.57 (m, 1 H), 1.99-2.21 (m, 1 H).

To a stirred mixture of 1H -pyrazole-4-carboxylic acid methyl ester (35.0 g, 277 mmol) and aqueous NaOAc (1.42 M, 1.33 L) in MeOH (1.05 L) was added Br dropwise at 0 °C ₂ (57.2 mL, 1.11 mol). The mixture was warmed to 25 °C, then stirred at 25 °C for 5 h. The reaction was quenched with _{saturated Na2S2O3} (1.50 L) and _extracted with EtOAc (3 x 2.0 L). The combined organic layers were washed with saturated Na ₂ S ₂ O ₃ , brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give methyl 3,5-dibromo-1 H -pyrazole-4-carboxylate Ester (69.0 g, 87% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.62 (br s, 1 H), 3.84 (s, 3 H). LCMS (ESI+) m/z: [MH] ⁺ 284.9.

To a stirred mixture of methyl 3,5-dibromo- 1H -pyrazole-4-carboxylate (59.0 g, 207 mmol) in THF (900 mL) was added NaH (9.14 g , 228 mmol, 60 wt%). The mixture was stirred at 0 °C for 30 min _{, then iodomethane-d3} ( 37.5 mL, 589 mmol) was added. The mixture was warmed to 25 °C, then stirred at 25 °C for 16 h. _The reaction was quenched with water (300 mL) and extracted with _CH2Cl2 (4 x 300 mL). _The combined organic layers were washed with _H2O , dried over _Na2SO4 , filtered, and _concentrated to give 3,5-dibromo-1-(methyl- d3 ) -1H -pyrazole-4 - Methyl carboxylate (62.0 g, 99% yield), which was used directly in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.79 (s, 3 H). LCMS (ESI+) m/z 301.9 [M+H] ⁺ _.

Add 3,5-dibromo-1-(methyl- d ₃ )-1 H -pyrazole-4-carboxylic acid methyl ester (10.0 g, 33.2 mmol) in THF (100 mL) at -10°C To the stirred mixture, ^iPrMgCl (2 M, 33.2 mL) was added dropwise. After the mixture was stirred at -10 °C for 1 h, the reaction was quenched with _H2O , followed by extraction with _CH2Cl2 ( _3x ). The combined organic layers were washed with _H2O , dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel column chromatography, _eluting with 25% ethyl acetate in petroleum ether, to provide 3-bromo-1-(methyl- d3 ) -1H -pyrazole- 4-Carboxylic acid methyl ester (3.50 g, 45% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (s, 1 H), 3.74 (s, 3 H). LCMS (ESI+) m/z 222.1 [M+H] ⁺ _.

Add 3-bromo-1-(methyl- d3 ) -1H -pyrazole-4-carboxylic acid _methyl ester (1.00 g, 4.50 mmol), 4-(trifluoromethyl)aniline ( 562 mg, 3.49 mmol), sodium tertiary butoxide (503 mg, 5.24 mmol), di-tertiary butyl (2',4',6'-triisopropyl-[1,1'-biphenyl] -2-yl)phosphane (296 mg, 0.698 mmol), para(dibenzylideneacetonyl)bis-palladium (319 mg, 0.349 mmol), and PhMe (10 mL). After the mixture was degassed and purged with _N2 (3x), it was stirred at 110 °C for 4 h, then cooled to rt. The reaction was quenched with water ( ₃₀ mL) and extracted with _CH2Cl2 (3 x 20 mL). The combined organic _layers were washed with _H2O , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate in petroleum ether, to provide 1-(methyl- d ₃ )-3-((4-(trifluoromethane yl)phenyl)amino) -1H -pyrazole-4-carboxylic acid methyl ester (800 mg, 71% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.50 (s, 1 H), 8.22 (d, J = 1.6 Hz, 1 H), 7.78 (br d, J = 8.0 Hz, 2 H), 7.60 ( br d, J = 8.0 Hz, 2 H), 3.79 (s, 3 H). LCMS (ESI+) m/z 302.9 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.61.

