TW202334137A - Pi3k inhibitors and methods of treating cancer - Google Patents

Abstract

Compounds of Formula (I) and pharmaceutically active salts thereof are provided, where the variables in Formula (I) are described herein. Such compounds and salts are PI3K inhibitors that are useful for treating conditions characterized by abnormal or excessive cellular proliferation, such as cancer and tumors.

Description

PI3K inhibitors and methods of treating cancer

This application generally relates to compounds that are PI3K inhibitors, and methods of using them to treat conditions characterized by abnormal or excessive cell proliferation, such as cancer and tumors.

instruction

Phosphoinositide 3-kinase (PI3K) is a family of enzymes capable of phosphorylating the 3-hydroxyl group of the inositol ring of phosphoinositide. See Vanhaesebroeck, B., Perry, MWD, Brown, JR et al . PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 20 , 741–769 (2021).

A variety of compounds with various chemical structures that inhibit PI3K have been evaluated for their ability to treat cancer and/or tumors. For example, Table 1 illustrates several PI3K inhibitors that have made progress in the US FDA approval process. Table 1 PI3K inhibitor structure alpelisib idelalisib duvelisib copancoxib (copanlisib)

The clinical progress of multiple compounds represents a milestone in the development of PI3K inhibitors. However, there is still a need for improved compounds that inhibit PI3K activity.

Various examples provide compounds of formula (I) and methods of using them.

One embodiment provides compounds of formula (I): (I) Or a pharmaceutically acceptable salt thereof, wherein: X is C or N; Y ¹ is CH, O, S, N, NH, or NCH ₃ ; Y ² is C or N; Z ¹ and Z ² are independent The ground system is CH or N; each Independently represents a single bond or a double bond, with the restriction that all chemical valences are met; W is C, CH, or N; Ring A is an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic ring Heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted bicyclic heteroaryl, wherein when the aforementioned ring A is substituted, it is -F, -Cl, -CN, -OH , one or more of unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy, or unsubstituted C ₁ - ₆ haloalkyl; R ¹ is H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl; R ² is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkenyl, wherein When the aforementioned R ² is substituted, it is substituted by a monocyclic heteroaryl, –OH, –F, –CN, –CO(NH ₂ ), –COOH, –CH ₂ OH, –CH ₃ , –CF ₃ , or – One or more of CF ₂ is substituted; or R ¹ and R ² together with W form an optionally substituted 4, 5, 6, or 7-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl group, wherein when the foregoing is substituted, it is -OH, -F, -CN, -CO( _NH2 ), -COOH, _-CH2OH , _-CH3 , _-CF3 , _-CF2 , or C One or more of ₁ -C ₆ alkyl groups are substituted; R ³ is H, –CN, –CHO, –CH=CH ₂ , –CH ₂ CN, –CH(CH ₃ )CN, –C(CH ₃ ) ₂ CN, C ₁ -C ₄ alkyl, –CH ₂ OH, –CH ₂ NH ₂ , –CH ₂ CH ₂ OH, –CH ₂ CH ₂ NH ₂ , or –CHCONH ₂ ; R ⁴ is H, –F, –CN, –CH ₃ , –CH ₂ CH ₃ , –CH(CH ₃ ) ₂ , –OH, or –OCH ₃ ; R ⁵ is H, –CH ₃ , –CH ₂ CH ₃ , –CF ₂ , –CF ₃ , or –CONH ₂ ; and R ⁶ is –COOH, –CN, _–CONH2 , oxadiazolone, –B(OH) ₂ , –PONH2 _, –PO( _CH3 ) ₂ , –CONHCH ₃ , –CONHCH ₂ CF ₃ , or –CONHCH ₂ CHF ₂ .

Another embodiment provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

Another embodiment provides a method for treating cancer or tumors, comprising administering to a subject suffering from cancer or tumors an effective amount of a compound described herein, or a pharmaceutically active salt thereof, or a medicament described herein composition.

These and other embodiments are described in greater detail below.

Cross-references to related applications

This application claims priority to U.S. Provisional Patent Application Serial No. 63/263,509, filed on November 3, 2021, and U.S. Provisional Patent Application Serial No. 63/267,959, filed on February 14, 2022, The entire texts of both are hereby incorporated by reference for all purposes.

PI3K is a promising target for cancer therapy. The PI3K pathway is often mutated and abnormally activated in many cancers, and plays a central role in tumor cell proliferation and survival. Gain-of-function mutations in PIK3CA (the gene encoding the p110α catalytic subunit of PI3K) are one of the most common somatic alterations in solid tumors. Therapies that selectively target mutations in the PI3K pathway are desirable for the treatment of mutant-driven cancers. definition

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

Whenever a group is described as "optionally substituted," the group may 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" group may be substituted by one or more groups individually and independently selected from: Substitution: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl) group), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-aminethioformyl, N-amine thioformyl group, C-amide group, N-amide group, S-sulfonamide group, N-sulfonamide group, C-carboxyl group, O-carboxyl group, nitro group, sulfenyl group ( sulfenyl), sulfenyl, sulfonyl, haloalkyl, haloalkoxy, amine, monosubstituted amine, disubstituted amine, monosubstituted amine (alkyl), and disubstituted amine (alkyl).

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. The indicated groups may include inclusive containing "a" to "b" carbon atoms. Therefore, "C ₁ to C ₄ alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e. 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 such definitions is assumed.

If two "R" groups are described as being "taken together," then the R groups and the atoms to which they are attached may form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle. For example, but not limited to, if R ^a and R ^b of the NR ^a R ^b group are described as "together," it means that they are covalently bonded to each other to form a ring:

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 alkyl groups include, but are not limited to, isopropyl, secondary butyl, tertiary butyl, and the like. Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group may have 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; for example, "1 to 30 carbon atoms" means means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers occurrences of the term "alkyl" without a specified numerical range). The alkyl group may also be a medium sized alkyl group having from 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted.

As used herein, the term "alkylene" refers to a divalent fully saturated linear aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptyl, and octyl. The alkylene group can be represents, followed by the number of carbon atoms, and then "*". For example, Represents ethyl group. Alkylene groups have 1 to 30 carbon atoms (whenever present herein, a numerical range such as "1 to 30" refers to each integer in the given range; for example, "1 to 30 carbon atoms" means Alkylene groups may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers occurrences of the term "alkyl" without a specified numerical range). Alkylene groups may also be medium-sized alkyl groups having from 1 to 12 carbon atoms. The alkylene group may also be a lower alkyl group having 1 to 4 carbon atoms. Alkylene groups may be substituted or unsubstituted. For example, a lower alkylene group can be obtained by replacing one or more hydrogens of the lower alkylene group and/or by replacing it with a C _3-6 monocyclic cycloalkyl group (e.g., ) by replacing two hydrogens on the same carbon.

The term "alkenyl" as used herein refers to a monovalent linear or branched chain group containing two to twenty carbon atoms of the 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 containing two to twenty carbon atoms in the 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 triple bonds) monocyclic or polycyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be fused, bridged, or spirolinked together. 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 compounds in which the cycloalkyl group contains a linkage to one or more non-adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and that are not connected by a bridge. Cycloalkyl groups may contain from 3 to 30 atoms in ring(s), from 3 to 20 atoms in ring(s), from 3 to 10 atoms in ring(s), in(more) ) contains 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 monocyclic alkyl groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-pyridyl, and tetradecanyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl ), and norbornanyl; and examples of spirocycloalkyl include spiro[3.3]heptane and spiro[4.5]decane.

As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic (such as bicyclic) hydrocarbon ring system containing one or more double bonds in at least one ring; but if there is more than one double bond, The double bond cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). For example, cycloalkenyl may 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 fused, bridged, or spirolinked together. Cycloalkenyl groups may be unsubstituted or substituted.

As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic (such as bicyclic) aromatic ring system (including a fused ring system in which two carbocyclic rings share a chemical bond), which With fully delocalized π-electron systems in all rings. The number of carbon atoms in the aryl group can vary. For example, the aryl group may 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 may be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic (such as bicyclic) aromatic ring system (a ring system with a fully delocalized pi-electron system) that contains one or more heteroaryl Atoms (eg, 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 the heteroaryl group 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 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, pyrrole, ethazole, benzothiazole, 1,2,3-ethadiazole, 1,2,4- Thiadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, Isothiazole, benzisinozole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyrimidine, pyridine, purine, pteridine, quinoline, isoquinoline, Quinazoline, quinoline, quinoline, and quinoline. Heteroaryl groups may be substituted or unsubstituted.

One of ordinary skill in the art will understand that the partial ring in the fused "A" ring in the following parts indicates that the "A" ring is aromatic:

For example, when any one or more of Q ₁ , Q ₂ , and Q ₃ are nitrogen, the moiety is heteroaryl. Similarly, when all Q ₁ , Q ₂ , and Q ₃ are carbon, such moiety is aryl.

As used herein, "heterocyclyl" or "heteroalicyclyl" refers to three, four, five, six, seven, eight, nine, ten to up to 18 membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms together with 1 to 5 heteroatoms constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned in this manner; however, a fully delocalized pi-electron system does not occur in all rings. The heteroatom(s) are elements other than carbon, including but not limited to oxygen, sulfur (such as -S-, -S(=O)-, or -S(=O) ₂ -), and nitrogen (such as - N=, -NH-, or -N(alkyl)-). Heterocycles may further contain one or more carbonyl or thiocarbonyl functionality such that the definition includes pendant oxy and thio systems such as lactams, lactones, cyclic imines, cyclic thioimines, and cyclic urethanes. When composed of two or more rings, the rings may be fused, bridged, or spirolinked together. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to one or more atoms in which the heterocyclyl or heteroalicyclyl group contains one or more non-adjacent atoms connected to it. A compound of bonded atoms. As used herein, the term "spiro" refers to two rings that share an atom and that are not connected by a bridge. Heterocyclyl and heteroalicyclic groups may contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), and 3 to 10 atoms in the ring(s). , Containing 3 to 8 atoms in the ring(s), Containing 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 heteroalicyclic ring may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1, 2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1 ,4-oxathiolane (1,4-oxathiin), 1,3-oxathiolane (1,3-oxathiolane), 1,3-dithiolane (1,3 -dithiole), 1,3-dithiolane (1,3-dithiolane), 1,4-oxothialane, tetrahydro-1,4-thiole, 2H-1,2-㗁𠯤, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxoperate, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3,5-Trioxazole, imidazoline, imidazolidine, isoethazoline, isoethazolidine, oxazoline, oxazolidine, oxazolidinone, thiazolidine, thiazolidine, pholine, oxygen , piperidine N-oxide, piperidine, piperidine, pyrrolidine, nitrogen (azepane), pyrrolidinone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazolidine, 2-side oxygen pyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, sulfur pholine, sulfur phenylene sulfide, sulfur Phenolines, and their benzo-fused analogs (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, "aralkyl" and "aryl(alkyl)" refer to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group attached as a substituent via a lower alkylene group. The lower alkylene group and heteroaryl group of the heteroaralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isothiazolylalkyl, and imidazolylalkyl base, and its benzo-fused analogues.

"Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic group or heteroaliphatic group connected via a lower alkylene group as a substituent ring base. The lower alkylene group and heterocyclyl group of the (heteroalicyclic)alkyl group may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-piran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl(methyl) and 1,3-thiazinan-4-yl(methyl)(methyl).

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

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

As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl) group attached as a substituent via a carbonyl group , heteroaryl (alkyl), and heterocyclyl (alkyl). Examples include formyl, acetyl, propylyl, benzylyl, and acrylyl. The acyl group may be substituted or unsubstituted.

"Cyano" refers to the "-CN" group.

The term "halogen atom" or "halogen" as used herein means any radioactively 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 can be the same as defined for O-carboxy. The thiocarbonyl group may be substituted or unsubstituted.

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

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

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

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

"C-amido" refers to the "-C(=O)N(R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl ( alkyl). The C-amide group may be substituted or unsubstituted.

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

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

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

"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. The O-carboxy group may be substituted or unsubstituted.

The terms "ester" and "C-carboxy" refer to the "-C(=O)OR" group, where R can be the same as defined for O-carboxy. The ester and C-carboxyl groups may be substituted or unsubstituted.

"Nitro" refers to the -NO ₂ "group.

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

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

"Sulfonyl" refers to the "SO ₂ R" group, where R may be the same as defined for the sulfenyl group. The sulfonyl group may be substituted or unsubstituted.

As used herein, "haloalky" refers to an alkyl group in which one or more hydrogen atoms are replaced by 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 may 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 groups may be substituted or unsubstituted.

The terms "amino" and "unsubstituted amino" as used herein refer to the –NH ₂ group.

The "mono-substituted amine" group refers to the " _-NHRA " group, where R _A can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, Heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. _RA may be substituted or unsubstituted. Monosubstituted amine groups may include, for example, monoalkylamine groups, mono-C ₁ -C ₆ alkylamine groups, monoarylamine groups, mono-C ₆ -C ₁₀ arylamine groups, and Similar. Examples of monosubstituted amine groups include, but are not limited to, −NH (methyl), −NH (phenyl), and the like.

The "di-substituted amine" group refers to the "-NR _A R _B " group, where R _A and R _B can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as used herein defined. R _A and R _B may independently be substituted or unsubstituted. Disubstituted amine groups may include, for example, dialkylamine groups, di-C ₁ -C ₆ alkylamine groups, diarylamine groups, di-C ₆ -C ₁₀ arylamine groups, and Similar. 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, "mono-substituted amine(alkyl)" refers to a mono-substituted amine (alkyl) attached as a substituent via a lower alkylene group (as provided herein). Monosubstituted amines (alkyl) may be substituted or unsubstituted. Mono-substituted amines (alkyl) may include, for example, monoalkylamine (alkyl) groups, mono-C ₁ -C ₆ alkyl amine (C ₁ -C ₆ alkyl) groups, monoarylamine (alkyl) groups. ) group, mono-C ₆ -C ₁₀ arylamine (C ₁ -C ₆ alkyl) group, and the like. Examples of monosubstituted amine (amino) groups include, but are not limited to, −CH ₂ NH (methyl), −CH ₂ NH (phenyl), −CH ₂ CH ₂ NH (methyl), −CH ₂ CH ₂ NH (phenyl), and the like.

As used herein, "di-substituted amine(alkyl)" refers to a disubstituted amine (as provided herein) attached as a substituent via a lower alkylene group. Disubstituted amines (alkyl) may be substituted or unsubstituted. Disubstituted amine (alkyl) groups may include, for example, dialkylamine (alkyl) groups, di-C ₁ -C ₆ alkyl amine (C ₁ -C ₆ alkyl) groups, diarylamine ( alkyl) groups, di-C ₆ -C ₁₀ arylamine (C ₁ -C ₆ alkyl) groups, and the like. Examples of disubstituted amines (alkyl) include, but are not limited to, −CH ₂ N (methyl) ₂ , −CH ₂ N (phenyl) (methyl), −NCH ₂ (ethyl) (methyl), − CH ₂ CH ₂ N(methyl) ₂ , −CH ₂ CH ₂ N(phenyl)(methyl), −NCH ₂ CH ₂ (ethyl)(methyl), and the like.

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

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

The term "pharmaceutically acceptable salt" means 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 the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl diphosphate). hydrogen salt). Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, etc. 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 an ammonium salt, an alkali metal salt (such as a sodium, potassium, or lithium salt), an alkaline earth metal salt (such as a calcium or magnesium salt), Carbonates, bicarbonates, organic bases (such as dicyclohexylamine, N-methyl-D-reduced glucosamine, (hydroxymethyl)methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine , triethanolamine, ethylenediamine), and salts with amino acids (such as arginine and lysine). For compounds of formula (I), one of ordinary skill in the art will understand that when the salt is formed by protonation of a nitrogen-based group (e.g., NH ₂ ), the nitrogen-based group can be positively charged Association (for example, NH ₂ can become NH ₃ ⁺ ), and this positive charge can be balanced by a negatively charged counterion (such as Cl ⁻ ).

The term "PI3K inhibition" and similar terms refer to the inhibition of the activity or function of the (PI3K) protein. Similarly, the term "PI3K inhibitor" refers to agents (including small molecules and proteins) that inhibit the function of the (PI3K) protein. As one of ordinary skill in the art will appreciate, there are many methods for assessing protein binding interactions, including, but not limited to, co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR), and Fluorescence polarization/anisotropy.

It will be understood that in any compound described herein having one or more chiral centers, each center may independently have an R-configuration, or an S-configuration, or an S-configuration, unless the absolute stereochemistry is explicitly indicated. its mixture. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched as a racemic mixture, diastereomerically pure, diastereomerically enriched, or stereoisomerically mixture. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds giving rise to 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 recited compound, all tautomeric forms are also intended to be included.

It should be understood that when compounds disclosed herein have unfilled valencies, the valencies should be filled with hydrogen or its isotopes, 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 may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo 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, hydrogen atoms may be explicitly revealed 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). Therefore, reference herein to compounds encompasses all potential isotopic forms unless the context clearly indicates otherwise.

It is 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 a pharmaceutically acceptable solvent, 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 during the crystallization procedure with a pharmaceutically acceptable solvent such as water, ethanol, or the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Furthermore, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.

When a range of values is provided, it is understood that the upper and lower limits of the range, as well as each intervening value between the upper and lower limits, are encompassed by the embodiments.

Unless expressly stated otherwise, the terms and phrases used in this application, and variations thereof (especially in the scope of the appended claims) are to be understood as open-ended rather than restrictive. 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, containing, or characterized by" and is inclusive or open-ended and does not exclude additional, non-enumerated elements or method steps; terminology “Having” should be read as “having at least”; the word “include” should be read as “including but not limited to”; the word “example” is used to provide an item for discussion Illustrative examples rather than an exhaustive or limiting list thereof; and the use of terms such as "preferably", "preferred", or "desired/desirable", and words of similar meaning This is not to be understood as implying that certain features are critical, necessary, or even essential 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 phrase "having at least" or "including at least". When used in the context of a compound, composition, or device, the word "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 regard to the use of substantially any plural and/or singular term herein, one of ordinary skill in the art may convert the plural into the singular and/or the singular into the plural as appropriate to the context and/or application. Various singular/plural permutations may be explicitly stated in this article for clarity. The indefinite article "a or an" does not exclude the plural. The mere fact that certain measures are listed in mutually distinct subheadings does not mean that a combination of these measures cannot be used to advantage. Any element symbols in the claimed scope 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: (I) X in formula (I) can be C or N. For example, in one embodiment, X is C. In another embodiment, X is N.

