Substituted Pyridopyrimidinones

Abstract

Disclosed herein are substituted pyridopyrimidinones, methods for their preparation, and uses.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 401,507, filed August 26, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Technical field) The present disclosure relates to substituted pyridopyrimidinones, and in particular compounds that are inhibitors of phosphoinositide 3-kinase (PI3K), and are therefore useful for treating diseases or disorders associated with PI3K regulation. The disclosure relates to compounds and compositions that inhibit PI3K, methods of treating diseases or disorders associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal anomaly syndrome), PIK3CA-associated overgrowth syndrome (PROS), breast cancer, brain tumor, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and methods of using PI3K inhibitors in combination with one or more other disorder or cancer treatments. [Background technology]

[0003] Cellular activity can be controlled by external signals that stimulate or inhibit intracellular activity. The process by which stimulatory or inhibitory signals are transmitted to cells, resulting in an intracellular response, is called signal transduction. Over the past few decades, a series of signal transduction reactions have been elucidated and found to play a central role in various biological responses. Defects in various components of signal transduction pathways have been found to be the cause of a vast number of diseases, including various cancers, inflammatory diseases, metabolic disorders, vascular diseases, and neurological disorders.

[0004] Kinases represent an important class of signal transduction molecules. Kinases are generally classified as protein kinases and lipid kinases, with certain kinases exhibiting dual specificity. Protein kinases are enzymes that phosphorylate other proteins and / or themselves (i.e., autophosphorylate). Protein kinases can generally be classified into three major groups based on their substrate utilization: tyrosine kinases, which primarily phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl); serine / threonine kinases, which primarily phosphorylate substrates on serine and / or threonine residues (e.g., mTORC1, mTORC2, ATM, ATR, DNA-PK, Akt); and dual specificity kinases, which phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0005] Lipid kinases are enzymes that catalyze the phosphorylation of intracellular lipids. These enzymes, the resulting phosphorylated lipids, and lipid-derived biologically active organic molecules play a role in various physiological processes, such as cell proliferation, migration, adhesion, and differentiation. A specific group of lipid kinases includes membrane lipid kinases (i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with cell membranes). Examples of such enzymes include phosphoinositide kinases (e.g., PI3-kinase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0006] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently mutated pathways in human cancer. PI3K signaling is also involved in many other diseases, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complication-related disorders, and cardiovascular inflammatory complications such as acute coronary syndromes.

[0007] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylates the 3'-OH group of phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with different substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G protein-coupled receptors to produce PIP3, which engages downstream effectors such as Akt / PDK1, the mTOR pathway, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play important roles in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.

[0008] PI3K isoforms are involved in a variety of human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations leading to the upregulation of PI3K isoforms appear to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations clustered at several hotspots in the helical and kinase domains. Because of the high mutation rate of PI3K, targeting this pathway may offer effective therapeutic strategies.

[0009] Mutations in genes involved in PI3K signaling are thought to be involved in various cancers, including endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric carcinoma, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar hepatocellular carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, various neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0010] The alpha (α) isoform of PI3K, for example, has been implicated in various human cancers. In angiogenesis, the alpha (α) isoform of PI3K has been shown to be selectively required for regulating endothelial cell migration. Mutations in the gene encoding PI3Kα or mutations leading to upregulation of PI3Kα are thought to occur in many human cancers (e.g., lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers). Mutations in the gene encoding PI3Kα are point mutations clustered at several hotspots (e.g., E542K, E545K, and H1047R) in the helical and kinase domains. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate of PI3Kα, targeting this pathway may provide effective therapeutic strategies. While other PI3K isoforms (e.g., PI3Kδ or PI3Kγ) are primarily expressed in hematopoietic cells, PI3Kα is constitutively expressed along with PI3Kβ.

[0011] Due to the central role of PI3Kα in controlling glucose homeostasis in the body, inhibition of PI3K in patients often leads to hyperglycemia and / or hyperinsulinemia. High circulating insulin levels have mitogenic and / or antiapoptotic effects on cancer cells, potentially counteracting the antiproliferative effects of PI3K inhibitors.