1-(Methyl- d ₃ )-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazole-4-carboxylic acid methyl ester (400 mg, To a mixture of 1.32 mmol) in MeOH (4 mL) and THF (0.4 mL), hydrazine hydrate (662 mg, 13.2 mmol) was added dropwise. After the mixture was degassed and purged with nitrogen (3x), it was stirred at 80 °C for 16 h, then cooled to rt. The reaction was quenched with _H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to provide 1-(methyl- d ₃ )-3-((4-(trifluoromethane yl)phenyl)amino) -1H -pyrazole-4-carbazide (300 mg, 71% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.37-9.46 (m, 2 H), 8.06 (s, 1 H), 7.64-7.72 (m, 2 H), 7.54-7.62 (m, 2 H) , 4.37 (br s, 2 H). LCMS (ESI+) m/z 302.8 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.52.

1-(Methyl- d ₃ )-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazole-4-carbazide (140 mg, 0.463 mmol ), ( S )-1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylate sodium (206 mg, 0.694 mmol) in DMF (2.0 mL) In the mixture, add O-(7-azabenzotriazol-1-yl)-N , N , N ', N '-tetramethyluronium hexafluorophosphate ( 211 mg, 0.555 mmol), and _Et3N (0.193 mL, 1.39 mmol). The mixture was stirred at rt for 16 h. The reaction was quenched with H ₂ O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to provide (S) -N '-(1-(4-methoxybenzyl)- 2-oxo-3-vinylpyrrolidine-3-carbonyl)-1-(methyl- d ₃ )-3-((4-(trifluoromethyl)phenyl)amino)-1 H - Pyrazole-4-carbazide (230 mg, 84% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.00-10.44 (m, 1 H), 9.58 (br s, 1 H), 9.22 (br s, 1 H), 8.19 (s, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.11-7.24 (m, 2 H), 6.91 (br d, J = 8.4 Hz, 2 H), 6.15 (dd, J = 17.2, 10.57 Hz, 1 H), 5.27-5.43 (m, 2 H), 4.29-4.45 (m, 2 H), 3.73 (s, 3 H), 3.24 (br dd, J = 8.4 , 4.4 Hz, 1 H), 3.11-3.18 (m, 1 H), 2.53-2.60 (m, 1 H), 2.19-2.24 (m, 1 H). LCMS (ESI+) m/z 560.1 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.56.

To (S) -N '-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)-1-(methyl- d ₃ ) To a mixture of -3-((4-(trifluoromethyl)phenyl)amino) -1H -pyrazole-4-carbazide (230 mg, 0.411 mmol) in CH ₂ Cl ₂ was added DIEA (0.143 mL, 0.822 mmol) and Burgess reagent (195 mg, 0.822 mmol). The mixture was warmed to 25 °C, then stirred at 25 °C for 12 h. _The reaction was quenched with _H2O (5 mL) and extracted with _CH2Cl2 (3 x 5 mL). _The combined organic layers were washed with water, dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether, to provide ( R )-1-(4-methoxybenzyl)-3-(5 -(1-(methyl- d ₃ )-3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (170 mg, 70% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 1 H), 8.36 (s, 1 H), 7.50-7.79 (m, 4 H), 7.17 (d, J = 8.4 Hz, 2 H ), 6.90 (d, J = 8.4 Hz, 2 H), 6.24 (dd, J = 17.6, 10.4 Hz, 1 H), 5.30-5.44 (m, 2 H), 4.28-4.49 (m, 2 H), 3.73 (s, 3 H), 2.83 (br d, J = 5.6 Hz, 2 H), 2.62-2.69 (m, 1 H), 2.41-2.48 (m, 1 H). LCMS (ESI+) m/z 542.2 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.61.

To ( R )-1-(4-methoxybenzyl)-3-(5-(1-(methyl- d ₃ )-3-((4-(trifluoromethyl)benzene) at 20°C Base) amino) -1 H -pyrazol-4-yl) -1,3,4- To a stirred mixture of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (160 mg, 0.295 mmol) in CH ₂ Cl ₂ (1.6 mL) was added trifluoromethanesulfonic acid (1.6 mL, 18 mmol) and TFA (1.6 mL, 21.6 mmol). After the mixture was stirred at 20 °C for 12 h, it was cooled to 0 °C, neutralized with saturated _NaHCO3 , and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with _brine , dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 70% ethyl acetate in petroleum ether, to provide ( R )-3-(5-(1-(methyl- d ₃ )- 3-((4-(trifluoromethyl)phenyl)amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 74 ) (21.8 mg, 16% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.53 (s, 1 H), 8.41 (s, 1 H), 8.25 (s, 1 H), 7.63-7.69 (m, 2 H), 7.56-7.62 (m, 2H), 6.22 (dd, J = 17.6, 10.8 Hz, 1H), 5.34-5.45 (m, 2H), 3.33-3.41 (m, 2H), 2.72-2.75 (m, 1H ), 2.50-2.70 (m, 1H). LCMS (ESI+) m/z 422.3 [M+H] ⁺ . ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.61. Example 75 ( R )-3-(5-(3-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-1-methyl-1H-pyrazol-4-yl)- 1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 75)