Y ¹ in formula (I) can be CH, O, S, or N, NH, or NCH ₃ . For example, in one embodiment, Y ¹ is CH. In another embodiment, ^Y1 is NH. In another embodiment, Y ¹ is N. In another embodiment, Y ¹ is O. In another embodiment, Y ¹ is S. In another embodiment, Y ¹ is NCH ₃ .

Y ² in formula (I) can be C or N. For example, in one embodiment, ^Y2 is C. In another embodiment, ^Y2 is N.

Z ¹ in formula (I) can be CH or N. For example, in one embodiment, Z ¹ is CH. In another embodiment, Z ¹ is N.

Z ² in formula (I) can be CH or N. For example, in one embodiment, ^Z2 is CH. In another embodiment, ^Z2 is N.

Each of the formula (I) Can independently represent a single or double bond.

W in formula (I) can be C, CH, or N. For example, in one embodiment, W is C. In another embodiment, W is CH. In another embodiment, W is N.

Ring A in formula (I) may be an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic heteroaryl group, an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted cycloalkyl group. Substituted bicyclic heteroaryl, wherein when the above is substituted, it is -F, -Cl, -CN, -OH, unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy group, or one or more of the unsubstituted C ₁ - ₆ haloalkyl groups. In one embodiment, Ring A can be an unsubstituted or substituted aryl group. In another embodiment, Ring A can be an unsubstituted or substituted monocyclic heteroaryl. In another embodiment, Ring A can be unsubstituted or substituted cycloalkyl. In one embodiment, Ring A can be an unsubstituted or substituted bicyclic heteroaryl.

R ¹ in formula (I) can be H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl. In one embodiment, ^R1 can be H. In another embodiment, R ¹ can be C ₁ -C ₆ alkyl. In another embodiment, R ¹ can be C ₁ -C ₆ alkenyl.

R ² in formula (I) may be R ² may be unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkenyl, wherein the aforementioned one is substituted When, it is substituted by one or more of –OH, –F, –CN, –CO( _NH2 ), –COOH, _–CH2OH , _–CH3 , _–CF3 , or _–CF2 . In one embodiment, R ² is unsubstituted or substituted C ₁ -C ₆ alkyl. In another embodiment, R ² is unsubstituted or substituted C ₁ -C ₆ alkenyl. In an alternative embodiment, R ¹ and R ² together with W may form an optionally substituted 4, 5, 6, or 7 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl, wherein When the foregoing is substituted, it is substituted by monocyclic heteroaryl (e.g., pyrazole), –OH, –F, –CN, –CO( _NH2 ), –COOH, _–CH2OH , _–CH3 , –CF ₃ , -CF ₂ , or C ₁ -C ₆ alkyl is substituted with one or more. For example, in one embodiment, R ¹ and R ² together with W can form an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle. In another embodiment, R ¹ and R ² together with W may form an optionally substituted 5- or 6-membered heteroaryl.

R ³ in formula (I) can be H, –CN, –CHO, –CH=CH ₂ , –CH ₂ CN, –CH(CH ₃ )CN, –C(CH ₃ ) ₂ CN, C ₁ -C _4Alkyl , –CH ₂ OH, –CH ₂ NH ₂ , –CH ₂ CH ₂ OH, –CH ₂ CH ₂ NH ₂ , or –CHCONH ₂ . In one embodiment, ^R3 can be H. In another embodiment, ^R3 can be CN. In another embodiment, R ³ can be C ₁ -C ₄ alkyl. In another embodiment, R ³ can be -CHO. In another embodiment, R ³ can be -CH=CH ₂ . In another embodiment, R ³ can be -CH ₂ CN. In another embodiment, R ³ can be -CH(CH ₃ )CN. In another embodiment, R ³ can be -C(CH ₃ ) ₂ CN. In another embodiment, R ³ can be -CH ₂ OH, -CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ NH ₂ , or -CHCONH ₂ .

R ⁴ in formula (I) can be H, –F, –CN, –CH ₃ , –CH ₂ CH ₃ , –CH(CH ₃ ) ₂ , –OH, or –OCH ₃ . In one embodiment, R ⁴ can be H, -F, -CN, or -CH ₃ . In another embodiment, R ⁴ can be –CH ₂ CH ₃ , –CH(CH ₃ ) ₂ , –OH, or –OCH ₃ .

R ⁵ in formula (I) can be H, –CH ₃ , –CH ₂ CH ₃ , –CF ₂ , –CF ₃ , or –CONH ₂ . In one embodiment, R ⁵ is H, –CH ₃ , or –CH ₂ CH ₃ . In another embodiment, ^R5 is _-CF2 , _-CF3 , or _-CONH2 .

R ⁶ in formula (I) can be –COOH, –CN, or –CONH ₂ . In one embodiment, R ⁶ can be -COOH. In another embodiment, R ⁶ can be -CN. In another embodiment, R ⁶ can be -CONH ₂ . In another embodiment, R ⁶ can be –CONH ₂ , oxadiazolone, –B(OH) ₂ , –PONH ₂ , –PO(CH ₃ ) ₂ , –CONHCH ₃ , –CONHCH ₂ CF ₃ , or –CONHCH ₂ CHF ₂ .

Those with ordinary knowledge in the art will understand that for any specific compound of formula (I), X, Y ¹ , Y ² , Z ¹ , Z ² , and , such that the chemical valency of the compound is satisfied, for example as illustrated by the compounds exemplified herein.

In various embodiments, compounds of formula (I) have a chemical structure selected from:

In various embodiments, compounds of Formula (I) have chemical structures as described in Table A, Table B, and/or the Examples below. Chemical (IUPAC) names are also provided for the convenience of those with ordinary knowledge in the art. In the event of inconsistency between the IUPAC name and the structure, the structure shall prevail. Table A Example structure IUPAC name 1 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a ]pyrimidin-9-yl)ethyl)amino)benzoic acid 2 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H-pirano[2,3- c]pyridin-8-yl)ethyl)amino)benzoic acid 3 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(hydroxymethyl)-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid 4 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(2-hydroxyethyl)-6-methyl-4-sideoxy- 4H- 8-yl)ethyl)amino)benzoic acid 5 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a ]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid 6 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-fluoro-7-methyl-4-sideoxy-4H-pyrido[1 ,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 7 (R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1 ,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 8 2-(((R)-1-(2-((R)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-pendantoxy-4H - 8-yl)ethyl)amino)benzoic acid 9 2-(((R)-1-(2-((S)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-pendantoxy-4H - 8-yl)ethyl)amino)benzoic acid 10 (R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[ 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 11 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid 12 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid 13 (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-side oxy-4H- 8-yl)ethyl)amino)benzoic acid 14 (R)-2-((1-(6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-side oxy-4H- 8-yl)ethyl)amino)benzoic acid 15 (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid 16 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquinazoline-8 -ethyl)amino)benzoic acid 17 (R)-5-(2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one 18 (R)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one 19 (S)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one 20 (R)-2-((1-(2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid twenty one (R)-2-((1-(6-methyl-2-(1-methyl-1H-pyrazol-3-yl)-4-side oxy-4H- 8-yl)ethyl)amino)benzoic acid twenty two (R)-2-((1-(2-(6-methoxypyridin-2-yl)-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid twenty three (R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- 8-yl)ethyl)amino)benzoic acid twenty four (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a] Pyrimidin-9-yl)ethyl)amino)benzoic acid 25 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1 ,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 26 (R)-2-((1-(3-cyano-2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid 27 (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquin oxazolin-8-yl)ethyl)amino)benzoic acid 28 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquino oxazolin-8-yl)ethyl)amino)benzoic acid synthesis

Compounds of formula (I) or pharmaceutically acceptable salts thereof can be manufactured in various ways by one of ordinary skill in the art using known techniques and guided by the detailed teachings provided herein, including the examples provided below. For example, in one embodiment, compounds of formula (I) are prepared according to the general schemes illustrated in Figures 1-3. pharmaceutical composition

Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable salt thereof. carriers, diluents, excipients, or combinations 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 delivery of compounds to an organism. Pharmaceutical compositions can also be prepared 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. to get. Pharmaceutical compositions will generally be designed for a specific intended route of administration.

The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not eliminate the biological activity and properties of the compound or cause significant harm or harm 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 a compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a frequently utilized vehicle 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 that is too small to be manufactured and/or administered. They may also be liquids used to dissolve drugs to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is an aqueous buffered solution such as, but not limited to, phosphate buffered saline that simulates the pH and isotonicity of human blood.

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

The pharmaceutical compositions described herein may be administered to human patients by themselves, or in pharmaceutical compositions in which they are mixed with other active ingredients (eg, in combination therapies), or carriers, diluents, excipients, or combinations thereof administered to human patients. Appropriate formulation depends on the route of administration chosen. Techniques for the 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, such as by conventional mixing, dissolving, granulating, dragee making, grinding, emulsifying, encapsulating, encapsulating, or tableting procedures. Furthermore, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts containing pharmaceutically compatible counter ions.

A variety of techniques exist in the art for administering compounds, salts, and/or compositions, 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 injection. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered orally.

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

If desired, the compositions may be presented in packaging or dispensing devices which may contain one or more unit dosage forms (containing the active ingredient). The packaging may, for example, comprise metal or plastic foil, such as a blister pack. The packaging or dispenser device may come with 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 product in a form prescribed by a governmental agency that reflects the agency's approval of the form of the drug for human or veterinary administration. give. For example, the notification may be labeling or product labeling approved by the U.S. Food and Drug Administration for use in prescription drugs. Compositions may also be prepared that may include compounds and/or salts described herein formulated in a compatible pharmaceutical carrier, placed in an appropriate container, and labeled for treatment of the indicated condition. Treatment uses and methods

Some embodiments described herein relate to a method for treating a cancer or tumor described herein, which may comprise administering to a subject having a cancer or tumor described herein an effective amount of a Compounds (eg, compounds of formula (I), or pharmaceutically acceptable salts thereof) or pharmaceutical compositions including compounds described herein (eg, compounds of formula (I), or pharmaceutically acceptable salts thereof). Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of Formula (I) ) compound, or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for the treatment of cancer or tumors described herein. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of Formula (I) compound, or a pharmaceutically acceptable salt thereof) for use in the treatment of cancer or tumors described herein.

Some embodiments described herein relate to a method for inhibiting the replication of a malignant growth or tumor described herein, which method may comprise contacting the growth or tumor with an effective amount of a compound described herein (e.g., formula ( I) Compound, or pharmaceutically acceptable salt thereof) contact. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for use in the manufacture of a method for inhibiting malignant growth described herein or Use of agents for tumor replication. In some embodiments, the use may include contacting the growth or tumor with the agent. Yet other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting malignant growth described herein or Tumor replication.

Some embodiments described herein relate to a method for treating a cancer described herein, which method may include contacting a malignant growth or tumor described herein with an effective amount of a compound described herein (e.g., formula ( I) Compound, or pharmaceutically acceptable salt thereof) contact. Other embodiments described herein relate to the use of an effective amount of a compound described herein (eg, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating a cancer described herein the use of. In some embodiments, the use includes contacting a malignant growth or tumor described herein with the agent. Yet other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth described herein or Tumor, wherein the malignant growth or tumor results from a cancer as described herein.

Examples of suitable malignant growths, cancers, and tumors include, but are not limited to: breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, non-small cell lung cancer , glioma, bladder cancer, soft tissue sarcoma, esophageal and gastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer.

As used herein, "subject" refers to an animal that is the subject 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, cattle, horses, primates such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and/or infant, such as a child or infant suffering from a fever. In other embodiments, the subject may 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 reduction to any degree of any undesirable signs or symptoms of a disease or condition may be considered treatment and/or therapy. Additionally, treatment may include actions that may worsen the 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 preparation that elicits an indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound, salt, or composition may be that amount necessary to prevent, alleviate, or ameliorate symptoms of a disease or condition, or prolong the survival of the subject treated. This response can occur in tissues, systems, animals, or humans and includes alleviation of signs or symptoms of the disease or condition being treated. In view of the disclosure provided herein, determination of effective amounts 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 treated (including humans), and the physical characteristics of the particular animal considered. Dosage may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant medications, and other factors that one of ordinary skill in the art of medicine will recognize.

For example, an effective amount of a compound is an amount that results in (a) reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) tumor elimination, and/or (d ) Long-term disease stabilization (growth arrest) of tumors. In the treatment of lung cancer, such as non-small cell lung cancer, a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and/or pain. As another example, an effective or therapeutically effective amount of a PI3K inhibitor is an amount that results in a reduction in PI3K protein activity. Methods for measuring reduced PI3K activity are known to those of ordinary skill in the art and can be determined by analyzing PI3K binding, for example, as illustrated in the Examples below.

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, disease or condition being treated. The nature and/or symptoms, and the age and condition of the patient vary, and the final decision will be made by the attending physician or clinician. Where pharmaceutically acceptable salts are administered, the dosage may be calculated as the free base. One of ordinary skill in the art will understand that, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges set forth herein to effectively and aggressively treat, in particular, an invasion. Disease or condition.

Generally, however, a suitable dosage will often range from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may be from about 0.10 mg/kg to about 7.5 mg/kg body weight/day, such as from about 0.15 mg/kg to about 5.0 mg/kg/recipient body weight/day, from 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 of active ingredient therebetween.

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

As will be readily apparent to one of ordinary skill in the art, useful in vivo doses to be administered and the specific mode of administration will depend upon the age, weight, severity of illness and species of mammalian species being treated, the specific compound employed, and The specific uses in which these compounds are employed vary. Determination of effective dose levels (i.e., the dose levels required to achieve the desired effect) can be determined by those of ordinary skill in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, the 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 made by comparison with established drugs such as cisplatin and/or gemcitabine

Dosage and time intervals can be individually adjusted to provide plasma levels or minimum effective concentrations (MEC) of the active moiety sufficient to maintain the modulatory effect. The MEC will vary for each compound, but can be estimated from in vivo and/or in vitro data. The dose required 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 most preferably between 50 to 90% of the time. . In the case of local administration or selective absorption, the local effective concentration of the drug may not be related to the 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 organ dysfunction. Conversely, the attending physician will also know if the clinical response is inadequate (to rule out toxicity) and adjust treatment to a higher level. The magnitude of the dosage administered in the management of the disorder of concern 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 may be assessed, for example, in part based on standard prognostic assessment methods. In addition, dosage and possible dosing frequency will vary based on the age, weight, and response of the individual patient. Programs similar to those discussed above may be used in veterinary medicine.

Known methods can be used to evaluate the efficacy and toxicity of the compounds, salts, and compositions disclosed herein. For example, the toxicology of a particular compound or a subgroup of compounds that share certain chemical moieties can be established by determining in vitro toxicity to cell lines, such as mammalian and preferably human cell lines. The results of such studies are often predictive of toxicity in animals (e.g., mammals) or more specifically in 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 efficacy 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, those skilled in the art can be guided by current best techniques in selecting the appropriate model, dose, route of administration, and/or regimen. Example

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 for 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 well-known organic synthesis steps, but not necessarily illustrated in a general scheme. Any steps shown in the general scheme can be used in any combination or in different orders 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 patent claims in any way. One of ordinary skill in the art will be able to recognize modifications to the disclosed synthesis and devise alternative approaches based on the disclosure herein.

Figure 1 depicts a general synthetic scheme 1 for the preparation of examples of compounds of formula (I). In Scheme ¹ , ^R3 , ^R5 , ^WR1R2 , and Ring A can be as described herein. The aromatic ring or heteroaromatic ring of 1a can be brominated with bromine, N-bromosuccinimide, or other brominating agents to obtain 1b. Ketone 1b is reacted with carbon disulfide under basic conditions to obtain 1c, where ^R3 is hydrogen. The resulting 1c was reacted with ethyl iodide to obtain 1d. The bromide of 1d can be replaced by palladium-catalyzed Heck reaction and Stille coupling to produce 1e. Alternatively, 1d can be reacted with 2-methyl-vinylboronic acid, followed by oxidative cleavage to give 1e. Ketone 1e can be subjected to reductive amination with tertiary butylsulfinamide to obtain 1f. One of ordinary skill in the art will understand that 1f can be obtained in a chiral pure form, or excess enantiomer can be enriched in this step to yield 1g. Provide 1 h for removal of the tertiary butylstyrene group under acidic conditions. Subsequent reaction of 1h with the leaving group of the methyl or tertiary butyl ester of 1i (ie, bromide under Pd-catalyzed conditions or methanesulfonyl group under basic conditions) provides 1j. The sulfide of 1j can be reacted directly with boric acid under palladium-catalyzed, copper-mediated conditions, followed by ester hydrolysis to obtain IA, the compound of formula (I). Alternatively, the sulfide of 1j can be oxidized to 1k, which undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IA. Conversion of R ³ from hydrogen to halogen (F, Cl, Br, I) and from iodide to cyano can occur at 1f, 1g, or 1j or prior to ester hydrolysis to obtain IA.