[0012] One way to overcome the problem of compensatory insulin and / or glucose production when PI3Kα inhibition has a systemic effect in mutant PI3Kα cancers is to develop inhibitors that are more selective for mutant PI3Kα than for wild-type PI3Kα. This would broaden drug administration options to selectively block disease-related mutant PI3Kα signaling in cancer cells without affecting wild-type PI3Kα in host tissues, which regulates systemic metabolism, thereby limiting toxicity and allowing for higher doses and more complete inhibition of the drug target.

[0013] Existing PI3Kα inhibitors have nearly equal potency against wild-type and mutant PI3Kα. Because the PI3Kα mutations are located far from the active site, it has been difficult to identify mutant-selective inhibitors. Therefore, inhibitors targeting the second peripheral binding pocket near known mutations (e.g., H1047R) may provide a pathway for selectively inhibiting PI3Kα. Thus, targeting the peripheral binding pocket of mutant PI3Kα may provide a valuable therapeutic target for drug development.

[0014] Therefore, kinases (eg, lipid kinases such as PI3K) are prime targets in drug discovery. Summary of the Invention

[0015] In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, X is N, O, or S; If X is N, then R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; If X is O or S, then R 1 does not exist; R 2 is phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, —C(O)—(C2-C4 alkyl), —C(O)—(C2-C4 alkenyl), —(C2-C4 alkyl)-C(O)OH, or —(C2-C4 cycloalkyl)-C(O)OH, where each phenyl and heteroaryl is selected from 1 to 5 R 7 may be optionally substituted with; R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 5 halogens; R 5 is C1-C3 alkyl, C2-C6 alkenyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, or 3- to 9-membered heterocyclyl, where each alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 1 to 5 R 6 and the heterocyclyl may be optionally unsaturated; R 8 is R A , halogen, or cyano; Y is a bond, NR 10 , S or O; where: Each R 6 independently -R A , -OR A , -C(O)OR A , oxo, cyano, halogen, (C1-C3 alkyl)-OR A , -C(O)N(R A )2, -C(O)R 11 , -N(R A )2, -N(R A )C(O)R A , -SO2R A , -R C or two geminal R 6 together with the carbons to which they are attached form a spirocyclic C3-C6 cycloalkyl or 3- to 12-membered heterocyclyl, or two vicinal R 6 However, they combine with the carbon to which they are attached to form condensed C 10 -C 14 Aryl, C8-C 12 Cycloalkyl or C3-C 12 forming a heterocyclyl; where each spirocyclic group and fused group is R B , -OR B , -C(O)OR B , (C1-C3 alkyl)-OR B , -C(O)N(R B )2, optionally substituted with oxo, cyano, halogen; where each RB are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C6)alkyl; R C is C3-C6 cycloalkyl, C3-C 12 Heterocyclyl, C3-C 12 heterocyclyl(C1-C6)alkyl, phenyl, phenyl(C1-C2)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(C1-C2)alkyl, wherein each cycloalkyl, heterocyclyl, phenyl, and heteroaryl is selected from 1 to 5 R 9 may be optionally substituted with; Each R 7 are independently cyano, halogen, oxo, C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, -P(O)(OH)R A or two geminal R 7 together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; Each R 9 are independently hydroxy, halogen, cyano, C-C alkyl, C-C alkoxy, halo(C-C) alkyl, or -SON(R 10 )2; Each R 10 are independently hydrogen or C1-C6 alkyl; R 11 is C1-C6 alkyl, C3-C6 cycloalkyl(C1-C6)alkyl, C3-C6 cycloalkyl, or phenyl, each group consisting of 1 to 5 R 7 may be optionally substituted with; Each R A are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C6)alkyl, or two geminal R Atogether with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; and Unless otherwise specified herein, each alkyl and cycloalkyl group is unsubstituted, substituted with 1 to 5 halogens, perfluorinated, or substituted with 1 to 3 groups selected from methyl, oxo, and carboxy; and However, if Y is a bond, then R 5 is not unsubstituted morpholinyl] and pharmaceutically acceptable salts thereof, and prodrugs, solvates, hydrates, isomers, deuterated compounds, and tautomers thereof.