To ( R )-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4 - To a stirred mixture of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 26 ) (67 mg, 0.16 mmol) in CH ₂ Cl ₂ :DMF (1:1), was added Selectfluor (407 mg, 1.15 mmol). After the mixture was stirred at rt for 16 h, it was diluted with brine (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated _. The residue was purified by silica gel column chromatography, eluting with 0 to 100% EtOAc/hexanes, and further purified by preparative HPLC to provide ( R )-3-(5-(3-( (3-fluoro-4-(trifluoromethyl)phenyl)amino)-1-methyl-1H-pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 75 ) (6.1 mg, 8.7%). ¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) δ 8.60-8.46 (m, 1H), 8.16 (s, 1H), 7.45 (d, J = 9.8 Hz, 2H), 6.36-6.21 (m, 1H ), 5.54-5.37 (m, 2H), 3.93 (s, 3H), 3.57-3.41 (m, 2H), 3.03-2.84 (m, 1H), 2.67-2.50 (m, 1H). LC-MS (APCI) m/z 437.1 [M+1] ⁺ . Example 76 ( S )-3-ethyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 76 )

To ( R )-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl under _N2 at rt )-1,3,4- To a mixture of oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ( 26 ) (21.1 mg, 0.050 mmol) in anhydrous MeOH (2.0 mL) was added Pd/C (5.4 mg, 0.05 mmol , 10% wt). After the mixture was purged with a _H2 balloon, it was stirred at rt for 16 h, then the _H2 atmosphere was replaced with _N2 . The mixture was filtered through a pad of Celite and washed with MeOH. The combined filtrates were concentrated to provide ( S )-3-ethyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyridine Azol-4-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ( 76 ) (11.1 mg, 49.7%). ¹ H NMR (DMSO- d ₆ ) δ: 8.55 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.57-7.68 (m, 4H), 4.03-4.19 (m, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 1H), 2.60-2.68 (m, 1H), 2.22-2.31 (m, 1H), 2.09 (dd, J = 13.9, 7.5 Hz, 1H), 1.88 ( dd, J = 13.9, 7.3 Hz, 1H), 0.89 (t, J = 7.4 Hz, 3H). MS (APCI) m/z 421.20 [M+H] ⁺ .