Figure 2 depicts a general synthetic scheme 2 for the preparation of examples of compounds of formula (I). In Scheme ² , ^R3 , ^R5 , ^WR1R2 , and Ring A can be as described herein. Aminopyridine 2a can be reacted with diester 2n to obtain 2b. The hydroxypyridine methanesulfonate of 2b can be acylated and replaced by an amine nucleophile to obtain 2c. The bromide of 2c can be replaced by palladium-catalyzed Heck reaction and Stille coupling to produce 2d. Alternatively, 2c can be reacted with 2-methyl-vinylboronic acid, followed by oxidative cleavage to give 2d. Ketone 2d can be subjected to reductive amination with tertiary butylsulfinamide to obtain 2e. One of ordinary skill in the art will understand that 2e may be obtained in a chiral pure form, or excess enantiomers may be enriched in this step to yield chiral pure 2e. Removal of the tertiary butylstyrene group under acidic conditions affords 2f. Subsequent reaction of 2f with the leaving group of the methyl or tertiary butyl ester of 2o (i.e., bromide under Pd-catalyzed conditions or methanesulfonyl group under basic conditions) provides IIA. Alternatively, the hydroxypyridine of 2b can be chlorinated to obtain 2 g, which undergoes nucleophilic displacement with methyl sulfide to obtain 2h. The bromide of 2h can be replaced by palladium-catalyzed Heck reaction and Stille coupling to produce 2i. Alternatively, 2h can be reacted with 2-methyl-vinylboronic acid followed by oxidative cleavage to give 2i. Ketone 2i can be subjected to reductive amination with tertiary butylsulfinamide to obtain 2j. Removal of the tertiary butylstyrene group under acidic conditions provides 2k. Subsequent reaction of 2k with the leaving group of the methyl or tertiary butyl ester of 2o (e.g., bromide under Pd-catalyzed conditions or methanesulfonyl group under basic conditions) provides 2l. 2 l of sulfide can be reacted with boric acid under palladium-catalyzed, copper-mediated conditions, followed by ester hydrolysis to obtain IIA, the compound of formula (I). Alternatively, the sulfide of 2l can be oxidized to sulfide 2m, which undergoes nucleophilic displacement with a primary or secondary amine, followed by ester hydrolysis to obtain IIA. Conversion of R ³ from hydrogen to iodine and to cyano can occur before 1f, 1g, or 1j or before hydrolysis of the ester to obtain IIA. Conversion of ^R from hydrogen to halogen (F, Cl, Br, I) and from iodide to cyano can occur in 2e, 2j, or 2l or prior to ester hydrolysis to obtain IIA.

Figure 3 depicts a general synthetic scheme 3 for the preparation of examples of compounds of formula (I). In Scheme 3, ^R3 , ^R5 , ^WR1R2 , and Ring A can be as described ^herein . The carboxylic acid of 3a can be treated with ^R3 - _NH2 under amide coupling conditions to obtain 3b. Amide 3b can be treated with triphosgene under heat to obtain 3c. The hydroxyl group of 3c was chlorinated to obtain 3d, which was further reacted with an amine nucleophile to obtain 3e. The bromide of 3e can be subjected to a Suzuki reaction with 2-methylvinylborate to obtain 3f. Oxidative cleavage of 3f produces 3 g of ketone, which is reduced to alcohol for 3 h. Alcohol 3h was treated with methanesulfonyl chloride to give mesylate 3i, which was replaced with amine 3k to give 3j. Hydrolysis of the ester of 3j provides IIIA, the compound of formula (I). Example 1 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2 -a]pyrimidin-9-yl)ethyl)amino)benzoic acid Step 1: Preparation of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a stirred solution of 3-bromo-5-methylpyridin-2-amine (2.50 g, 13.4 mmol) in DCM (25 mL) at 0 °C was added malondichloride (1.96 g, 14.0 mmol) , and the mixture was stirred at rt for 48 h. The reaction was quenched with water (25 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and evaporated to dryness under reduced pressure to provide crude 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a ]pyrimidin-4-one (1.8 g, 51%) which was used in the next step without further purification. MS (ESI) 255.0 [M+H] ⁺ . Step 2: Preparation of 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a stirred solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.80 g, 7.10 mmol) in DCM (18 mL) was added TEA (1.96 mL, 14.2 mmol) and the mixture was stirred for 10 min. Methanesulfonyl chloride (1.21 g, 10.7 mmol) was added dropwise at 0 °C, and the reaction was stirred at rt for 4 h. TEA (4.9 mL, 35.2 mmol) was added at 0 °C, followed by 4,4-dimethylpiperidine hydrochloride (3.18 g, 21.3 mmol), and the reaction was stirred at 50 °C for 24 h. The reaction was cooled to rt, quenched with water (25 mL), and the mixture was extracted with DCM (2 × 25 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H -Pyrido[1,2-a]pyrimidin-4-one (0.53 g, 21%). MS (ESI) 350.2 [M+H] ⁺ . Step 3: Preparation of 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

9-Bromo-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.00 g, 2.86 mmol ) and a stirred solution of tributyl(1-ethoxyvinyl)stannane (2.06 g, 5.72 mmol) in 1,4-dioxane (10 mL) was purged with N ₂ for 15 min. PdCl ₂ (PPh ₃ ) ₂ (200 mg, 0.286 mmol) was added and the reaction mixture was stirred at 90 °C for 24 h. The reaction was cooled to rt and 2N HCl (25 mL) was added. The reaction mixture was stirred at 50 °C for 30 min. The reaction was cooled to rt and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried ( _Na2SO4 ) _, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-7-methyl -4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 55%). MS (ESI) 314.3 [M+H] ⁺ . Step 4: (R)-N-((R)-1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido Preparation of [1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide

To 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.500 g, To a stirred solution of (R)-2-methylpropane-2-sulfinamide (0.386 g, 3.19 mmol) in THF (4 mL), Ti(OEt) ₄ (2.18 g, 9.58 mmol). The reaction was stirred at 80 °C for 16 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was dissolved in THF (5 mL) and cooled to 0 °C. AcOH (0.577 g, 9.60 mmol) and NaCNBH ₃ (0.226 g, 3.60 mmol) were added and the reaction was stirred at rt for 5 h. The reaction was quenched with water (5 mL) and the mixture was extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-N-((R)-1-(2-(4,4-dimethylpiperidine-1 -yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (0.275 g, 40%). Chiral purity 98% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 419.5 [M+H] ⁺ . Step 5: (R)-9-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2- a] Preparation of pyrimidin-4-one

To (R)-N-((R)-1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-pendantoxy-4H- Pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (0.39 g, 0.93 mmol) in 1,4-dioxane (4 mL) To the solution in , 4 M HCl in dihexane (4 mL) was added. The reaction was stirred at rt for 2 h. The reaction was evaporated to dryness and triturated with diethyl ether. The residue was neutralized with saturated _NaHCO3 (15 mL) and extracted with EtOAc (2 × 20 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , DCM/MeOH) to provide (R)-9-(1-aminoethyl)-2-(4,4-dimethylpiperidine-1 -(yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.27 g, 92%). Chiral purity 98% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 315.8 [M+H] ⁺ . Step 6: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1, Preparation of 2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate

To (R)-9-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a] To a stirred solution of pyrimidin-4-one (0.200 g, 0.640 mmol) and methyl 2-bromobenzoate (0.163 g, 0.758 mmol) in 1,4-dioxane (4 mL), Cs ₂ CO ₃ was added (0.620 g, 1.91 mmol), and the reaction _was purged with N for 15 min. Pd ₂ (dba) ₃ (0.058 g, 0.064 mmol) and XanthPhos (0.055 mg, 0.095 mmol) were added and the reaction was stirred at 95 °C for 16 h. The reaction was quenched with water (4 mL) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -7-Methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid methyl ester (0.17 g, 60%). Chiral purity 98% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 449.5 [M+H] ⁺ . Step 7: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1, Preparation of 2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1 To a stirred solution of 2-a]pyrimidin-9-yl)ethyl)amino)benzoate methyl ester (0.170 mg, 0.379 mmol) in THF:MeOH (1:1, 2 mL), 2 M NaOH was added solution (1 mL, 2 mmol). The reaction was stirred at rt for 16 h. The reaction was neutralized in 2N HCl and concentrated under reduced pressure. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by chiral SFC (Chiralcel-ED-H (30 × 250 mm column) 20% MeOH) to provide (R)-2-((1-(2-(4,4-dimethyl (piperidin-1-yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (80 mg, 48 %). 99.6% chiral purity (Chiralcel-OD-3 (4.6 × 250 mm column) 20% MeOH); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 8.58-8.51 (m, 2H), 7.81 (d, J= 7.6 Hz, 1H), 7.55 (s, 1H), 7.18 (t, J =7.2 Hz, 1H), 6.52 (t, J =7.2 Hz, 1H), 6.32 (d, J =8 Hz, 1H), 5.63 (s, 1H), 5.20 (s, 1H), 3.66 (m, 4H), 2.23 (s, 3H), 1.57-1.55 (d, J= 6.8 Hz, 3H), 1.38-1.35 (m, 4H), 0.98 (s, 6H); MS (ESI) 433.4 [MH] ^- . Example 2 (R)-2-((1-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy- 4H -pirano[2, 3- c ]pyridin-8-yl]ethylamino)benzoic acid Step 1: Preparation of ethyl 2-bromo-3-hydroxy-6-methylisonicotinate

To a stirred solution of 5-hydroxy-2-methylisonicotinate ethyl ester (22.0 g, 122 mmol) in DMF (220 mL) at 0 °C was added NBS (21.9 g, 122 mmol) and incubated at rt Stir for 1 h. Upon completion, the reaction mixture was quenched with cold water (220 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried ( _Na2SO4 ) and filtered, then _concentrated to provide ethyl 2-bromo-3-hydroxy-6-methylisonicotinate (23 g, 72%). MS (ESI) 262.1 [M+H] ⁺ . Step 2: Preparation of 2-bromo-3-hydroxy-6-methylisonicotinic acid

2-Bromo-3-hydroxy-6-methylisonicotinate ethyl ester (17.0 g, 65.7 mmol) in THF:MeOH:H ₂ O (170 mL, 3:1:1) at 0 °C To the stirred solution, add LiOH ^. H ₂ O (13.78 g, 328.3 mmol). The reaction mixture was stirred at rt for 16 h. Upon completion, the solvent was removed under reduced pressure. Water (25 mL) was added and the mixture was neutralized with 2N HCl. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated to provide 2-bromo-3-hydroxy-6 _- methylisonicotinic acid (13 g, 85%). MS (ESI) 232.0 [M+H] ⁺ . Step 3: Preparation of 2-bromo-3-hydroxy- N -methoxy- N -methoxy- N ,6-dimethylisonicotinamide

To a stirred solution of 2-bromo-3-hydroxy-6-methylisonicotinic acid (5.50 g, 28.3 mmol) in DMF (55 mL) at 0 °C was added N,O-dimethylhydroxylamine Hydrochloride (4.10 g, 42.4 mmol), HATU (16.1 g, 42.4 mmol), and DIPEA (14.4 mL, 84.8 mmol). The resulting mixture was stirred at rt for 16 h. Upon completion, the reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated to provide 2-bromo-3-hydroxy-N-methoxy-N,6-dimethylisonicotinamide (2.8 g, 43%). MS (ESI) 275.1 [M+H] ⁺ . Step 4: Preparation of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one

To a stirred solution of 2-bromo-3-hydroxy-N-methoxy-N,6-dimethylisonicotinamide (3.00 g, 10.9 mmol) in THF (30 mL) at 0 °C, Add 3M MeMgBr in THF (10.94 mL, 32.84 mmol). The reaction was stirred at rt for 16 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (40 mL) and extracted with EtOAc (2 × 50 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography to afford 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one (2.2 g, 87%). MS (ESI) 232.0 [M+H] ⁺ . Step 5: Preparation of 8-bromo-4-hydroxy-6-methyl- 2H -pirano[2,3- c ]pyridine-2-thione

To a stirred solution of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one (3.00 g, 13.0 mmol) in THF (60 mL) at -78 °C , 2M NaHMDS (9.80 mL, 19.6 mol) in THF. The reaction was then stirred at 0 °C for 1 h. The reaction was cooled to -78°C and _CS2 (1.20 mL, 19.6 mol) was added. The reaction was stirred at rt for 16 h. Upon completion, it was cooled to -50° _C and 15% _H2SO4 was added dropwise until the mixture was neutralized. The reaction was stirred at rt for 30 min then concentrated. The residue was triturated with DCM (30 mL) to provide 8-bromo-4-hydroxy-6-methyl-2 H -pirano[2,3- c ]pyridine-2-thione (2.5 g, 70 %), which was used in the next step without further purification. MS (ESI) 274.0 [M+H] ⁺ . Step 6: Preparation of 8-bromo-2-(ethylthio)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one

To a stirred solution of 8-bromo-4-hydroxy-6-methyl-2 H -pirano[2,3- c ]pyridine-2-thione (2.00 g, 7.38 mmol) in acetone (30 mL) , add K ₂ CO ₃ (2.03 g, 14.8 mmol). The reaction was stirred at rt for 15 min. To the resulting suspension was added EtI (0.60 mL, 7.4 mmol). The reaction was stirred at rt for 16 h. After completion, the reaction mixture was concentrated. The residue was dissolved in DCM (25 mL) and washed with water (2 × 25 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography to provide 8-bromo-2-(ethylthio)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one (0.6 g, 27%). MS (ESI) 300.1 [M+H] ⁺ . Step 7: Preparation of 8-bromo-2-(ethylsulfonyl)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one

8-Bromo-2-(ethylthio)-6-methyl-4 H -pirano[2,3- c ]pyridin-4-one (1.8 g, 6.02 mmol) was dissolved in DCM ( To the stirred solution in 38 mL), m-CPBA (4.15 g, 24.08 mmol) was added, followed by stirring at rt for 16 h. Upon completion, the reaction was quenched with water (30 mL) and washed with saturated aqueous _NaHCO3 and water (30 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography to provide 8-bromo-2-(ethylsulfonyl)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one ( 1.3 g, 65%). MS (ESI) 322.5 [M+H] ⁺ . Step 8: Preparation of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one

To 8-bromo-2-(ethylsulfonyl)-6-methyl-4 H -pirano[2,3- c ]pyridin-4-one (1.30 g, 3.92 mmol) and 4 To a stirred solution of 4-difluoropiperidine hydrochloride (1.17 g, 7.85 mmol) in DCM (20 mL), DIEA (2.05 mL, 11.8 mmol) was added. The reaction was stirred at rt for 16 h. Upon completion, the reaction was quenched with water (20 mL) and extracted with DCM (2 × 100 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography to provide 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2,3 - c ]pyridin-4-one (1.2 g, 87%). MS (ESI) 351.0 [M+H] ⁺ . Step 9: 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one Preparation

To 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4 H -pirano[2,3- c ]pyridin-4-one (0.600 g, To a stirred suspension of 1.71 mmol) in 1,4-dioxane (6 mL), add tributyl(1-ethoxyvinyl)stannane (0.680 g, 1.71 mmol) and Pd(PPh ₂ ) Cl ₂ (60 mg, 0.08 mmol). The mixture was purged with _N2 and then heated at 90 °C for 24 h. After cooling to rt, 2N HCl (10 mL) was added to the reaction mixture. The reaction was heated at 50 °C for 30 min. The volatiles were evaporated under pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with _{saturated Na2CO3} (30 mL). The organic layer was then washed with _brine , dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography to provide 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2 ,3- c ]pyridin-4-one (500 mg, 93%). MS (ESI) 315.3 [M+H] ⁺ . Step 10: N-((R)-1-(2,(4,4-dimethylpiperidin-1-yl)-6-methyl-4-side oxy-4H-pirano[2, Preparation of 3- c ]pyridin-8-yl)ethyl)-2-methylpropane-2-sulfinamide

To 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2,3- c ]pyridin-4-one (0.900 g, 2.86 mmol) and (R)-2-methylpropane-2-sulfinamide (1.30 g, 11.5 mmol) in THF (9 mL), were added Ti(OiPr) ₄ (6.50 mL , 22.9 mmol). The reaction was refluxed for 24 h. After cooling to rt, the reaction was quenched with brine (40 mL) and then diluted with EtOAc (40 mL). The precipitate was removed by filtering through a pad of celite, which was washed with EtOAc (3 × 20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic layers were washed with water (75 mL) and brine (100 mL). The organic layer was then dried ( _Na2SO4 ) and filtered _, then concentrated. The residue was dissolved in THF (12 mL) and AcOH (1.15 g, 19.2 mmol) and _NaCNBH3 (0.450 g, 7.19 mmol) was added at -15°C. The resulting mixture was stirred at rt for 10 h. Upon completion, the reaction was quenched with saturated _{aqueous Na2CO3} solution at 0°C until the pH was approximately 8 to 9. The mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried ( _Na2SO4 ), filtered, and concentrated _. The residue was purified by flash chromatography to provide N-((R)-1-(2,(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendant oxygen (0.6 g , 51%). MS (ESI) 420.4 [M+H] ⁺ . Step 11: (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2, Preparation of 3- c ]pyridin-4-one

To N-((R)-1-(2,(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H-pirano[2,3- c ] Pyridin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.600 g, 1.48 mmol) in 1,4-dioxane (3 mL) was added HCl (4M in 1,4-dioxane, 6 mL). The reaction was stirred at rt for 3 h. Upon completion, the solvent was removed under reduced pressure and the reaction was triturated with diethyl ether (2 × 5 mL). The product was dissolved in water (5 mL), neutralized with saturated _NaHCO3 , and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated to provide (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidine-1- ( 0.37 g , 82%). MS (ESI) 316.4 [M+H] ⁺ . Step 12: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy- 4H -pirano[ Preparation of 2,3- c ]pyridin-8-yl)ethylamino)benzoic acid methyl ester

To (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4H -pirano[2,3- c ] To a stirred solution of pyridin-4-one (370 mg, 1.17 mmol) in 1,4-dioxane (3.7 mL), methyl 2-bromobenzoate (277 mg, 1.29 mmol) and Cs ₂ were added CO ₃ (1.08 g, 3.52 mmol). The reaction mixture was degassed with _N2 for 15 min. Pd ₂ (dba) ₃ (107 mg, 0.117 mmol) and XanthPhos (101 mg, 0.176 mmol) were added, and the resulting mixture was degassed with _N again for 15 min. The reaction was heated at 95 °C for 16 h. Upon completion, the reaction mixture was filtered through a pad of celite. The volatiles were removed under reduced pressure, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was washed further with EtOAc (2 × 20 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by chiral SFC (Lux Cellulose-C4 (30 × 250 mm column), 30% MeOH) to provide (R)-2-((1-(2-(4,4-dimethyl Methyl piperidin-1-yl)-6-methyl-4-side oxy-4H-pirano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (130 mg, 24%). 99.2% chiral purity (Chiralpak AS-H (4.6 × 250 mm column) 20% MeOH with 0.5% modifier). MS (ESI) 450.8 [M+H] ⁺ . (R)-2-((1-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy- 4H -pirano[2,3- c ]pyridin-8-yl]ethylamino)benzoic acid Step 13: (R)-2-((1-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy- 4H -pirano[2 , Preparation of 3- c ]pyridin-8-yl]ethylamino)benzoic acid