Examples 77 to 81 were prepared using procedures similar to those shown for Examples 1 to 28 and 78 and were readily commercially available or prepared by known and published procedures, or in the present application, with modifications Starting material preparation. [Form C] compound structure IUPAC name ¹ H NMR (400 Hz): δ ppm LCMS (m/z) 77 (R )-3-(5-(1-methyl-3-(((1 r ,4 R )-4-(trifluoromethyl)cyclohexyl)amino)-1 H -pyrazole-4- Base) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.23 (br s, 1H), 8.12 (s, 1H), 6.24-6.17 (m, 1H), 5.42-5.35 (m, 2H), 5.17 (d , J = 8.0 Hz, 1H), 3.71 (s, 1H), 3.45-3.36 (m, 2H), 3.28-2.27 (m, 1H), 2.49-2.45 (m, 1H), 2.38-2.21 (m, 1H ), 2.18-2.15 (m, 2H), 1.92-1.89 (m, 2H), 1.39-1.24 (m, 5H). 425.40 [M+H] ⁺ . 78 ( S )-1-(hydroxymethyl)-3-methyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyridine Azol-4-yl)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.54 (s, 1H), 8.40 (s, 1H), 7.66-7.58 (m, 4H), 6.02 (t, J = 6.3 Hz, 1H), 4.69 -4.58 (m, 2H), 3.87 (s, 3H), 3.58-3.52 (m, 2H), 2.65-2.56 (m, 1H), 2.18-2.10 (m, 1H), 1.56 (s, 3H). 437.10 [M+H] ⁺ . 79* ( R )-1-(( S )-2,2-difluoro-1-hydroxyethyl)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl )amino)-1 H -pyrazol-4-yl)-1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.53 (br s, 1H), 8.40 (s, 1H), 7.68-7.56 (m, 4H), 7.20 (br s, 1H), 6.27-5.99 ( m, 2H), 5.45-5.33 (m, 3H), 3.88 (s, 3H), 3.70-3.66 (m, 1H), 3.44-3.40 (m, 1H), 2.79-2.71 (m, 1H), 2.51- 2.48 (m, 1H). 499.32 [M+H] ⁺ 80* (( R )-1-(( R )-2,2-difluoro-1-hydroxyethyl)-3-(5-(1-methyl-3-((4-(trifluoromethyl)benzene Base) amino) -1 H -pyrazol-4-yl) -1,3,4- Oxadiazol-2-yl)-3-vinylpyrrolidin-2-one ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.53 (br s, 1H), 8.38 (s, 1H), 7.66-7.59 (m, 4H), 7.20 (d , J = 6.0 Hz, 1H), 6.24-5.98 (m, 2H), 5.46-5.37 (m, 3H), 3.88 (s, 3H), 3.55-3.51 (m, 2H), 2.72-2.73-2.70 (m, 1H), 2.51-2.44 (m , 1H). 499.35 [M+H] ⁺ 81 ( R )-3-Ethyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1 ,3,4- Oxadiazol-2-yl)pyrrolidin-2-one ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.35 (s, 1H), 7.63-7.47 (m, 4H), 3.91-3.80 (m, 2H), 3.80-3.79 (m, 1H), 3.23- 3.14 (m, 2H), 2.67-2.54 (m, 1H), 2.31-2.17 (m, 1H), 2.08 (br dd, J = 13.8, 7.3 Hz, 1H), 1.86 (br dd, J = 13.8, 7.2 Hz, 1H), 0.89 (br t, J = 7.2 Hz, 3H). 421.10 [M+H] ⁺ Compounds with * are stereoisomers. Both stereoisomers were obtained and stereochemistry was arbitrarily assigned. Example A TEAD reporter assay

TEAD luciferase reporter assay MCF-7 (BPS Bioscience, cat#60618) cells were seeded and treated with inhibitors and 0.1% v/v DMSO the next day. After 24 h of incubation with inhibitors, luciferase activity was assessed using Firefly luciferase reagent (Promega, E1501). Discs were read on a M5e disc reader (Molecular Devices) using the luciferase assay protocol. Compound potency was determined by _IC50 values generated with GraphPad Prism software. The results are provided in Table 1 and demonstrate that the compound of formula (I) or a pharmaceutically acceptable salt thereof is an inhibitor of TEAD. [Table 1] compound IC ₅₀ range 1A D. 1B B 2A A 2B D. 3A D. 3B A 4A E. 4B C 5A D. 5B A 6A D. 6B C 7A C 7B E. 8A B 8B E. 9A B 9B D. 10A A 10B A 11 C 12 D. 13 C 14 E. 15 D. 16 E. 17 E. 18 B 19 C 20 C twenty one C twenty two D. twenty three E. twenty four A 25 D. 26 A 27 D. 28 C 29A B 29B D. 30 C 31 E. 32 D. 33 f 34 C 35 f 36 A 37 B 38 f 39 B 40 C 41 E. 42 B 43 A 44 C 45 A 46 C 47 D. 48 D. 49 E. 50 C 51 C 52 f 53 A 54 D. 55 C 56 A 57 A 58 D. 59 D. 60 A 61 A 62 C 63 C 64 D. 65 B 66 A 67 D. 68 E. 69 C 70 A 71 A 72 E. 73 B 74 A 75 A 76 A 77 B 78 C 79 A 80 A 81 D. A: <15 nM; B: >15 and <25 nM; C: >25 nM and <100 nM; D: >100 nM and <1000 nM; E: >1000 nM and <3000 nM; F >3000 nM Examples B Solubility