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H-pirano) at 0°C To a stirred solution of [2,3-c]pyridin-8-yl)ethyl)amino)benzoate (130 mg, 0.28 mmol) in MeOH (1.3 mL), NaOH (2N, 1.16 mL, 2.31 mmol). The reaction was stirred at rt for 16 h. Upon completion, the solvent was removed under reduced pressure and the mixture was acidified with 2N HCl. The mixture was extracted with EtOAc (3 × 50 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by achiral SFC to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-yl) Oxy-4H-pirano[2,3-c]pyridin-8-yl)ethyl)amino)benzoic acid (25 mg, 20%), 99.8% chiral purity (Chiralcel-OD-3 (4.6 × 250 mm column) 20% MeOH). ¹ H NMR (400 MHz, DMSO-d6) δ 12.66 (br s, 1H), 8.87 (br s, 1H), 7.79 (d, J =8 Hz, 1H), 7.56 (s, 1H), 7.29 (s , 1H), 6.77 (d, J =4 Hz, 1H), 6.53 (m, 1H), 5.63 (s, 1H), 5.2 (br s, 1H), 3.58 (m, 4H), 2.50 (s, 3H ), 1.57-1.42 (m, 7H), 0.98 (s, 6H). MS (ESI) 436.4 [M+H] ⁺ . Example 3 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(hydroxymethyl)-6-methyl-4-pendantoxy- 4H- Preparation of 8-yl)ethyl)amino)benzoic acid

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-side oxy) at 0°C -4H- To a stirred solution of phosphonium-8-yl)ethyl)amino)benzoic acid (Example 11) (70.0 mg, 0.152 mmol) in THF (2.1 mL) was added NaBH ₄ (11.5 mg, 0.303 mmol). The reaction was stirred at rt for 30 min. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by reverse phase HPLC chromatography (C18, H ₂ O/CH ₃ CN) to provide (R)-2-((1-(2-(4,4-dimethylpiperidine- 1-yl)-3-(hydroxymethyl)-6-methyl-4-pentoxy-4H- Diphenyl)ethyl)amino)benzoic acid (5 mg, 8%). Chiral purity 96.4% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H) , 8.50 (s, 1H), 7.80 (d, J =8 Hz, 1H), 7.63 (s, 1H), 7.39-7.38 (m, 1H), 7.20 (t, J= 12 MHz, 1H), 6.54- 6.51 (t, J =12.3 Hz, 1H), 6.43 (d, J =8 Hz, 1H), 5.05 (s, 1H), 4.78 (t, J =12 Hz , 1H), 4.38-4.31 (m, 2H ), 3.69-3.67 (m , 4H), 2.31 (s, 3H), 1.58 (d, J =4 Hz , 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H); MS (ESI) 463.3 [MH] ^- . Example 4 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(2-hydroxyethyl)-6-methyl-4-side oxygen Base-4H- 8-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Dimethyl-8-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(2-(4,4-dimethylpiperidine- 1-yl)-6-methyl-4-side oxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate provided the title compound (1.7 g, 95%), MS (ESI) 435.4 [M+H] ⁺ . Step 2: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of benzyl 8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- To a stirred solution of phosphonium-8-yl)ethyl)amino)benzoic acid (1.70 g, 3.91 mmol) in DMF (8.5 mL) was added K ₂ CO ₃ (810 mg, 5.87 mmol). The reaction was stirred at rt for 30 min and benzyl bromide (797 mg, 4.30 mmol) was added at 0°C. The reaction was stirred at rt for 6 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 × 20 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -6-Methyl-4-Pendantoxy-4H- Benzyl-8-yl)ethyl)amino)benzoate (1.5 g, 73%). Chiral purity 98.4% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 525.6 [M+H] ⁺ . Step 3: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-6-methyl-4-sideoxy-4H- Preparation of benzyl 8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-6-methyl-4-sideoxy-4H- Benzyl-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(4,4-dimethylpiperidine)) according to the procedure of step 10 of Example 11 (Din-1-yl)-6-methyl-4-pendantoxy-4H- Benzyl-8-yl)ethyl)amino)benzoate provided the title compound (1.2 g, 64%). Chiral purity 99.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 651.2 [M+H] ⁺ . Step 4: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-3-vinyl-4H- Preparation of benzyl 8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-3-vinyl-4H- Benzyl-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(4,4-dimethylpiperdate)) according to the procedure of step 11 of Example 11 (ridin-1-yl)-3-iodo-6-methyl-4-pendantoxy-4H- Benzyl (8-yl)ethyl)amino)benzoate and tributyl(vinyl)stannane were added to provide the title compound (300 mg, 70%). Chiral purity 99.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 551.6 [M+H] ⁺ . Step 5: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(2-hydroxyethyl)-6-methyl-4-yl) Oxygen-4H- Preparation of benzyl 8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-3-vinyl- 4H- To a stirred solution of benzyl benzoate (300 mg, 0.545 mmol) in THF (1.5 mL), 9-boronbicyclo[3.3.1]nonane (10.9 mL) was added , 5.45 mmol) 0.5 M solution in THF. The reaction was stirred at rt for 5 h. 2N NaOH (1.5 mL) and 30% H ₂ O ₂ (1.5 mL) were added at 0 °C, and the reaction was stirred at rt for 16 h. The reaction was quenched with saturated _NaHCO3 (15 mL) and extracted with EtOAc (2 × 15 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-(2-Hydroxyethyl)-6-methyl-4-pendantoxy-4H- Benzyl-8-yl)ethyl)amino)benzoate (200 mg, 64%). MS (ESI) 569.7 [M+H] ⁺ . Example 4 Step 5: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-(2-hydroxyethyl)-6-methyl-4 -Pendant oxygen group-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

To a suspension of 10% Pd/C (100 mg) in THF (2 mL) was added (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl )-3-(2-hydroxyethyl)-6-methyl-4-pendantoxy-4H- Benzyl-8-yl)ethyl)amino)benzoate (200 mg, 0.351 mmol). The reaction was stirred at rt for 12 h under _H2 atmosphere. The reaction was filtered through a bed of celite, which was washed with DCM (10 mL). Evaporate the solvent. The residue was purified by preparative SFC (Chiralcel-OX-3 (4.6 × 250 mm column) 40% (0.25% DEA in MeOH)) to provide (R)-2-((1-(2 -(4,4-dimethylpiperidin-1-yl)-3-(2-hydroxyethyl)-6-methyl-4-pendantoxy-4H- Phosphen-8-yl)ethyl)amino)benzoic acid (17 mg, 10%). Chiral purity 97.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H ), 8.76 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.14 (s, 1H), 6.51-6.48 (t, J =12 Hz, 1H) , 6.39 (s, 1H), 5.05 (s, 1H), 4.71 (s, 1H), 3.61-3.60 (m , 2H), 3.44-3.42 (m, 4H), 2.60 (t, J =12 Hz , 2H ), 2.29 (s, 3H), 1.57 (d, J =8 Hz , 3H), 1.48-1.45 (m, 4H), 0.98 (s, 6H); MS (ESI) 479.9 [M+H] ⁺ . Example 5 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2 -a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid Step 1: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1, Preparation of 2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid methyl ester

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a ]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid methyl ester was prepared from (R)-9-(1-aminoethyl)-2- according to the procedure of step 6 of Example 1 (4,4-dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and methyl 2-bromo-6-fluorobenzoate, The title compound (100 mg, 27%) was obtained. Chiral purity 99.8% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 467.5 [M+H] ⁺ . Example 5 Step 2: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[ Preparation of 1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a ]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid was prepared from (R)-2-((1-(2-(4,4-di Methylpiperidin-1-yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid methyl ester to obtain the title compound (69 mg, 71%). Chiral purity 99.4% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.15 (bs, 1H ), 8.51 (s, 1H), 8.14-8.13 (m, 1H), 7.57 (d, J =1.6 Hz, 1H), 7.18-7.13 (m, 1H), 6.34 (dd, J =11.6, 8.4 Hz, 1H), 6.15 (d, J =8.8 Hz, 1H), 5.62 (s, 1H), 5.19-5.16 (m, 1H), 3.64 (bs, 4H), 2.23 (s, 3H), 1.56-1.54 (d , J =6.8 Hz, 3H), 1.38-1.35 (m, 4H), 0.97 (s, 6H); MS (ESI) 451.3 [MH] ^- . Example 6 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-fluoro-7-methyl-4-sideoxy-4H-pyrido [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1, Preparation of 2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a ]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester was prepared from (R)-9-(1-aminoethyl)-2-( 4,4-Dimethylpiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 2-bromobenzoic acid tertiary butyl ester to obtain the title compound (150 mg, 48%). Chiral purity 99.6% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 491.6 [M+H] ⁺ . Step 2: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-fluoro-7-methyl-4-sideoxy-4H-pyridine Preparation of tertiary butyl[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2- To a stirred solution of a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (300 mg, 0.610 mmol) in DCM (3 mL), Selectfluor (1.00 g, 2.80 mmol) was added. The reaction was stirred at 50 °C for 16 h. The reaction was quenched with water (5 mL) and extracted with DCM (2 × 5 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-Fluoro-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester (80 mg, 26 %). Chiral purity 99.6% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 509.6 [M+H] ⁺ . Step 3: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-fluoro-7-methyl-4-sideoxy-4H-pyridine Preparation of [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-fluoro-7-methyl-4-pendantoxy-4H) at 0°C To a stirred solution of -pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (80 mg, 0.16 mmol) in DCM (0.4 mL), TFA ( 0.8 mL). The reaction was stirred at rt for 4 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in EtOAc (25 mL). The organic layer was washed with saturated _NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried ( _Na2SO4 ) _, filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-Fluoro-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (34 mg, 56%). Chiral purity 99.6% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (bs, 1H ), 8.48 (s, 1H), 8.39-8.37 (m, 1H), 7.80 (d, J =7.6 Hz, 1H), 7.57 (s, 1H), 7.21 (t, J =15.6 Hz, 1H), 6.55 (t, J =12 Hz, 1H), 6.33 (d, J =12 Hz, 1H), 5.23-5.22 (m, 1H), 3.77-3.74 (m, 4H), 2.25 (s, 3H), 1.58- 1.57 (d, J =4 Hz, 3H), 1.43-1.42 (m, 4H), 0.99 (s, 6H); MS (ESI) 451.3 [MH] ^- . Example 7 (R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyridine Preparation of tertiary butyl[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[ To a stirred solution of 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (150 mg, 0.306 mmol) in DCM (1.5 mL) was added N-chlorosuccinimide Amine (48.0 mg, 0.367 mmol). The reaction was stirred at 0 °C to rt for 1 h. The reaction was quenched with water (2 mL) and extracted with DCM (2 × 4 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidine- 1-yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester (60 mg, 37 %). Chiral purity 98.1% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 525.6 [M+H] ⁺ . Step 2: (R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyridine Preparation of [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid

(R)-2-((1-(3-chloro-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1 ,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(3-chloro-2-(4)) according to the procedure of step 3 of Example 6 ,4-dimethylpiperidin-1-yl)-7-methyl-4-side oxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester to obtain the title compound (26 mg, 56%). Chiral purity 98.1% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d6) δ 12.73 (bs, 1H) , 8.54 (s, 1H), 8.38 (d, J =4 Hz, 1H), 7.80 (dd, J =1.6, J =8.0, 1H), 7.65-7.64 (m, 1H), 7.22 (t, J = 8.4 Hz, 1H), 6.55 (t, J =7.2 Hz, 1H), 6.36 (d, J =8.4 Hz, 1H), 5.25-5.22 (m, 1H), 3.69-3.67 (m, 4H), 2.27 ( s, 3H), 1.60-1.58 (d, J =8 Hz, 3H), 1.47-1.44 (m, 4H), 0.98 (s, 6H); MS (ESI) 469.6 [M+H] ⁺ . Examples 8 and 9 2-(((R)-1-(2-((R)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-side Oxygen-4H- Diphenyl-8-yl)ethyl)amino)benzoic acid and 2-(((R)-1-(2-((S)-3-(1H-pyrazol-4-yl)piperidine-1- base)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid Step 1: 2-(((R)-1-(2-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-pendantoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(ethylsulfonyl)-6-methyl-4-pendantoxy-4H- Tertiary butyl benzoate (400 mg, 0.848 mmol) and 3-(1H-pyrazol-4-yl)piperidine dihydrochloride (228 mg, 1.02 mmol) ) to a stirred solution in DCM (4 mL), add DIPEA (0.444 mL, 2.50 mmol). The reaction was stirred at rt for 16 h. Water (5 mL) was added to the reaction, and the mixture was extracted with DCM (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 2-(((R)-1-(2-3-(1H-pyrazol-4-yl)piperidine- 1-yl)-6-methyl-4-side oxy-4H- Dibutyl-8-yl)ethyl)amino)benzoate (260 mg, 58%). MS (ESI) 529.7 [M+H] ⁺ . The diastereomers were separated by chiral SFC chromatography (Chiralpak AS-H (4.6 × 250 mm column) 40% MeOH) to give peak 1 (75 mg) and peak 2 (80 mg). Peak 1: Chiral purity 98.7% (Chiralpak AS-H (4.6 × 250 mm column), 40% MeOH); MS (ESI) 529.5 [M+H] ⁺ . Peak 2: Chiral purity 99.2% (Chiralpak AS-H (4.6 × 250 mm column), 40% MeOH); MS (ESI) 529.6 [M+H] ⁺ . Step 2: 2-(((R)-1-(2-((R)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-oxygen Base-4H- Diphenyl-8-yl)ethyl)amino)benzoic acid and 2-(((R)-1-(2-((S)-3-(1H-pyrazol-4-yl)piperidine-1- base)-6-methyl-4-side oxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

2-(((R)-1-(2-((R)-3-(1H-pyrazol-4-yl)piperidin-1-yl)-6-methyl-4-pendantoxy-4H - Diphenyl-8-yl)ethyl)amino)benzoic acid and 2-(((R)-1-(2-((S)-3-(1H-pyrazol-4-yl)piperidine-1- base)-6-methyl-4-side oxy-4H- Phosphonium-8-yl)ethyl)amino)benzoic acid was synthesized from peak 1 and peak 2 from the separation in step 1 following the procedure of step 3 of Example 6 to provide the title compound. From Peak 1: (29 mg, 41%). Chiral purity 99.8% (Chiralpak AS-H (4.6 × 250 mm column), 40% MeOH); ¹ H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 8.37 (d, J= 8 Hz, 1H), 7.82-7.80 (d, J= 8.0 Hz, 1H), 7.62-7.61 (m, 1H), 7.52 (s, 2H), 7.37-7.36 (m, 1H), 7.24 (t, J = 15 Hz 1H), 6.54 (t, J =15 Hz, 1H), 6.45 (d, J= 8 Hz, 1H), 5.64 (s, 1H), 5.07-5.04 (m, 1H), 4.16-4.07 (m , 2H), 3.16-3.06 (m, 2H), 2.88-2.82 (m, 1H), 2.32 (s, 3H), 2.07-2.05 (m, 1H), 1.81-1.79 (m, 1H), 1.69-1.64 (m, 2H), 1.56 (d, J =7 Hz, 3H); MS (ESI) 472.6 [M+H] ⁺ . From Peak 2: (23 mg, 32%), chiral purity 99.0% (Chiralpak AS-H (4.6 × 250 mm column), 40% MeOH); ¹ H NMR (400 MHz, DMSO-d6) δ 12.5 ( s, 1H), 8.33 (d, J= 6 Hz, 1H), 7.81-7.79 (d, J= 8.0 Hz, 1H), 7.60-7.61 (m, 1H), 7.55 (s, 2H), 7.35-7.34 (m, 1H), 7.-7.21 (t, J =7.2 Hz, 1H), 6.57-6.55 (m, 1H), 6.43-6.40 (d, J =8 Hz, 1H), 5.61 (s, 1H) , 5.09-5.04 (m, 1H), 4.02-4.00 (m, 2H), 3.16-3.06 (m, 2H), 2.86-2.80 (m, 1H), 2.29 (s, 3H), 2.07-2.05 (m, 1H), 1.77-1.57 (m, 6H).; MS (ESI) 472.6 [M+H] ⁺ . Examples 8 and 9 are diastereomers and the stereochemistry shown for each at C(3) of the piperidine ring is arbitrarily assigned and therefore may be opposite to that depicted. Example 10 (R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyridine And[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-7-methyl-4-sideoxy-4H-pyridine Preparation of tertiary butyl[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[ To a stirred solution of 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (400 mg, 0.816 mmol) in DCM (4 mL) was added N-iodosuccinyl Amine (183 mg, 0.816 mmol). The reaction was stirred at rt for 1 h. The reaction was quenched with water (5 mL) and extracted with DCM (2 × 5 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-iodo-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (450 mg, 89 %). Chiral purity 98.0% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 617.7 [M+H] ⁺ . Step 2: (R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-pendantoxy-4H- Preparation of tertiary butyl pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-7-methyl-4-pendantoxy-4H- To a stirred solution of pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tertiary butyl ester (400 mg, 0.649 mmol) in NMP (4 mL), CuCN (112 mg, 0.973 mmol). The reaction was stirred in the microwave at 130 °C for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2 × 15 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidine) -1-yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid tertiary butyl ester (320 mg, 96%). Chiral purity 99.6% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 516.5 [M+H] ⁺ . Example 10 Step 3: (R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-pendantoxy- Preparation of 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid

(R)-2-((1-(3-cyano-2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[ 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(3-cyano-2- (4,4-dimethylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino) Tert-butyl benzoate to obtain the title compound (53 mg, 59%); chiral purity 99.6% (Chiralcel OD-3 (4.6 × 250 mm column), 30% (0.5% DEA in MeOH)) ; ¹ H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 8.47 (s, 1H), 8.54 (d, J =6.4 Hz, 1H), 7.81 (dd, J= 8 Hz, J= 1.6 Hz , 1H), 7.71 (d, J =2.0 Hz, 1H), 7.22 (t, J =4 Hz, 1H), 6.56 (t, J =4 Hz, 1H), 6.35 (d, J= 8.4 Hz, 1H ), 5.15-5.10 (m, 1H), 3.94-3.91 (m, 4H), 2.25 (s, 3H), 1.57-1.55 (d, J=6.8 Hz, 3H), 1.47-1.45 (m, 4H), 1.00 (s, 6H); MS (ESI) 458.3 [MH] ^- . Example 11 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid Step 1: Preparation of 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one

To a stirred solution of 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (200 g, 133 mmol) in DMF (800 mL) at 0 °C was added NBS ( 236.7 g 133.0 mmol) in DMF (800 mL). The reaction mixture was stirred at rt for 2 h. The reaction was quenched with water (2000 mL) and stirred for 30 min. The product was collected by filtration and dissolved in EtOAc (2000 mL). The organic layer was washed with water (2 × 1 L). The organic layer was then dried (Na ₂ SO ₄ ), filtered, and evaporated to dryness to provide 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (250 g, 82% ). MS (ESI) m/z 228.9 [M+H] ⁺ . Step 2: 8-bromo-4-hydroxy-6-methyl-2H- Preparation of H-2-thione

To a stirred solution of 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (250 g, 1.09 mol) in THF (2500 mL) at -78 °C was added 2M NaHMDS in THF (1528 mL, 3056 mmol). The reaction was stirred at 0 °C for 2 h. The reaction was cooled to -78°C and _CS2 (66.35 mL, 1.310 mmol) was added. The reaction was stirred at rt for 24 h. The reaction was cooled to _-50 °C and 15% _H2SO4 (2500 mL) was added dropwise. The reaction was stirred at -50°C for 30 min. The layers were separated, and the aqueous layer was extracted with EtOAc (1250 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The crude residue was triturated with DCM (1250 mL). The product was collected and dried under high vacuum to provide 8-bromo-4-hydroxy-6-methyl-2H- H-2-thione (152 g, 64%). MS (ESI) 273.0 [M+H] ⁺ . Step 3: 8-bromo-2-(ethylthio)-6-methyl-4H- Preparation of H-4-one

To 8-bromo-4-hydroxy-6-methyl-2H- To a stirred solution of phospho-2-thione (152 g, 563 mmol) in acetone (1520 mL) was added K ₂ CO ₃ (93.3 g, 675 mmol). The reaction was stirred at rt for 15 min. Iodoethane (159.0 mL, 1978 mmol) was added and the reaction was stirred at 60 °C for 16 h. The solvent was evaporated and water (760 mL) was added. The mixture was extracted with DCM (1520 mL). The organic layer was dried ( _Na2SO4 ) _, filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 8-bromo-2-(ethylthio)-6-methyl-4H- H-4-one (120.5 g, 72%). MS (ESI) 299.0 [M+H] ⁺ . Step 4: 8-bromo-2-(ethylsulfonyl)-6-methyl-4H- Preparation of H-4-one

To 8-bromo-2-(ethylthio)-6-methyl-4H- at 0°C To a stirred solution of phospho-4-one (19.0 g, 63.5 mmol) in DCM (190 mL) was added m -CPBA (43.84 g, 254.2 mmol). The reaction was stirred at rt for 16 h. The reaction was quenched with water (200 mL). The layers were separated and the organic layer was washed with saturated _NaHCO3 (3 × 100 mL). _The separated organic layer was dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 8-bromo-2-(ethanesulfonyl)-6-methyl-4H- H-4-one (12 g, 57%). MS (ESI) 331.1 [M+H] ⁺ . Step 5: 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- Preparation of H-4-one

To 8-bromo-2-(ethylsulfonyl)-6-methyl-4H- at 0°C To a stirred solution of methyl-4-one (10.0 g, 28.6 mmol) and 4,4-dimethylpiperidine hydrochloride (5.42 g, 36.2 mmol) in DCM (100 mL, 10V), DIPEA (11.7 g, 90.6 mmol). The reaction was stirred at rt for 16 h. The reaction was quenched with water (100 mL). _The organic layer was separated, dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H - H-4-one (7 g, 67%). MS (ESI) 350.1. Step 6: 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- Preparation of H-4-one

8-Bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- Stirring solution of phosphonium-4-one (15 g, 43 mmol) and tributyl(1-ethoxyvinyl)stannane (17.1 g, 47.3 mmol) in 1,4-dioctane (150 mL) Purge with _N2 for 15 min. PdCl ₂ (PPh ₃ ) ₂ (1.50 g, 2.14 mmol) was added and the reaction was stirred at 90 °C for 12 h. The reaction was cooled to rt and 2N HCl (150 mL) was added. The reaction was stirred at 50 °C for 1 h. Cool the reaction to rt. The mixture was extracted with EtOAc (2 × 150 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl -4H- H-4-one (11.5 g, 83%). MS (ESI) 314.3 [M+H] ⁺ . Step 7: (R)-N-((R)-1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- Preparation of methyl-8-yl)ethyl)-2-methylpropane-2-sulfinamide

To 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- To a stirred solution of phosphonium-4-one (11.5 g, 36.7 mmol) and (R)-2-methylpropane-2-sulfinamide (8.89 g, 73.5 mmol) in THF (115 mL), Ti was added (OEt) ₄ (50.25 g, 220.4 mmol). The reaction was stirred at 60 °C for 12 h. The reaction was quenched with water (115 mL) and extracted with EtOAc (2 × 100 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The crude oil was dissolved in THF (180 mL) cooled to -15°C. AcOH (20.76 mL, 346.2 mmol) and NaCNBH ₃ (8.04 g, 129.8 mmol) were added. The reaction was stirred at -15 °C and allowed to warm to rt over 5 h. The reaction was quenched with saturated _NaHCO3 (360 mL), and the mixture was extracted with EtOAc (2 × 250 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-N-((R)-1-(2-(4,4-dimethylpiperidine-1 -base)-6-methyl-4-side oxy-4H- Phosphen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (10 g, 65%). Chiral purity 87% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 419.5 [M+H] ⁺ . Step 8: (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- Preparation of H-4-one

To (R)-N-((R)-1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- To a stirred solution of phosphonium-8-yl)ethyl)-2-methylpropane-2-sulfinamide (10.0 g, 29.9 mmol) in 1,4-dioxane (50 mL), was added 4M HCl in hexanes (100 mL). The reaction was stirred at rt for 6 h. The reaction was concentrated and the residue was triturated with diethyl ether (100 mL). The compound was neutralized with saturated _NaHCO3 (100 mL) and extracted with EtOAc (2 × 100 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , DCM/MeOH) to provide (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidine-1 -base)-6-methyl-4H- H-4-one (6.5 g, 86%). Chiral purity 89% (Chiralcel OX-3 (4.6 × 250 mm column), 30% (0.5% DEA in MeOH)); MS (ESI) 315.5 [M+H] ⁺ . Step 9: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H- To a stirred solution of phosphonium-4-one (5.80 g, 18.5 mmol) and tertiary butyl 2-bromobenzoate (7.11 g, 27.7 mmol) in 1,4-dioxane (58 mL), Cs ₂ was added CO ₃ (18.0 g, 55.4 mmol). The reaction was purged with _N for 15 min. Add Pd ₂ (dba) ₃ (1.68 g, 1.84 mmol) and Xantphos (1.60 g, 2.76 mmol). The reaction was stirred at 95 °C for 16 h. The reaction was quenched with water (60 mL) and extracted with EtOAc (2 × 50 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) and chiral SFC chromatography (Chiralpak-IG (25 × 250 mm), 25% MeOH) to provide (R)-2- ((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate (6 g, 66%). Chiral purity 99.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 491.6 [M+H] ⁺ . Step 10: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- To a stirred solution of tertiary butyl benzoate (1.00 g, 2.04 mmol) in DCM (15 mL), N-iodosuccinimide (367 mg, 1.63 mmol). The reaction was stirred at rt for 5 h. The reaction was quenched with water (10 mL) and extracted with DCM (10 mL). The organic layer was dried ( _Na2SO4 ) _, filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-Iodo-6-methyl-4-pendantoxy-4H-𠳭鏏-8-yl)ethyl)amino)benzoic acid tertiary butyl ester (900 mg, 71%). Chiral purity 97.9% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 617.6 [M+H] ⁺ . Step 11: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-3-vinyl-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-iodo-6-methyl-4-pendantoxy-4H- Tertiary butyl (8-yl)ethyl)amino)benzoate (1.00 g, 1.93 mmol) and tributyl(vinyl)stannane (2.58 g, 8.12 mmol) in 1,4-dimethane (10 mL) was purged with _N2 for 20 min. Pd(PPh ₃ ) ₄ (93.7 mg, 0.081 mmol) was added and the reaction was stirred at 90 °C for 16 h. The reaction was diluted with water (10 ml) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -6-Methyl-4-Pendantoxy-3-Ethyl-4H- Dibutyl-8-yl)ethyl)amino)benzoate (700 mg, 83%). Chiral purity 98.4% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 517.7 [M+H] ⁺ . Step 12: 2-(((1R)-1-(3-(1,2-dihydroxyethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl- 4-Pendant oxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-3-vinyl-4H- To a stirred solution of tertiary butyl benzoate (700 mg, 1.36 mmol) in acetone (7 mL) and water (7 mL), potassium osmate dihydrate was added (25 mg, 0.067 mmol) and 4-methyl Phinoline-N-oxide (274 mg, 2.03 mmol). The reaction was stirred at rt for 18 h. The solvent was evaporated and the residue was triturated with DCM (5 mL). The resulting product was collected by filtration and dried under high vacuum to provide 2-(((1R)-1-(3-(1,2-dihydroxyethyl)-2-(4,4-dimethylpiperidine) (Din-1-yl)-6-methyl-4-pendantoxy-4H- Dibutyl-8-yl)ethyl)amino)benzoate (650 mg, 87%). MS (ESI) 551.8 [M+H] ⁺ . Step 13: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-sideoxy-4H - Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To 2-(((1R)-1-(3-(1,2-dihydroxyethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4- Side oxygen group-4H- To a stirred solution of tertiary butyl benzoate (650 mg, 1.18 mmol) in DCM (5.2 mL) and MeOH (5.2 mL), sodium periodate (1.01 g, 4.73 mmol). The reaction was stirred at rt for 28 h. The solvent was evaporated and water (10 mL) was added. The mixture was extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3-formyl-6-methyl-4-sideoxy-4H- Dibutyl-8-yl)ethyl)amino)benzoate (270 mg, 44%). MS (ESI) 519.7 [M+H] ⁺ . Step 14: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-sideoxy-4H - Preparation of 8-yl)ethyl)amino)benzoic acid

(R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-formyl-6-methyl-4-sideoxy-4H- Dimethyl-8-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(2-(4,4-dimethylpiperidine- 1-yl)-3-formyl-6-methyl-4-sideoxy-4H- Dimethyl-8-yl)ethyl)amino)benzoic acid tertiary butyl ester was used to obtain the title compound (11 mg, 22%). Chiral purity 97.3% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H ), 9.93 (s, 1H), 8.34-8.32 (m, 1H), 7.81 (d, J =12 Hz, 1H), 7.68 (d, J =4 Hz , 1H), 7.43 (d, J= 2.4 Hz , 1H), 7.23 (t, J= 20 Hz, 1H), 6.56 (t, J= 8 Hz, 1H), 6.49 (d, J =12 Hz , 1H), 5.07-5.04 (m, 1H), 3.62 -3.61 (m, 4H), 2.31 (s, 3H), 1.61-1.59 (d, J=8 Hz, 3H), 1.55-1.52 (m, 4H), 1.00 (s, 6H); MS (ESI) 463.6 [M+H] ⁺ . Example 12 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid Step 1: 8-acetyl-2-(ethylthio)-6-methyl-4H- Preparation of H-4-one

8-ethyl-2-(ethylthio)-6-methyl-4H- Phosphonium-4-one was prepared from 8-bromo-2-(ethylthio)-6-methyl-4H- according to the procedure of step 6 of Example 11. Phosphonium-4-one and tributyl(1-ethoxyvinyl)stannane were added to provide the title compound (47 g, 45%). MS (ESI) 263.3 [M+H] ⁺ . Step 2: (R)-N-((R)-1-(2-(ethylthio)-6-methyl-4-sideoxy-4H- Preparation of methyl-8-yl)ethyl)-2-methylpropane-2-sulfinamide

To 8-ethyl-2-(ethylthio)-6-methyl-4H- To a stirred solution of phosphonium-4-one (47.5 g, 181 mmol) and (R)-2-methylpropane-2-sulfinamide (43.94 g, 362.6 mmol) in THF (475 mL), Ti was added (OEt) ₄ (206.8 g, 906.5 mmol). The reaction was stirred at reflux for 24 h. Cool the reaction to rt. Water (475 mL) and EtOAc (250 mL) were added with stirring. The mixture was filtered through a pad of celite, which was rinsed with EtOAc (250 mL). The layers were separated and the aqueous layer was washed with EtOAc (200 mL). The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated to give _an oil. The crude oil was dissolved in THF (500 mL) and cooled to -15°C. AcOH (63.41 mL, 1.094 mol) and NaCNBH ₃ (42.98 g, 684.0 mmol) were added at -15°C. The reaction was stirred from -15 °C to rt over 5 h. The reaction was quenched with saturated _NaHCO3 (950 mL). The mixture was extracted with EtOAc (950 mL). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered, and concentrated to provide racemic (R)-N-(1-(2-(ethylthio)-6-methyl-4-side oxygen Base-4H- Phosphen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (35 g, 53%). 30 g of racemic material was purified by chiral SFC (Chiralpak-IG (4.6 × 150 mm column) 15% MeOH) to provide (R)-N-((R)-1-(2-( Ethylthio)-6-methyl-4-sideoxy-4H- Phosphen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (12 g, 18%). Chiral purity 99.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 368.4 [M+H] ⁺ . Step 3: (R)-8-(1-aminoethyl)-2-(ethylthio)-6-methyl-4H- Preparation of H-4-one

(R)-8-(1-Aminoethyl)-2-(ethylthio)-6-methyl-4H- Phosphonium-4-one was prepared according to the procedure of step 8 of Example 11 from (R)-N-((R)-1-(2-(ethylthio)-6-methyl-4-side oxy- 4H- Phosphonium-8-yl)ethyl)-2-methylpropane-2-sulfinamide provided the title compound (7.2 g, 84%). Chiral purity 99.7% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); MS (ESI) 264.2 [M+H] ⁺ . Step 4: (R)-2-((1-(2-(ethylthio)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(ethylthio)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-8-(1-aminoethyl)-2-(ethylsulfide) according to the procedure of step 9 of Example 11. base)-6-methyl-4H- phosphonium-4-one and tert-butyl 2-bromobenzoate to provide the title compound (4.3 g, 48%). Chiral purity 99.7% (Chiralpak IC (4.6 × 250 mm column), 0.5% DEA in MeOH); MS (ESI) 440.5 [M+H] ⁺ . Step 5: (R)-2-((1-(2-(ethylsulfonyl)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(ethylsulfonyl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(ethylthio)-6) according to the procedure of step 4 of Example 11 -Methyl-4-Pendantoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate provided the title compound (2 g, 55%). MS (ESI) 472.4 [M+H] ⁺ . Step 6: (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl methyl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(ethylsulfonyl)- 6-Methyl-4-Pendantoxy-4H- tert-butyl phosphonium-8-yl)ethyl)amino)benzoate and 4,4-difluoropiperidine hydrochloride to provide the title compound (4.3 g, 48%). MS (ESI) 499.6 [M+H] ⁺ . Step 7: (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3-iodo-6-methyl-4-pendantoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3-iodo-6-methyl-4-pendantoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(4,4-difluoro) Piperidin-1-yl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate provided the title compound (155 mg, 85%). MS (ESI) 625.6 [M+H] ⁺ . Step 8: (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-side oxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(4,4-difluoro) Piperidin-1-yl)-3-iodo-6-methyl-4-pendantoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate provided the title compound (103 mg, 80%). MS (ESI) 524.2 [M+H] ⁺ . Step 9: (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-side oxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

(R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- Di-8-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(3-cyano-2-(4,4-bis)) according to the procedure of step 3 of Example 6. Fluoroperidin-1-yl)-6-methyl-4-side oxy-4H- tert-butyl(phosphonium-8-yl)ethyl)amino)benzoate to provide the title compound (19 mg, 19%). Chiral purity 99.1% (Chiralcel OD-3 (4.6 × 250 mm column), 30% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.78 (s, 1H), 8.34-8.32 (d, J =5.6 Hz , 1H), 7.81 (dd, J =8 Hz , 1.6 Hz , 1H), 7.66-7.65 (m, 1H), 7.46-7.45 (m, 1H), 7.23 (t , J =16 Hz, 1H), 6.57 (t, J =14 Hz , 1H), 6.46 (d, J =8.4 Hz, 1H), 5.05-5.02 (m, 1H), 4.01-3.98 (m , 4H) , 2.23-2.31 (m, 7H), 1.58 (d, J =4 Hz , 3H); MS (ESI) 466.3 [MH] ^- . Example 13 (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

To (R)-2-((1-(2-(ethylthio)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate (200 mg, 0.46 mmol) and (6-methylpyridin-2-yl)boronic acid (250 mg, 1.82 mmol) in 1,4- To a stirred solution in dihexane (4 mL), Cs ₂ CO ₃ (592 mg, 1.82 mmol) and copper(I) 3-methylsalicylate (293 mg, 1.37 mmol) were added. The resulting mixture was purged with _N2 for 15 min, followed by addition of Pd( _PPh3 ) ₄ (52.5 mg, 0.045 mmol). The reaction was heated at 90 °C for 24 h. After cooling to rt, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by preparative HPLC (Acquity UPLC BEH C18, (50 mm × 2.1 mm column), H ₂ O/ACN, with 10 mM NH ₄ HCO ₃ as modifier) to provide (R)- 2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-pendantoxy-4H- Dibutyl-8-yl)ethyl)amino)benzoate (60 mg, 28%). MS (ESI) 471.6 [M+H] ⁺ . Step 2: (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

To (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl)-4-pendantoxy-4H- To a stirred solution of tert-butyl(di-8-yl)ethyl)amino)benzoate (60 mg, 0.13 mmol) in DCM (0.6 mL) was added TFA (0.9 mL). The reaction was stirred at rt for 12 h. After completion, the reaction mixture was concentrated. The residue was purified by flash chromatography ( _SiO2 , EtOAc/petroleum ether) to provide (R)-2-((1-(6-methyl-2-(6-methylpyridin-2-yl) )-4-Pendant oxy-4H- Diphenyl)ethyl)amino)benzoic acid (23.7 mg, 44%). ¹ H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.46 (d, J =5.6 Hz, 1H), 8.07 (d, J =7.6 Hz, 1H), 7.94 (t, J =7.6 Hz, 1H), 7.82 (d, J =1.2 Hz, 1H), 7.80 (d, J =1.6 Hz, 1H), 7.58 (d, J =4 Hz, 1H), 7.50 (d, J =7.6 Hz 1H ), 7.22 (m, 2H), 6.55 (m, 2H), 5.38 (t, J =6.4 Hz, 1H), 2.60 (s, 3H), 2.37 (s, 3H), 1.69 (d, J =6.8 Hz , 3H). 99.90% purity (X Bridge BEH C18 (4.6 × 50 mm column) ACN/H ₂ O with 10 mM NH ₄ HCO ₃ as modifier). MS (ESI) 413.3 [MH] ^- . Example 14 (R)-2-((1-(6-methyl-2-(1-methyl- 1H -pyrazol-4-yl)-4-pendantoxy- 4H- 8-yl)ethyl)amino)benzoic acid

Example 14 was prepared analogously to Example 13. ¹ H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.55 (s, 1H), 8.42 (d, J =4 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, J =1.2 Hz, 1H), 7.70 (d, J =1.2 Hz, 1H), 7.51 (d, J =2 Hz, 1H), 7.21 - 7.26 (m, 1H), 6.74 (s, 1H), 6.50-6.57 (m, 2H), 5.33 (m, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 1.63 (d, J =6.4 Hz, 3H). 99.6% chiral purity (Chiralcel-AD-3 (4.6 × 250 mm column) 30% MeOH with 0.5% DEA as modifier). MS (ESI) 402.0 [MH] ^- . Example 15 (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid

Example 15 was prepared analogously to Example 13. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (s, 1H), 8.47 (s, 1H), 8.41 (d, J =6 Hz, 1H), 7.82 (dd, J =8.0, 1.6 Hz, 1H), 7.71-7.70 (m, 1H), 7.48 (d, J =2 Hz, 1H), 7.24-7.20 (m, 1H), 6.56 (t, J =8 Hz, 1H), 6.49 (s, 1H ), 6.43 (d, J =8.4 Hz, 1H), 5.31-5.24 (m, 1H), 3.85 (s, 3H), 2.51-2.47 (m, 3H), 2.34 (s, 3H), 1.61 (d, J =6.4 Hz , 3H). 99.75% chiral purity (Chiralpak AS-H (4.6 × 250 mm column) 20% MeOH with 0.5% DEA as modifier). MS (ESI) 416.4 [MH] ⁺ . Example 16 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquinazoline -8-yl)ethyl)amino)benzoic acid Step 1: Preparation of 2-amino-3-bromo- N ,5-dimethylbenzamide

To a solution of 2-amino-3-bromo-5-methylbenzoic acid (2.13 g, 9.25 mmol) in DMF (19.99 mL) was added DIEA (4.93 mL, 27.8 mmol) under N _at rt. . The reaction mixture was cooled to 0 °C, then T3P (50% in DMF, 4.7 mL, 9.25 mmol) was added, followed by 2M methylamine in THF (6.48 mL, 12.95 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous _NaHCO3 (25 mL), followed by extraction with EtOAc (2 × 25 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated to provide 2-amino-3-bromo-N,5-dimethylbenzamide (1.47 g, 66% ), which was used in the next step without further purification. ¹ H NMR (400 MHz, methanol-d4) δ ppm 7.37 (d, J=2.69 Hz, 1 H), 7.25 (dd, J=1.96, 0.73 Hz, 1 H), 2.86 (s, 3 H), 2.22 (s, 3 H); LCMS 243.0 [M+H] ⁺ . Step 2: Preparation of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4( 3H )-one

Triphosgene (0.400 g, 1.33 mmol) was added to 2-amino-3-bromo-N,5-dimethylbenzamide (0.81 g, 3.33 mmol) in CH ₂ Cl ₂ (33.3 mL) ) in the flask. The reaction was heated at reflux for 19 h. After cooling to rt, the reaction was concentrated under reduced pressure to provide 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one (0.91 g, 101%), which It was used in the next step without further purification. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 7.88 (s, 1 H), 7.86 - 7.90 (m, 1 H), 7.78 (s, 1 H), 3.39 (s, 3 H), 2.40-2.38 (m, 3 H), 2.38-2.37 (m, 3 H); LCMS 269.0 [M+H] ⁺ . Step 3: Preparation of 8-bromo-2-chloro-3,6-dimethylquinazolin-4( 3H )-one

Combine 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3 H )-one (1.20 g, 4.48 mmol, P(O)Cl ₃ (5.11 mL, 53.7 mmol), and DIEA (3.18 mL, 17.90 mmol) of the mixture was added to a 100 mL round-bottomed flask, followed by heating at 95 °C overnight. After cooling to rt, _excess P(O)Cl was removed by pressure. The residual The material was diluted with CH ₂ Cl ₂ and then cooled in an ice bath, then a suspension of aqueous NaHCO ₃ (5 M, 20 mL) was added. The resulting suspension was stirred for 15 min; the precipitate was filtered under pressure and filtered with DCM (2 × 150 mL). The organic layer was washed with water and brine, dried (MgSO ₄ ), filtered, and concentrated to provide 8-bromo-2-chloro-3,6-dimethylquinazoline-4(3 H ) - Ketone (1.77 g, 61%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.02 (s, 1H), 7.91 (s, 1H), 3.32 (s, 3H), 2.44 (s, 3H); LCMS 289.0 [M+H] ⁺ . Step 4: 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3, Preparation of 6-dimethylquinazoline-4(3 H )-one

Dissolve 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3 H )-one (1.77 g, 3.72 mmol), 4,4-dimethyl in DMSO (9.31 mL) Piperidine (0.550 g, 4.84 mmol, and N,N-diisopropylethylamine (1.99 mL, 11.2 mmol) was heated at 90 °C overnight. After cooling to rt, the reaction mixture was quenched with water (10 mL) , extracted with DCM (3 × 10 mL), extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography Purification (SiO ₂ , EtOAc/Hex) to provide 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoline-4( 3H ) -Ketone (1.15 g, 85%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.87 (d, J =1.59 Hz, 1 H), 7.80 (dd, J =1.83, 0.86 Hz, 1 H ), 3.43 (s, 3 H), 3.18 - 3.26 (m, 4 H), 2.38 (s, 3 H), 1.46 - 1.53 (m, 4 H), 1.00 (s, 6 H); LCMS 365.1 [M +H] ⁺ . Step 5: 2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-8-(prop-1-en-2-yl)quinazoline Preparation of -4(3 H )-ketone

8-Bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4( 3H )-one (1.15 g, 3.16 mmol), Pd (PPh ₂ )Cl ₂ (0.11 g, 0.16 mmol), K ₂ CO ₃ (1.31 g, 9.49 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl) )-1,3,2-dioxaborolane (1.84 mL, 9.49 mmol) in 1,4-dioxane (14.77 mL) and water (6.33 mL) was degassed for 15 min and then Heat at 50°C overnight. 1,4-dioxane is removed under pressure, then diluted with ethyl acetate and washed with water and brine. The aqueous layer is back-extracted with EtOAc (1x). The combined organic layers are dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide 2-(4,4-dimethylpiperidin-1-yl) -3,6-Dimethyl-8-(prop-1-en-2-yl)quinazolin-4(3 H )-one (1.01 g, 97%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (dd, J =2.08, 0.86 Hz, 1 H), 7.40 (d, J =1.71 Hz, 1 H), 5.13 (dd, J =2.26, 0.79 Hz, 1 H), 5.11 - 5.21 (m, 1 H), 3.44 (s, 3 H), 3.06 - 3.17 (m, 4 H), 2.38 (s, 3 H), 2.25 (s, 3 H), 1.44 - 1.52 (m, 4 H ), 0.99 (s, 6 H); LCMS 362.0 [M+H] ⁺ ｡ Step 6: 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6- Preparation of dimethylquinazoline-4(3 H )-one

To 2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-8-(prop-1-en-2-yl)quinazoline-4(3 H )- To a vigorously stirred solution of ketone (1.00 g, 3.07 mmol) in CH ₂ Cl ₂ (18.68 mL) and ACN (18.68 mL), 2,6-dimethylpyridine (0.71 mL, 6.15 mmol) and water were added sequentially. (28.0 mL), and NaIO ₄ (2.63 g, 12.29 mmol). To the resulting mixture, a stock solution of ruthenium(III) chloride hydrate (0.03 g, 0.108 mmol) in water (0.035 M, 3.0 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and washed with _CH2Cl2 ( _2x ). The combined organic layers were washed with brine, dried ( _MgSO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-di Methylquinazolin-4( 3H )-one (0.57 g, 57%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.01 (dd, J =2.26, 0.79 Hz, 1 H), 7.75 - 7.72 (m, 1 H), 3.46 (s, 3 H), 3.24 - 3.15 (m, 4 H), 2.78 (s, 3 H), 2.41 (s, 3 H), 1.53 - 1.46 (m, 4 H), 1.00 (s, 6 H); LCMS 328.2 [M+H] ⁺ . Step 7: 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4( 3H )-one Preparation

To 8-acetyl- _2- (4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoline-4( 3H )- To a yellow suspension of ketone (0.22 g, 0.66 mmol) in MeOH (2 mL) was added NaBH ₄ (0.04 g, 0.99 mmol). The reaction was stirred at rt overnight. Upon completion, the reaction mixture was quenched with saturated _NaHCO3 (5 mL), followed by extraction with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated to provide 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl) (0.22 g, 100% ) , which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.69 (s, 1H), 7.64 (d, J =2.1 Hz, 1H), 5.46 - 5.39 (m, 1H), 5.14 (d, J =4.6 Hz , 1H), 3.44 (s, 3H), 3.23 - 3.07 (m, 4H), 2.39 (s, 3H), 1.54 - 1.44 (m, 4H), 1.37 (d, J =6.4 Hz, 3H), 0.99 ( s, 6H); LCMS 330.2 [M+H] ⁺ ｡ Step 8: 1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-side oxygen Preparation of ethyl-3,4-dihydroquinazolin-8-yl)ethyl methanesulfonate

2-(4,4-dimethylpiperidin- ₁ -yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazoline-4( To a solution in 3 H )-ketone (0.23 g, 0.65 mmol), DIEA (0.250 mL, 1.42 mmol) and methanesulfonyl chloride (0.100 mL, 1.29 mmol) were added. The reaction was stirred for 1 h, then quenched with water and extracted with DCM (2x). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated to provide 1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4 -Pendant oxy-3,4-dihydroquinazolin-8-yl)ethyl methanesulfonate (0.27 g, 101%) which was used in the next step without further purification. Step 9: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquinazole) Preparation of methyl lin-8-yl)ethyl)amino)benzoate

1-(2-(4,4-dimethylpiperidin-1-yl)-3,6 _- dimethyl-4-sideoxy-3,4-dihydroquinazoline- To a solution of 8-yl)ethyl methanesulfonate (0.27 g, 0.66 mmol), DIEA (0.59 mL, 3.28 mmol) and methyl anthranilate (0.21 mL, 1.64 mmol) were added. The reaction mixture was heated at 60°C overnight. Upon completion, the ACN was removed by pressure and then quenched with water. The reaction mixture was extracted with EtOAc (2x). The combined organic layers were washed with _brine , dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6- Methyl dimethyl-4-pentyloxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (0.22 g, 74%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.39 (d, J =7.5 Hz, 1H), 7.78 (dd, J =8.0, 1.7 Hz, 1H), 7.71 (dd, J =2.1, 0.9 Hz , 1H), 7.50 (d, J =2.0 Hz, 1H), 7.24 (ddd, J =8.5, 7.0, 1.6 Hz, 1H), 6.62 (d, J =8.4 Hz, 1H), 6.51 (t, J = 7.3 Hz, 1H), 5.36 (t, J =7.0 Hz, 1H), 3.81 (s, 3H), 3.47 (s, 3H), 3.29 - 3.17 (m, 4H), 2.33 (s, 3H), 1.60 ( d, J =6.7 Hz, 3H), 1.52 (t, J =5.5 Hz, 4H), 1.02 (s, 6H); LCMS 463.2 [M+H] ⁺ . Step 10: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquinazole) Preparation of lin-8-yl)ethyl)amino)benzoic acid

Lithium hydroxide monohydrate (2N, 0.069 mL, 0.14 mmol) was added to 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-yl) at rt Methyl dimethyl-4-pentoxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (0.016 g, 0.035 mmol) in MeOH (1.0 mL) and THF ( 0.50 mL) in a stirred suspension. The resulting solution was heated at 60°C overnight. After cooling to 0 °C, HCl (2N, aqueous solution) was added to adjust the pH to 2. The solvent was removed under pressure, then diluted with water and extracted with DCM (2x). The combined organic layers were washed with _brine , dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6- Dimethyl-4-pentanoxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (16.7 mg, 67%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.60 (br s, 1H), 8.43 (s, 1H), 7.77 (dd, J =7.9, 1.7 Hz, 1H), 7.70 (dd, J =2.1 , 0.9 Hz, 1H), 7.46 (d, J =2.1 Hz, 1H), 7.18 (ddd, J =8.5, 7.0, 1.7 Hz, 1H), 6.52 - 6.46 (m, 2H), 5.40 (br s, 1H ), 3.32 (s, 3H), 3.23 (br t, J =5.5 Hz, 4H), 2.32 (s, 3H), 1.60 - 1.46 (m, 7H), 1.00 (s, 6H); LCMS 449.3 [M+ H] ⁺ . Example 17 (R)-5-(2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one Step 1: (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzohydrazine

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- To a stirred solution of methyl-8-yl)ethyl)amino)benzoic acid (200 mg, 0.460 mmol) in DMF (2 mL), HATU (0.26 g, 0.69 mmol) and DIPEA (0.23 mL, 1.4 mmol) were added ). The reaction was stirred at 0 °C for 5 min. Hydrazine hydrate (34 mg, 0.69 mmol) was added and the reaction was stirred at rt for 16 h. The reaction was quenched with water (5 mL) and stirred for 10 min. The mixture was extracted with EtOAc (2 × 5 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , MeOH/DCM) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)- 6-Methyl-4-Pendantoxy-4H- Diphenyl)ethyl)amino)benzohydrazine (180 mg, 87%). MS (ESI) 449.5 [M+H] ⁺ . Step 2: (R)-5-(2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one

To (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- To a stirred solution of phosphonium-8-yl)ethyl)amino)benzohydrazine (180 mg, 0.400 mmol) in THF (1.8 mL) was added Et ₃ N (0.12 mL, 0.80 mmol), followed by 1 ,1-carbonyldiimidazole (84.6 mg, 0.520 mmol). The reaction was stirred at rt for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). _The combined organic layers were dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by preparative SFC chromatography (YMC Diol 120 (21 × 210 mm column) 20% MeOH) to provide (R)-5-(2-((1-(2-(4, 4-dimethylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Diaz-8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one (60 mg, 32%). Chiral purity 99.5% (Chiralpak AS-H (4.6 × 250 mm column), 40% (0.2% 7 M NH ₃ in CH ₃ CN:MeOH (1:1))); ¹ H NMR (400 MHz , DMSO-d ₆ ) δ 12.50 (bs, 1H), 7.61-7.60 (m, 1H), 7.54 (dd, J =8.0, 1.2 Hz, 1H), 7.37-7.36 (d, J =2.0 Hz, 1H) , 7.26-7.25 (m, 1H), 7.21 (t, J =7.2 Hz, 1H), 6.68 (t, J =7.2 Hz, 1H), 6.52 (d, J =8.4 Hz, 1H), 5.52 (s, 1H), 5.16-5.12 (m, 1H), 3.55-3.52 (m, 4H), 2.29 (s, 3H), 1.60 (d, J =6.4 Hz, 3H), 1.41-1.39 (m, 4H), 0.97 (s, 6H); MS (ESI) 475.3 [M+H] ⁺ . Example 18 (R)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one Step 1: (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

(R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Difluoro-8-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(2-(4,4-difluoropiperidine-1) according to the procedure of step 3 of Example 6 -base)-6-methyl-4-side oxy-4H- tert-butyl(phosphonium-8-yl)ethyl)amino)benzoate to provide the title compound (500 g, 70%). Chiral purity 99.7% (Chiralcel OD-3 (4.6 × 250 mm column), 30% (0.5% DEA in MeOH)); MS (ESI) 443.2 [M+H] ⁺ . Step 2: (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzohydrazine

(R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Difluoro-8-yl)ethyl)amino)benzohydrazine was prepared from (R)-2-((1-(2-(4,4-difluoropiperidine)) according to the procedure of step 1 of Example 17 -1-yl)-6-methyl-4-sideoxy-4H- Diuron-8-yl)ethyl)amino)benzoic acid provided the title compound (285 mg, 55%). MS (ESI) 457.3[M+H] ⁺ . Step 3: (R)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-side oxy-4H- Preparation of 8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one