Solubility is judged at pH 7.4. Several compounds showed excellent solubility (compared to (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1, 3,4- Oxadiazol-2-yl) pyrrolidin-2-one), which is the desired drug properties, as shown in Table 2. [Table 2] compound Thermodynamic solubility (uM) 2B 41.1 30 86.2 1.56 Kinetic solubility (uM) 40 143

Furthermore, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that various modifications can be made without departing from the spirit of the disclosure. Therefore, it should be clearly understood that the forms disclosed herein are for illustration only and are not intended to limit the scope of the disclosure, but also cover all modifications and alternatives that come with the true scope and spirit of the disclosure provided herein.

Claims (96)

A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: (I) wherein: Ring A is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted monocyclic heterocyclyl, unsubstituted or substituted Bicyclic heteroaryl, or unsubstituted or substituted bicyclic heterocyclic group, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclic group, the bicyclic heteroaryl, or the bicyclic heterocyclic When the group is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heteroaryl, the bicyclic heteroaryl, or the bicyclic heteroaryl are selected from the group consisting of: Substituent substitution: -F, -Cl, -CN, unsubstituted C ₁ - ₆ alkyl, deuterium substituted C ₁ - ₆ alkyl, hydroxyl, unsubstituted C ₁ - ₆ alkoxy, And unsubstituted C ₁ - ₆ haloalkyl; X ¹ is absent, –(CH ₂ ) _n –NR ^3a –, –O–, –S–, –S(O)–, –S(=O ) ₂ -, or -C(R ⁴ R ⁵ )-; X ² , X ³ , and X ⁴ are independently N, NR ^3b , O, S, or CR ^3c ; R ¹ is unsubstituted or substituted Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocyclyl, wherein when the cycloalkyl, the aryl, the hetero When the aryl group and the heterocyclic group are substituted, the aryl group, the heteroaryl group, and the heterocyclic group are substituted by one or more substituents selected from the group consisting of: -F, - Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy, and unsubstituted C ₁ - ₆ haloalkoxy; R ² is unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ heterocyclyl, ,or ; R ^3a , R ^3b , and R ^3c are independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; R ⁴ and R ⁵ are independently hydrogen or unsubstituted or substituted C ₁ - C ₆ alkyl; or R ⁴ and R ⁵ together form unsubstituted or substituted C _3-8 cycloalkyl, wherein the substituted cycloalkyl is independently selected from substituents of the group consisting of Substitution 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; R ⁶ is hydrogen , -F, -Cl, -CN, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ - C ₆ alkenyl, unsubstituted or substituted C _2-6 alkynyl, unsubstituted or substituted C ₁ -C ₆ haloalkyl, unsubstituted or substituted C _1-6 alkoxy, Unsubstituted or substituted hydroxyalkyl, or unsubstituted or substituted aminoalkyl; R ⁷ is hydrogen, cyano, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted Or substituted C ₁ -C ₆ haloalkyl, or unsubstituted or substituted hydroxyalkyl; Y ¹ is –CH ₂ –, –CH ₂ CH ₂ –, –O–, –OCH ₂ –, – CF ₂ –, –CHF–, or –C(CH ₃ ) ₂ –; R ⁸ is hydrogen, –F, –CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; and R ⁹ is hydrogen, -F, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ haloalkyl; or R ⁸ and R ⁹ together form an unsubstituted or substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl is independently selected from the group consisting of Group of substituents substituted 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl; And R ¹⁰ and R ¹¹ are independently hydrogen or unsubstituted or substituted C ₁ -C ₆ alkyl; or R ¹⁰ and R ¹¹ together form an unsubstituted or substituted 3 to 8 membered heterocyclic group; n is 0 or 1; and the premise is is aromatic; provided that ring A is unsubstituted or substituted phenyl; and ^R is unsubstituted or substituted aryl; ^R cannot be selected from the group consisting of: unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted oxygen , unsubstituted or substituted oxygen, unsubstituted or substituted tetrahydrofuran, unsubstituted or substituted 1,3-dioxolane, unsubstituted or substituted tetrahydropyran, Unsubstituted or substituted 1,3-bis Alkane, unsubstituted or substituted piperidine, and unsubstituted or substituted pyrrolidine; provided that ^X is NH; and ^R is unsubstituted or substituted tetrahydropyran; Ring A cannot