(R)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Diazole-8-yl)ethyl)amino)phenyl)-1,3,4-dioxadiazole-2(3H)-one was prepared from (R)-2- according to the procedure of step 2 of Example 17 ((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-sideoxy-4H- Chromium-8-yl)ethyl)amino)benzohydrazine to provide the title compound (60 mg, 34%). Chiral purity 99.2% (Chiralcel OD-3 (4.6 × 250 mm column), 30% MeOH); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.50 (s, 1H), 7.62 (s, 1H) , 7.55 -7.53 (dd, J = 7.6, 1.2 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.68 ( t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.67 (s, 1H), 5.18 - 5.15 (t, J = 6.4 Hz, 1H), 3.70 - 3.68 (m, 4H ), 2.30 (s, 3H), 2.15 - 2.05 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H). MS (ESI) 481.4 [MH] ^- . Example 19 (S)-5-(2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methyl-4-pendantoxy-4H- ((8-yl)ethyl)amino)phenyl)-1,3,4-oxadiazole-2(3H)-one

Example 19 was prepared analogously to Example 18. Chiral purity 99.7% (Chiralpak IG-3 (4.6 × 150 mm column), 60% CO ₂ , 40% MeOH, with 0.5% DEA); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.65 (s , 1H), 7.63 (s, 1H), 7.60-7.55 (m, 1H), 7.39 (s, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H) , 6.71 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.68 (s, 1H), 5.20-5.15 (m, 1H), 3.75-3.65 (m, 4H), 2.30 (s, 3H), 2.15-2.05 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H). MS (ESI) 481.44 [MH] ^- . Example 20 (R)-2-((1-(2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid

Example 20 was prepared analogously to Example 13. 97.5% Chiral Purity (Chiralpak AS-H (4.6 × 250 mm column) 20% MeOH with 0.5% DEA as modifier); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.86 (br s, 1H), 8.51 (br s, 1H), 7.82 (dd, J =8.0, 1.6 Hz, 1H), 7.74 (s, 2H), 7.50 (d, J =2.0 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.20-7.16 (m, 1H), 6.72 (s, 1H), 6.54 (t, J =7.2 Hz, 1H), 5.24-5.22 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H), 1.61 (d, J =6.4 Hz, 3H); MS (ESI) 416.4 [MH] ^- . Example 21 (R)-2-((1-(6-methyl-2-(1-methyl-1H-pyrazol-3-yl)-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid

Example 21 was prepared analogously to Example 13. 99.5% Chiral Purity (Chiralpak AS-H (4.6 × 250 mm column) 20% MeOH with 0.5% DEA as modifier); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.77 (br s, 1H), 8.45 (br s, 1H), 7.95 (d, J =2.0 Hz, 1H), 7.81 (dd, J =7.6, 1.2 Hz, 1H), 7.73 (d, J =1.2 Hz, 1H), 7.55 (d, J =1.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.01 (d, J =2.0 Hz, 1H), 6.78 (s, 1H), 6.56-6.51 (m, 2H), 5.28 ( t, J =6.4 Hz, 1H), 3.99 (s, 3H), 2.35 (s, 3H), 1.65 (d, J =6.4 Hz, 3H); MS (ESI) 402.3 [MH] ^- . Example 22 (R)-2-((1-(2-(6-methoxypyridin-2-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid

Example 22 was prepared analogously to Example 13. 99.8% Chiral Purity (Lux Cellulose-2 (4.6 × 250 mm column) 30% MeOH with 0.5% DEA as modifier); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.75 (br s, 1H), 8.44 (d, J =6.4 Hz, 1H), 7.95 (t, J =7.6 Hz, 1H), 7.87 (d, J =7.2 Hz, 1H), 7.81 (dd, J =8.0, 1.6 Hz, 1H,), 7.76 (d, J =1.2 Hz, 1H), 7.58 (d, J =2 Hz, 1H), 7.25-7.20 (m, 2H), 7.07 (d, J = 8 Hz, 1H), 6.55 (t, J =7.6 Hz, 2H), 5.39-5.33 (m, 1H), 4.00 (s, 3H), 2.37 (s, 3H), 1.69 (d, J =6.8 Hz, 3H); MS (ESI) 429.3 [MH] ^- . Example 23 (R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-pendantoxy-4H- 8-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate was prepared from (R)-2-((1-(2-(ethylsulfonate)) following a procedure similar to that used in step 5 of Example 11 acyl)-6-methyl-4-pendantoxy-4H- Dimethyl-8-yl)ethyl)amino)benzoate tertiary butyl ester and 4-methylpiperidine-4-carbonitrile hydrochloride to provide the title compound (0.270 g, 68%). MS (ESI) 502.6 [M+H] ⁺ . Step 2: (R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Preparation of 8-yl)ethyl)amino)benzoic acid

(R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- Di-8-yl)ethyl)amino)benzoic acid was prepared from (R)-2-((1-(2-(4-cyano-4)) following a procedure similar to that used in step 3 of Example 6 -Methylpiperidin-1-yl)-6-methyl-4-sideoxy-4H- tert-butyl(phosphonium-8-yl)ethyl)amino)benzoate to provide the title compound (50 mg, 21%). Chiral purity 99.6% (Chiralpak AS-H (4.6 × 250 mm column), 20% (0.5% DEA in MeOH)); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.76 (br s, 1H), 8.44 (br s, 1H), 7.81 (dd, J =7.67, 1.2 Hz, 1H), 7.61 (d, J =1.2 Hz, 1H), 7.38 (d, J =1.6 Hz, 1H), 7.23 (t, J =7.2 Hz, 1H), 6.55 (t, J =7.2 Hz, 1H), 6.45 (d, J =8.4 Hz, 1H), 5.61 (s, 1H), 5.08 (t, J =5.2 Hz , 1H), 4.15-4.10 (m, 2H), 3.18 (t, J =12.0 Hz, 2H), 2.30 (s, 3H), 2.00-1.95 (m, 2H), 1.73-1.65 (m, 2H), 1.64 (d, J =4.0 Hz, 3H), 1.48 (s, 3H); MS (ESI) 444.3 [MH] ^- . Example 24 (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-pendantoxy-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid

Example 24 was prepared analogously to Example 1. 99.8% Chiral Purity (Chiralpak IG (4.6 × 250 mm column) 40% MeOH with 0.5% DEA as modifier); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.72 (br s, 1H) , 8.56 (s, 1H), 8.40 (d, J =6.4 Hz, 1H), 7.80 (d, J =7.60 Hz, 1H) 7.62 (s, 1H), 7.25-7.21 (m, 1H), 6.55 (t , J =7.2 Hz, 1H), 6.39 (d, J =8.4 Hz, 1H), 5.80 (s, 1H), 5.24 (t, J =6.4 Hz, 1H), 3.83-3.82 (m, 4H), 2.25 (s, 3H), 2.08-2.00 (m, 4H), 1.58 (d, J =6.4 Hz, 3H); MS (ESI) 441.4 [MH] ^- . Example 25 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-pendantoxy-4H-pyrido [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid

Example 25 was prepared analogously to Example 10. 99.8% Chiral Purity (Chiralpak IG (4.6 × 250 mm column) 40% MeOH with 0.2% DEA as modifier); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.76 (br s, 1H) , 8.55 (s, 1H), 8.40 (br s, 1H), 7.82-7.79 (m, 2H), 7.24-7.20 (m, 1H), 6.57 (t, J =7.2 Hz, 1H), 6.36 (d, J =8.4 Hz, 1H), 5.18 (t, J =12.4 Hz, 1H), 4.03 (t, J =5.2 Hz, 4H), 2.28 (s, 3H), 2.19-2.12 (m, 4H), 1.57 ( d, J =6.4 Hz, 3H); MS (ESI) 468.5 [M+H] ⁺ . Example 26 (R)-2-((1-(3-cyano-2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-pendantoxy- 4H- 8-yl)ethyl)amino)benzoic acid Step 1: (R)-2-((1-(2-(ethylthio)-3-iodo-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

N-iodosuccinimide (0.635 g, 2.82 mmol) was added as a solid to (R)-2-((1-(2-(ethylthio)) in 6 mL of 1,2-DCE at 0°C -6-Methyl-4-Pendantoxy-4H- Dimethyl-8-yl)ethyl)amino)benzoic acid tertiary butyl ester (1.24 g, 2.82 mmol). The ice bath was removed and the reaction was stirred at rt for 12 h. 100 mg of N-iodosuccinimide was added and the reaction was stirred at rt for 1 h. The reaction was _{diluted with DCM (15 mL) and washed with 10% Na2S2O3 ( 20} mL), saturated _NaHCO3 (20 mL), and brine (20 mL). _The solution was dried ( _Na2SO4 ), filtered, and concentrated. The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide (R)-2-((1-(2-(ethylthio)-3-iodo-6-methyl-4 -Pendant oxygen group-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate (1.5 g, 94%). MS (ESI) 566.1 [M+H] ⁺ . Step 2: (R)-2-((1-(3-cyano-2-(ethylthio)-6-methyl-4-sideoxy-4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

Copper cyanide (0.238 g, 2.65 mmol) was added to (R)-2-((1-(2-(ethylthio)-3-iodo-6-methyl-4-pendoxy-4H- In a mixture of tertiary butyl benzoate (0.500 g, 0.884 mmol) and diisopropylethylamine (0.770 mL, 4.42 mmol) in NMP (1.0 mL). The reaction was stirred at 105 °C for 16 h. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was washed with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried ( _Na2SO4 ), filtered, and _concentrated . The residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide (R)-2-((1-(3-cyano-2-(ethylthio)-6-methyl- 4-Pendant oxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate (0.298 g, 73%). MS (ESI) 465.2 [M+H] ⁺ . Step 3: (R)-2-((1-(3-cyano-2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-side oxy) -4H- Preparation of tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate

(R)-2-((1-(3-cyano-2-(ethylthio)-6-methyl-4-pendantoxy-4H- Tertiary butyl benzoate (0.288 g, 0.620 mmol), Cs ₂ CO ₃ (0.404 g, 1.24 mmol), and (1,4-dimethyl-1H- Pyrazol-3-yl)boronic acid (0.174 g, 1.24 mmol) was suspended in 1,4-dioxane (2 mL). Purge the _suspension with N for 10 min. Copper thiophene-2-carboxylate (0.249 g, 1.24 mmol) and palladium (triphenylphosphine) (0.072 g, 0.062 mmol) were added. The suspension was purged with _N2 for 10 min with stirring. The reaction was stirred at 90 °C for 24 h. The reaction was diluted with EtOAc (10 mL) and filtered through celite. Rinse the celite pad with EtOAc (2 × 10 mL). The solvent was removed and the residue was purified by flash chromatography (SiO ₂ , EtOAc/Hex) to provide (R)-2-((1-(3-cyano-2-(1,4- Dimethyl-1H-pyrazol-3-yl)-6-methyl-4-sideoxy-4H- Tertiary butyl phosphonium-8-yl)ethyl)amino)benzoate (0.132 g, 43%). MS (ESI) 499.2 [M+H] ⁺ . Step 4: (R)-2-((1-(3-cyano-2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-side oxy) -4H- Preparation of 8-yl)ethyl)amino)benzoic acid formate

Towards the (R)-2-((1-(3-cyano-2-(1,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-yl) at 0°C Oxygen-4H- To a solution of tert-butyl (8-yl)ethyl)amino)benzoate (0.125 g, 0.251 mmol) in 1 mL of DCM, TFA (1 mL) was added. The ice bath was removed and the reaction was stirred at rt for 5 h. The solvent was removed and the crude residue was purified by reverse phase HPLC (water, _CH3CN , 0.1% formic acid) to provide (R)-2-((1-(3-cyano-2-(1 ,4-dimethyl-1H-pyrazol-3-yl)-6-methyl-4-side oxy-4H- Phosphen-8-yl)ethyl)amino)benzoate formate (60 mg, 49%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 13.47 (br s, 1H), 8.99 (br d, J =5.9 Hz, 1H), 8.14 (d, J =2.0 Hz, 1H), 7.79-7.80 ( m, 1H), 7.74 (s, 1H), 7.56 (dd, J =8.8, 2.0 Hz, 1H), 7.50 (d, J =2.1 Hz, 1H), 6.71 (s, 1H), 6.54 (d, J =9.0 Hz, 1H), 5.29 (quin, J =6.3 Hz, 1H), 3.91 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 1.65 (d, J =6.6 Hz, 3H ); MS (ESI) 443.2 [M+H] ⁺ . Examples 27 and 28 (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-pendantoxy-3,4 -Dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3 ,6-Dimethyl-4-Pendantoxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid Step 1: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquinazole) Preparation of methyl lin-8-yl)ethyl)amino)benzoate

The diastereoisomers (prepared in Example 16 step 9) were separated by chiral SFC chromatography (Chiralcel OD-H (30 × 250 mm column), 70% CO ₂ %, 30% ACN) to give Peak 1 (85 mg, 51%) and peak 2 (65 mg, 39%) were found. Peak 1: Chiral purity 96.8% (Chiralpak IC-3 (4.6 × 250 mm column), 70% CO ₂ , 30% (0.5% DEA in MeOH)); MS (ESI) 463.6 [M+H] ⁺ . Peak 2: Chiral purity 98.1% (Chiralpak IC-3 (4.6 × 250 mm column), 70% CO ₂ , 30% (0.5% DEA in MeOH)); MS (ESI) 463.6 [M+H] ⁺ . Step 2: (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4- Preparation of dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

(S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquin Azolin-8-yl)ethyl)amino)benzoic acid was synthesized from isolated peak 1 from step 1 to provide the title compound. To a stirred solution of peak 1 (95 mg, 0.21 mmol) in MeOH (0.95 mL) at 0 °C was added 2N NaOH (0.62 mL, 1.23 mmol). The resulting mixture was stirred at 40 °C for 5 h. After completion, the reaction mixture was concentrated under reduced pressure. Ice-cold water (5 mL) was added, and the mixture was acidified with 2N HCl (until pH = ~6). The precipitated solid was filtered, dried under vacuum, and then purified by achiral SFC to provide (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)- 3,6-Dimethyl-4-pentanoxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (22 mg, 24%). Chiral purity 99.8% (Chiralpak IJ-3 (30 × 250 mm column), 70% CO ₂ , 30% MeOH). Specific optical rotation [α]D25℃ (C = 0.1% in MeOH) +280.60. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.55 (br s, 1H), 9.19 (br s, 1H), 7.77 (d, J =7.2 Hz, 1H), 7.68 (s, 1H), 7.46 ( d, J =1.6 Hz, 1H), 7.00 (t, J =7.2 Hz, 1H), 6.39 (t, J =7.4 Hz, 1H), 6.32 (d, J =8.0 Hz, 1H), 5.38 (d, J =5.6 Hz, 1H), 3.47 (s, 3H), 3.23 (br. s, 4H), 2.30 (s. 3H), 1.54-1.50 (m, 4H), 1.00 (s, 6H). MS (ESI) 447.4 [MH] ^- . (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-sideoxy-3,4-dihydroquino Preparation of oxazolin-8-yl)ethyl)amino)benzoic acid

To a stirred solution of peak 2 (70 mg, 0.15 mmol) in MeOH (0.7 mL) at 0 °C was added NaOH (2N, 0.45 mL, 0.91 mmol). The resulting mixture was stirred at 50 °C for 5 h. After completion, the reaction mixture was concentrated under reduced pressure. Ice-cold water (1 mL) was added, and the mixture was acidified (pH = ~6) with 2N HCl. The precipitate was collected by filtration and triturated in n-pentane (2 × 5 mL) to provide (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl) -3,6-Dimethyl-4-pentanoxy-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (36 mg, 53%). Chiral purity 97.5% (Chiralpak IG-3 (4.6 × 150 mm column), 80% CO ₂ , 20% MeOH (0.5% DEA in MeOH)). Specific optical rotation [α]D25℃ (C = 0.1% in MeOH) -389.28. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.36 (br s, 1H), 9.13 (br s, 1H), 7.73 (dd, J =1.2, 7.8 Hz, 1H), 7.68 (d, J =0.8 Hz), 7.46 (d, J =1.6 Hz, 1H), 7.01 (t, J =7.2 Hz, 1H), 6.40 (t, J =7.4 Hz, 1H), 6.34 (d, J =8.0 Hz, 1H) , 5.38 (d, J =6.4 Hz, 1H), 3.47 (s, 3H), 3.23 (br s, 4H), 2.30 (s, 3H), 1.53-1.51 (m, 4H), 1.01 (s, 6H) . MS (ESI) 447.4 [MH] ^- . Examples 29 to 39