be unsubstituted or substituted; provided that ^R cannot be unsubstituted or substituted piperidine or unsubstituted or substituted pyrrolidine; and provided that the compound of formula (I) or its pharmaceutically acceptable Accepted salts may not be selected from the group consisting of: (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3- Base) -1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3 -base)-1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrrolidin -2-base]-[1,3,4] Oxadiazol-2-yl}-pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl] -1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]- 1,3,4- Oxadiazol-2-yl]pyrrolidin-2-one, 3-ethyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridine-3-yl)- 1,3,4- Oxadiazol-2-yl)pyrrolidin-2-one; and , or a pharmaceutically acceptable salt of any one of the foregoing. Such as the compound of claim 1, wherein R ² is . The compound according to claim 2, wherein Y ¹ is -CH ₂ -. The compound according to claim 2, wherein Y ¹ is -CH ₂ CH ₂ -. The compound as claimed in item 2, wherein Y ¹ is -O-. The compound according to claim 2, wherein Y ¹ is -OCH ₂ -. The compound according to claim 2, wherein Y ¹ is -CF ₂ -. Such as the compound of claim 2, wherein Y ¹ is -CHF-. The compound according to claim 2, wherein Y ¹ is -C(CH ₃ ) ₂ -. The compound as claimed in any one of items 2 to 9, wherein R ⁶ is hydrogen. The compound as claimed in any one of items 2 to 9, wherein R ⁶ is -F or -Cl. The compound as claimed in any one of items 2 to 9, wherein R ⁶ is —CN. The compound according to any one of claims 2 to 9, wherein R is ^{unsubstituted} or substituted C _3-6 cycloalkyl. The compound according to any one of claims 2 to 9, wherein R ⁶ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound according to any one of claims 2 to 9, wherein R ⁶ is unsubstituted or substituted C ₂ -C ₆ alkenyl or unsubstituted or substituted C _2-6 alkynyl. The compound according to any one of claims 2 to 9, wherein R ⁶ is unsubstituted or substituted C ₁ -C ₆ haloalkyl. The compound according to any one of claims 2 to 9, wherein R is ^{unsubstituted} or substituted C _1-6 alkoxy. The compound as claimed in any one of claims 2 to 9, wherein R ⁶ is an unsubstituted or substituted hydroxyalkyl group. The compound as claimed in any one of claims 2 to 9, wherein ^R is unsubstituted or substituted aminoalkyl. The compound as claimed in any one of items 2 to 19, wherein R ⁷ is hydrogen. The compound as claimed in any one of items 2 to 19, wherein R ⁷ is a cyano group. The compound according to any one of claims 2 to 19, wherein R ⁷ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound according to any one of claims 2 to 19, wherein R ⁷ is unsubstituted or substituted C ₁ -C ₆ haloalkyl. The compound according to any one of claims 2 to 19, wherein R ⁷ is an unsubstituted or substituted hydroxyalkyl group. Such as the compound of claim 1, wherein R ² is . The compound as claimed in item 25, wherein ^R is hydrogen. The compound as claimed in item 25, wherein R ⁸ is -F. The compound as claimed in item 25, wherein R ⁸ is -CN. The compound of claim 25, wherein R ⁸ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound of claim 25, wherein R ⁸ is an unsubstituted C ₁ -C ₆ haloalkyl group. The compound according to any one of claims 25 to 30, wherein R ⁹ is hydrogen. The compound as claimed in any one of items 25 to 30, wherein R ⁹ is -F. The compound according to any one of claims 25 to 30, wherein R ⁹ is —CN. The compound according to any one of claims 25 to 30, wherein R ⁹ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound according to any one of claims 25 to 30, wherein R ⁹ is an unsubstituted C ₁ -C ₆ haloalkyl group. The compound of claim 25, wherein R ⁸ and R ⁹ together form an unsubstituted or substituted monocyclic cycloalkyl group, wherein the substituted monocyclic cycloalkyl group is independently selected from the group consisting of The substituent is substituted 1 to 6 times: halogen, hydroxyl, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, and unsubstituted C _1-4 haloalkyl. The compound of claim 25, wherein R ⁸ and R ⁹ together form an unsubstituted monocyclic heterocyclic group. The compound according to any one of claims 25 to 37, wherein R ¹⁰ is hydrogen. The compound according to any one of claims 25 to 37, wherein R ¹⁰ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound according to any one of claims 25 to 39, wherein R ¹¹ is hydrogen. The compound according to any one of claims 25 to 39, wherein R ¹¹ is unsubstituted or substituted C ₁ -C ₆ alkyl. The compound according to any one of claims 25 to 37, wherein R ¹⁰ and R ¹¹ together form unsubstituted or substituted C _3-8 cycloalkyl. The compound according to any one of claims 1 to 42, wherein is selected from the group consisting of: imidazole, pyrazole, Azole, 1,3,4- Oxadiazoles, triazoles, and 1,3,4-thiadiazoles. The compound according to any one of claims 1 to 42, wherein X ² is CR ^3c ; X ³ is N; and X ⁴ is NH. The compound according to any one of claims 1 to 42, wherein X ² is CR ^3c ; X ³ is N; and X ⁴ is O. The compound according to any one of claims 1 to 42, wherein X ² is N; X ³ is CR ^3c ; and X ⁴ is O. The compound according to any one of claims 1 to 42, wherein X ² is N; X ³ is N; and X ⁴ is O. The compound according to any one of claims 1 to 42, wherein X ² is CR ^3c ; X ³ is N; and X ⁴ is S. The compound according to any one of claims 1 to 42, wherein X ² is N; X ³ is N; and X ⁴ is S. The compound according to any one of claims 1 to 42, wherein X ² is NR ^3b ; X ³ is N; and X ⁴ is CR ^3c . The compound according to any one of claims 1 to 50, wherein ring A is an unsubstituted or substituted phenyl group. The compound according to any one of claims 1 to 50, wherein ring A is an unsubstituted or substituted monocyclic heteroaryl. The compound according to any one of claims 1 to 50, wherein ring A is an unsubstituted or substituted monocyclic heterocyclic group. The compound according to any one of claims 1 to 50, wherein ring A is an unsubstituted or substituted bicyclic heteroaryl. The compound according to any one of claims 1 to 50, wherein ring A is an unsubstituted or substituted bicyclic heterocyclic group. The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of pyridine, pyrazole, triazole, and imidazole. The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of 1H-indazole and pyrazolo[1,5-a]pyridine. The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of pyridin-2-one and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole . The compound according to any one of claims 51 to 58, wherein ring A is unsubstituted. The compound according to any one of claims 51 to 58, wherein ring A is substituted, and ring A is substituted by one or more substituents selected from the group consisting of: -F, -Cl, -CN, Unsubstituted C _1-6 alkyl _{, deuterium-substituted C 1-6 alkyl , hydroxy, unsubstituted C 1-6 alkoxy} , and unsubstituted C _1-6 haloalkyl. The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , ,and , where the asterisk indicates the point of attachment to ^X1 . The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of: and , where the asterisk indicates the point of attachment to ^X1 . The compound according to any one of claims 1 to 50, wherein ring A is selected from the group consisting of: and , where the asterisk indicates the point of attachment to ^X1 . The compound according to any one of claims 1 to 63, wherein ^X does not exist. The compound according to any one of claims 1 to 63, wherein X ¹ is -NR ^3a -. The compound according to any one of claims 1 to 63, wherein X ¹ is —O— or —S—. The compound according to any one of claims 1 to 63, wherein X ¹ is -S(O)- or -S(=O) ₂ -. The compound according to any one of claims 1 to 63, wherein X ¹ is -CH ₂ -. The compound according to any one of claims 1 to 63, wherein X ¹ is —CH(unsubstituted C ₁ -C ₆ alkyl)—. The compound according to any one of claims 1 to 63, wherein X ¹ is —CH(substituted C ₁ -C ₆ alkyl)—. The compound according to any one of claims 1 to 63, wherein X ¹ is -C(unsubstituted C ₁ -C ₆ alkyl) ₂ -. The compound according to any one of claims 1 to 63, wherein X ¹ is -C(substituted C ₁ -C ₆ alkyl) ₂ -. The compound according to any one of claims 1 to 63, wherein X1 is -C(R ⁴ R ⁵ )-, wherein R ⁴ and R ⁵ together form an unsubstituted C _3-8 cycloalkyl group. The compound according to any one of claims 1 to 63, wherein X1 is -C(R ⁴ R ⁵ )-, wherein R ⁴ and R ⁵ together form a substituted C _3-8 cycloalkyl group, wherein the substituted Cycloalkyl is substituted 1 to 6 times with substituents independently selected from the group consisting of halogen, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, And unsubstituted C _1-4 haloalkyl. The compound according to any one of claims 1 to 74, wherein ^R is unsubstituted or substituted cycloalkyl. The compound according to any one of claims 1 to 74, wherein ^R is unsubstituted or substituted aryl. The compound of claim 