The compounds of Examples 29 to 39 were prepared using procedures similar to those described for Examples 1 to 28, including selection of appropriate starting materials that are readily available from commercial sources, prepared by known and/or published procedures, or Provided as otherwise described herein. Compound structures, IUPAC names, and selected analytical data are summarized in Table B. Table B Example structure IUPAC name, ¹ H NMR , and LCMS 29 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1 ,2-a]pyrimidin-9-yl)ethyl)amino)benzamide ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.73 (d, J =6.0 Hz, 1H), 8.54 (s , 1H), 7.91 (br s 1H), 7.75 (d, J =1.6 Hz, 1H,), 7.62 (dd, J =8.0, 1.2 Hz, 1H), 7.25 (br s, 1H), 7.11 (t, J =7.2 Hz, 1H), 6.53 (t, J =7.2 Hz, 1H), 6.30 (d, J =8.4 Hz, 1H), 5.12 (t, J =6.4 Hz, 1H), 4.03 (t, J = 5.4 Hz, 4H), 2.27 (s, 3H) 2.14- 2.17 (m, 4H), 1.53 (d, J =6.8 Hz, 3H); LCMS (m/z): 465.3 [MH] ^- ｡ 30 (R)-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-side oxy-9-(1-((2-(5-side oxy-4, 5-Dihydro-1,3,4-ethadiazol-2-yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile ¹ H NMR ( 400 MHz, DMSO- d ₆ ): δ 12.59 (br s, 1H), 8.55 (s, 1H), 7.78 (d, J= 1.2 Hz , 1H), 7.54 (dd, J =1.2, 8.0 Hz, 1H) , 7.37 (br s, 1H), 7.17 (t, J =7.2 Hz, 1H), 6.69 (t, J =7.6 Hz, 1H), 6.42 (d, J =8.4 Hz, 1H), 5.21-5.26 (m , 1H), 4.04 (t, J =5.2 Hz, 4 H), 2.27 (s, 3H), 2.19-2.12 (m, 4H), 1.59 (d, J =6.8 Hz, 3H); LCMS (m/z ): 506.3 [MH] ^- ｡ 31 (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyra[ 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.66 (br s, 1H), 8.75 (d, J =7.6 Hz , 1H), 8.38 (d, J =0.8 Hz, 1H), 7.80 (dd, J =7.8, 1.2 Hz, 1H), 7.33 (t, J =7.2, 1H), 6.79 (d, J =8.4 Hz, 1H), 6.57 (t, J =7.6 Hz, 1H), 5.47-5.52 (m, 1H), 4.07 (t, J =5.2 Hz, 4H), 2.48 (s, 3H) 2.13-2.20 (m, 4H) , 1.56 (d, J =6.8 Hz, 3H);LCMS (m/z): 469.5 [M+H] ⁺ ｡ 32 (S)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyra[ 1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.60 (br s, 1H), 8.79 (br s, 1H), 8.38 (s, 1H), 7.80 (d, J =7.6 Hz, 1H), 7.31 (t, J =6.8 Hz, 1H), 6.78 (d, J =8.4 Hz, 1H), 6.56 (t, J =7.2 Hz, 1H), 5.46-5.50 (m, 1H), 4.07 (t, J =5.2 Hz, 4H), 2.47 (s, 3H), 2.20-2.13 (m, 4H), 1.56 (d, J =6.4 Hz , 3H); LCMS (m/z): 469.5 [M+H] ⁺ ｡ 33 (R)-2-((1-(2-(2-azabicyclo[2.1.1]hex-2-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2 -a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (DMSO-d6): δ 12.69 (br s, 1H), 8.45-8.55 (m, 2H), 7.80 (dd, J = 7.9, 1.6 Hz, 1H), 7.56 (d, J =2.1 Hz, 1H), 7.20 (t, J =7.8 Hz, 1H), 6.52 (t, =7.2 Hz, 1H), 6.37 (d, J =8.4 Hz, 1H), 5.31-5.47 (m, 1H), 5.22 (br s, 1H), 4.71-5.05 (m, 1H), 3.40-3.47 (m, 2H), 2.89-3.04 (m, 1H), 2.22 (d, J =0.9 Hz, 3H), 2.02 (br s, 2H), 1.58 (d, J =6.6 Hz, 3H), 1.40 (br d, J =6.1 Hz, 2H); LCMS (m/z) : 405.2 [M+H] ⁺ ｡ 34 (R)-2-((1-(2-(2-azabicyclo[2.1.1]hex-2-yl)-3-cyano-7-methyl-4-sideoxy-4H-pyridine And[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO-d6): δ 12.75 (br s, 1H), 8.46 (s, 2H), 7.80 (dd, J =7.9, 1.6, Hz, 1H), 7.69 (d, J =1.8 Hz, 1H), 7.16-7.23 (m, 1H), 6.54 (t, J =7.5 Hz, 1H), 6.36 ( d, J =8.6 Hz, 1H), 5.25 (br s, 1H), 5.09-5.18 (m, 1H), 3.81 (s, 2H), 2.97-3.04 (m, 1H), 2.24 (s, 3H), 2.06 (br d, J =10.9 Hz, 2H), 1.56 (d, J =6.6 Hz, 3H), 1.46 (br d, J =3.3 Hz, 2H); LCMS (m/z): 430.2 [M+H ] ⁺ ｡ 35 2-(((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.1]hept-3-yl)-7-methyl-4-side oxy-4H -pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO-d6): δ 8.79-8.90 (m, 1H), 8.56-8.58 ( m, 1H), 7.80 (dd, J =7.8, 1.6 Hz, 1H), 7.60 (s, 1H), 7.13 (br t, J =7.4 Hz, 1H), 6.49 (t, J =7.3 Hz, 1H) , 6.25-6.33 (m, 1H), 5.46 (s, 1H), 5.20-5.27 (m, 1H), 4.20-4.35 (m, 1H), 3.74-3.90 (m, 2H), 3.57-3.71 (m, 1H), 3.03-3.10 (m, 2H), 2.24 (d, J =0.9 Hz, 4H), 2.00-2.06 (m, 1H), 1.51-1.66 (m, 4H); LCMS (m/z): 455.2 [M+H] ⁺ ｡ 36 (R)-2-((1-(2-(4-cyano-4-fluoropiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO d ₆ ): δ 12.72 (br s, 1H), 8.56 (s, 1H), 8.42 (d, J= 5.6 Hz, 1H), 7.81 (d, J =7.2 Hz, 1H), 7.63 (s, 1H), 7.23 (t, J =7.6 Hz, 1H), 6.55 (t, J =7.6 Hz , 1H), 6.38 (d, J =8.4 Hz, 1H), 5.80 (s, 1H), 5.22-5.27 (m, 1H), 3.76-3.89 (m, 4H), 2.19-2.36 (m, 7H), 1.58 (d, J =6.8 Hz, 3H);LCMS (m/z): 448.3 [MH] ^- ｡ 37 (R)-2-((1-(3-cyano-2-(4-cyano-4-fluoropiperidin-1-yl)-7-methyl-4-pentoxy-4H-pyrido [1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.76 (br s, 1H), 8.55 (s, 1H), 8.47 (br s, 1H), 7.79-7.83 (m, 2H), 7.20 (t, J =7.6 Hz, 1H), 6.56 (t , J =7.6 Hz, 1H), 6.35 (d , J =8.4 Hz, 1H), 5.17-5.20 (m, 1H), 4.21-4.25 (m, 2H), 3.87 (t, J =11.4 Hz, 2H), 2.28-2.46 (m, 7H), 1.57 (d, J =6.4 Hz , 3H); LCMS (m/z): 475.5 [M+H] ⁺ ｡ 38 (R)-2-((1-(3-cyano-2-(4-cyano-4-methylpiperidin-1-yl)-7-methyl-4-sideoxy-4H-pyridine And[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.76 (br s, 1H), 8.52 (s, 1H) , 8.41 (br s, 1H), 7.81 (dd, J =7.8, 1.6 Hz, 1 H), 7.77 (d, J =1.6 Hz, 1 H), 7.20-7.24 (m, 1H), 6.56 (t, J =7.2 Hz, 1H), 6.36 (d, J =8.8 Hz, 1H), 5.15-5.18 (m, 1H), 4.66-4.71 (m, 2H), 3.32-3.37 (m, 2H), 2.27 (s , 3H), 2.02-2.07 (m, 2H), 1.67-1.73 (m, 2H), 1.57 (d, J =6.4 Hz, 3H), 1.39 (s, 3H); LCMS (m/z): 469.3 [ MH] ^- ｡ 39 2-(((1R)-1-(3-cyano-2-(4,4-difluoro-3-hydroxypiperidin-1-yl)-7-methyl-4-pendantoxy-4H- Pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid ¹ H NMR (400 MHz, DMSO-d6) δ 12.80 (br s, 1H), 8.53 (s, 1H), 8.47-8.52 (m, 1H), 7.74-7.83 (m, 2H), 7.16-7.22 (m, 1H), 6.55 (t, J =7.5 Hz, 1H), 6.34 (t, J =8.9 Hz, 1H) , 5.75 (s, 2H), 5.18 (br d, J =3.2 Hz, 1H), 3.97-4.14 (m, 4H), 3.84-3.95 (m, 2H), 2.27 (s, 3H), 1.57 (d, J =6.6 Hz, 3H);LCMS (m/z): 484.2 [M+H] ⁺ ｡ Example A

ADP-Glo assay was used to measure ligand inhibition of the lipid kinase activity of PI3Ka (p110a/p85a) and PI3K (p110a(H1047R)/p85a). The kinase reaction utilizes ATP and produces ADP as a by-product. ADP production was quantified by ADP-Glo luminescence detection. The kinase reaction with the lipid substrate PI(4,5)P2:PS (10 µM) was performed in the presence of ATP (10 µM), the reaction was quenched, and the remaining ATP was depleted with ADP-Glo ^™ reagent. ADP is converted into ATP, which is measured using the luciferase/luciferin reaction. The substrate (PI(4,5)P2:PS) was prepared in fresh reaction buffer. Deliver the kinase into the substrate solution and mix gently. Compounds were delivered into the kinase reaction mixture (Echo550; nanoliter range) in 100% DMSO by acoustic technology and incubated at room temperature for 20 min. ATP was delivered into the reaction mixture to initiate the reaction, and the mixture was incubated at 30°C for 60 min. The reaction was quenched with ADP-Glo reagent and incubated for 40 min. Detection mixture was added and the mixture was incubated for 30 min. Luminescence was measured and converted to µM ADP production based on the ADP standard curve. Nonlinear regression was performed using Graphpad Prism software to obtain standard curves and IC ₅₀ values. The large ratio between wild type (WT) (PI3Ka (p110a/p85a) and H1047R mutant (PI3K (p110a(H1047R)/p85a)) IC50 indicates that the compound is active in the H1047R assay and less active in the wild type. Activity in WT may lead to toxicities such as hyperglycemia, hyperinsulinemia, gastrointestinal toxicity, and rash, so compounds that preferentially inhibit the H104R mutant would be beneficial as they reduce toxicity.

Compound toxicity was assessed in T47D cells using the Cell Titer-Glo (CTG) assay. T47D cells were cultured in RPMI1640 medium with 10% FBS and 1% penicillin/streptomycin. The medium was removed, the cells were treated with 0.25% trypsin, and the cell number was counted using a Vi-CELL XR Cell Viability Analyzer. Cells were seeded (3000 cells/100 uL) in a 96-well plate and cultured overnight. Cells were treated with various concentrations of compounds in DMSO and cultured for 5 days. Remove the plate from the incubator and allow to cool to rt within 30 min. 100 uL of CellTiter-Glo reagent (Promega, Cat. No. G7571) was added to each well and the luminescence was read after 20 min using the EnVision Multilabel Reader. The inhibition rate is calculated as: inhibition % = (ZPE-X)/(ZPE-HPE)*100%, and the IC ₅₀ value is calculated using XL Fit software.

The results are shown in Table 2 and demonstrate that the compound of formula (I) is an inhibitor of PI3Ka H1047R. Table 2 EX PI3Ka_H1047R IC ₅₀ (nM) PI3Ka IC ₅₀ (nM) (wild type) WT/H1047R (ratio) T47D IC50 (nM) 1 B F 29 D 2 D F 7 D 3 C F 10 A 4 C F 11 B 5 D F 9 N/A 6 B E 20 C 7 C E 8 A 8 C F 17 F 9 B E 14 F 10 A D 6 A 11 B D 9 D 12 A D 11 C 13 A D 58 B 14 B C 3 C 15 A A 2 C 16 D F 4 N/A 17 N/A N/A N/A F 18 D E 5 F 19 F F N/A F 20 B E 19 E twenty one A D 6 C twenty two A A 1.5 D twenty three D E 4 E twenty four B D 10 D 25 B D 12 A 26 D D 1 F 27 F F 1 F 28 C F 13 C 29 A B 1.7 A 30 C C 1.2 B 31 D E 6.2 B 32 F F 1 D 33 B E 19 C 34 A C 5.7 A 35 C E 18 C 36 D F 6.6 D 37 C D 2.3 B 38 C D 7 B 39 C D 5 D Series A ≤ 250 nM Series B > 250 nM and ≤ 500 nM Series C > 500 nM and ≤ 1000 nM Series D > 1000 nM and ≤ 5,000 Series E > 5000 nM and < 10,000 nM Series F > 10,000 nM N/A: Not possible have to

Furthermore, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those of ordinary skill in the art will understand that various modifications can be made without departing from the spirit of the disclosure. Accordingly, it is to be clearly understood that the form disclosed herein is for illustration only and is not intended to limit the scope of the disclosure but to encompass all modifications and alternatives consistent with the true scope and spirit of the disclosure.

[Fig. 1] Schematic 1 shows a general synthetic scheme for Examples of preparing compounds of formula (I). [Figure 2] illustrates Scheme 2, which is a general synthetic scheme for Examples of preparing compounds of formula (I). [Figure 3] illustrates Scheme 3, which is a general synthetic scheme for Examples of preparing compounds of formula (I).

Claims (43)

A compound of formula (I), (I) Or a pharmaceutically acceptable salt thereof, wherein X is C or N; Y ¹ is CH, O, S, N, NH, or NCH ₃ ; Y ² is C or N; Z ¹ and Z ² are independently Department CH or N; each Independently represents a single bond or a double bond, with the restriction that all chemical valences are met; W is C, CH, or N; Ring A is an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic ring Heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted bicyclic heteroaryl, wherein when the aforementioned ring A is substituted, it is -F, -Cl, -CN, -OH , one or more of unsubstituted C ₁ - ₆ alkyl, unsubstituted C ₁ - ₆ alkoxy, or unsubstituted C ₁ - ₆ haloalkyl; R ¹ is H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkenyl; R ² is unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ alkenyl, wherein When the aforementioned R ² is substituted, it is substituted by one of –OH, –F, –CN, –CO( _NH2 ), –COOH, _–CH2OH , _–CH3 , _–CF3 , or _–CF2, or More than one substituted; or R ¹ and R ² together with W form an optionally substituted 4, 5, 6, or 7-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl, wherein the aforementioned When substituted, it is substituted by monocyclic heteroaryl, –OH, –F, –CN, –CO( _NH2 ), –COOH, _–CH2OH , _–CH3 , _–CF3 , _–CF2 , or C One or more of ₁ -C ₆ alkyl groups are substituted; R ³ is H, –CN, –CHO, –CH=CH ₂ , –CH ₂ CN, –CH(CH ₃ )CN, –C(CH ₃ ) ₂ CN, C ₁ -C ₄ alkyl, –CH ₂ OH, –CH ₂ NH ₂ , –CH ₂ CH ₂ OH, –CH ₂ CH ₂ NH ₂ , or –CHCONH ₂ ; R ⁴ is H, –F, –CN, –CH ₃ , –CH ₂ CH ₃ , –CH(CH ₃ ) ₂ , –OH, or –OCH ₃ ; R ⁵ is H, –CH ₃ , –CH ₂ CH ₃ , –CF ₂ , –CF ₃ , or –CONH ₂ ; and R ⁶ is –COOH, –CN, _–CONH2 , oxadiazolone, –B(OH) ₂ , –PONH2 _, –PO( _CH3 ) ₂ , –CONHCH ₃ , –CONHCH ₂ CF ₃ , or –CONHCH ₂ CHF ₂ . Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein X is C. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is CH or N. For example, the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NH or NCH ₃ . Such as the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is O or S. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is O. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is C. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is N. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein Z ¹ is CH. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ^Z1 is N. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Z ² is CH. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Z ² is N. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein W is C. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein W is CH. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein W is N. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted or substituted aryl group. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted or substituted monocyclic heteroaryl group. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted or substituted cycloalkyl group. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted or substituted bicyclic heteroaryl group. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein ^R1 is H. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C ₁ -C ₆ alkyl group. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₆ alkenyl. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R ² is an unsubstituted or substituted C ₁ -C ₆ alkyl group. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R ² is an unsubstituted or substituted C ₁ -C ₆ alkenyl group. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² and W together form an optionally substituted 4, 5, 6, or 7-membered heterocycle. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² together with W form an optionally substituted 5- or 6-membered heteroaryl group. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R ³ is H. For example, the compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R ³ is –CN, –CHO, –CH= _CH2 , _–CH2CN , –CH( _CH3 )CN, –C(CH ₃ ) ₂ CN, or C ₁ -C ₄ alkyl. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R ³ is –CH ₂ OH, –CH ₂ NH ₂ , –CH ₂ CH ₂ OH, –CH ₂ CH ₂ NH ₂ , or –CHCONH ₂ . The compound of any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H, –F, –CN, or –CH ₃ . The compound of any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is –CH ₂ CH ₃ , –CH(CH ₃ ) ₂ , –OH, or –OCH ₃ . The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is H, –CH ₃ , or –CH ₂ CH ₃ . The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is –CF ₂ , –CF ₃ , or –CONH ₂ . Such as the compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is –CN, oxadiazolone, –B(OH) ₂ , –PONH ₂ , –PO(CH ₃ ) ₂ , –CONHCH ₃ , –CONHCH ₂ CF ₃ , or –CONHCH ₂ CHF ₂ . The compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is –COOH or –CONH ₂ . Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following: Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound series is shown in Table A or Table B herein. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. A method for treating cancer or tumors, which comprises administering to a subject suffering from the cancer or the tumor an effective amount of a compound as claimed in any one of claims 1 to 38 or a pharmaceutically active salt thereof, or as claimed Pharmaceutical compositions in Item 39. The method of claim 40, wherein the cancer or the tumor is selected from the group consisting of breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer, colorectal cancer, and non-small cell lung cancer. , glioma, bladder cancer, soft tissue sarcoma, esophageal and gastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer. The use of an effective amount of a compound according to any one of claims 1 to 38 or a pharmaceutically active salt thereof, or a pharmaceutical composition according to claim 39 in the manufacture of a medicament for treating cancer or tumors. The use of claim 42, wherein the cancer or the tumor is selected from the group consisting of breast cancer, brain cancer, prostate cancer, head and neck cancer, endometrial cancer, gastric cancer, lymphoma, ovarian cancer, lung cancer , colorectal cancer, non-small cell lung cancer, glioma, bladder cancer, soft tissue sarcoma, esophageal and gastric cancer, salivary gland cancer, thyroid cancer, hepatobiliary cancer, renal cell carcinoma, melanoma, pancreatic cancer, cervical cancer, and small bowel cancer .