76, wherein R ¹ is unsubstituted or substituted phenyl. The compound according to any one of claims 1 to 74, wherein ^R is unsubstituted or substituted heteroaryl. The compound as claimed in any one of claims 1 to 74, wherein ^R is an unsubstituted or substituted heterocyclic group. The compound according to any one of claims 75 to 79, wherein R ¹ is unsubstituted. The compound according to any one of claims 75 to 79, wherein R ¹ is substituted by one or more substituents selected from the group consisting of: -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , Unsubstituted C _1-6 alkyl _{, unsubstituted C 1-6 alkoxy ,} and unsubstituted C _1-6 haloalkoxy _. The compound as claimed in any one of items 1 to 74, wherein R ^is ; Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are independently CR ¹² or N; and each R ¹² is hydrogen, -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C ₁ -C ₆ alkyl, unsubstituted C _{1 -6} alkoxy, and unsubstituted C _{1 -6} haloalkoxy. The compound according to claim 82, wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ is CR ¹² . The compound according to claim 82, wherein at least one of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ is N. The compound of claim 82, wherein one of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ is N; and the other four of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ CR ¹² of each department. The compound of claim 82, wherein two of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ are N; and the remaining three of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ CR ¹² of each department. The compound as claimed in any one of items 1 to 74, wherein R ^is ; Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , and Z ¹⁰ are independently CHR ¹³ ; and each R ¹³ is hydrogen, -F, -Cl, -CF ₃ , -CH ₂ CF ₃ , unsubstituted C _{1 -} C ₆ alkyl, unsubstituted C _1-6 alkoxy, and unsubstituted C _1-6 haloalkoxy _. The compound of claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and , or a pharmaceutically acceptable salt of any one of the foregoing. The compound of claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , 1, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or a pharmaceutically acceptable salt of any one of the foregoing. A pharmaceutical composition comprising an effective amount of any one of the compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 89, and pharmaceutically acceptable carriers, diluents, and excipients , or a combination thereof. A use of a compound according to any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving a disease, wherein the disease is selected from autoimmune disorders, inflammatory conditions, or cancer formed groups. As used in claim 91, wherein the disease is selected from the group consisting of mesothelioma, renal cell carcinoma, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, Oral squamous cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, Uveal melanoma, pancreatic adenocarcinoma, renal papillary cell carcinoma, rectal adenocarcinoma, bladder urothelial carcinoma, esophageal cancer, head and neck squamous cell carcinoma, squamous cell carcinoma, cancer resistant to EGFR inhibitors, and cancers resistant to MEK inhibitors. Use of a compound according to any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD. A method for improving a disease, comprising administering an effective amount of the compound according to any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof to a subject suffering from the disease, wherein the disease is selected from autologous The group consisting of immune disorders, inflammatory conditions, or cancer. The method of claim 94, wherein the disease is selected from the group consisting of mesothelioma, renal cell carcinoma, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, Oral squamous cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, Uveal melanoma, pancreatic adenocarcinoma, renal papillary cell carcinoma, rectal adenocarcinoma, bladder urothelial carcinoma, esophageal cancer, head and neck squamous cell carcinoma, squamous cell carcinoma, cancer resistant to EGFR inhibitors, and cancers resistant to MEK inhibitors. A method for inhibiting YAP/TAZ-TEAD protein-protein interaction and/or inhibiting lipid binding to TEAD, which comprises allowing cells to be treated with an effective amount of a compound as claimed in any one of claims 1 to 89 or a pharmaceutically acceptable Exposure to salt wherein the cell line is cancerous.