[0016] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound or salt as otherwise described herein, in association with a pharmaceutically acceptable carrier, excipient, or diluent.

[0017] In another aspect, the disclosure provides a method for treating a disease or disorder associated with modulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need of treatment a therapeutically effective amount of any compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0018] In another aspect, the disclosure provides a method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0019] In another aspect, the disclosure provides a method of treating cancer or disease, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0020] The compounds of the present disclosure selectively bind to H1047R mutant PI3Kα and not to wild-type PI3Kα.

[0021] Other aspects and embodiments of the present disclosure will be apparent from consideration of the detailed description herein. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention relates to inhibitors of PI3K alpha. In particular, the present invention relates to compounds that inhibit PI3K alpha activity, pharmaceutical compositions containing therapeutically effective amounts of such compounds, and methods of use thereof.

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. All patents, patent applications, and publications disclosed herein are incorporated by reference to the extent not inconsistent with this disclosure. Terms and scopes have the definitions generally defined unless expressly defined otherwise.

[0024] For convenience, chemical groups are defined and referred to throughout primarily as monovalent chemical groups (e.g., alkyl, aryl, etc.). However, these terms may also be used to indicate corresponding polyvalent groups in appropriate structures apparent to those skilled in the art. For example, an "alkyl" group generally refers to a monovalent group (e.g., CH3-CH2-), but in some situations a divalent linking group may be "alkyl," in which case one skilled in the art would understand that alkyl is the divalent group equivalent to the term "alkylene" (e.g., -CH2-CH2-). (Similarly, in situations where a divalent group is required and "aryl" is described, one skilled in the art would understand that the term "aryl" refers to the corresponding divalent group, arylene.) All atoms are understood to have normal valences for forming bonds (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6 depending on the oxidation state of S).

[0025] The term "amino" refers to -NH2.

[0026] The term "acetyl" refers to -C(O)CH3.

[0027] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0028] As used herein, the term "alkyl" refers to saturated, straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56 10 , C 11 and C 12 The alkyl groups may be branched or straight chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0029] As used herein, the term "alkenyl" refers to an unsaturated, straight- or branched-chain aliphatic group having one or more carbon-carbon double bonds and 2 to 12 carbon atoms. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C 10 , C 11 and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0030] As used herein, the term "alkynyl" refers to an unsaturated, straight- or branched-chain aliphatic group having one or more carbon-carbon triple bonds and 2 to 12 carbon atoms. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C 10 , C 11 and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0031] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined above, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0032] The term "alkoxy" refers to -O(C1-C6 alkyl).

[0033] As used herein, the term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups containing 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C2 10 , C 11 and C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0034] The term "heteroalkyl" refers to an alkyl group, as defined above, where one or more carbon atoms in the chain are independently O, S, or NR x where R x refers to an alkyl group that is hydrogen or a C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0035] An "aryl" group is a C6-C aryl group containing one to three aromatic rings. 14 It is an aromatic moiety. Therefore, "aryl" includes C6, C 10 , C 13 , and C 14For example, an aryl group is a cyclic hydrocarbon group having a C6-C 10 An aryl group. Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are non-aromatic, but at least one ring is aromatic (e.g., indenyl).

[0036] An "aralkyl" or "arylalkyl" group includes an aryl group covalently bonded to an alkyl group, which is bonded to another group through the alkyl portion of the group. Examples of aralkyl groups include, but are not limited to, -(C-C)alkyl (C-C), including benzyl, phenethyl, and naphthylmethyl. 10 For example, a C1-C3 aralkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0037] A "heterocyclyl" or "heterocycle" or "heterocycloalkyl" group refers to a mono- or bicyclic (fused or spiro) structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms, e.g., 4 to 8 atoms), in which one or more ring atoms are independently -C(O)-, N, NR 4, O, or S, with the remaining ring atoms being quaternary carbon or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thianyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. Examples of heterocyclic groups containing spiro rings include azaspiro[2.5]octan-6-yl, 5-azaspiro[2.4]heptan-5-yl, 6-azaspiro[3.4]octan-6-yl, 5-oxa-7-azaspiro[3.4]octan-7-yl, 5,5-dimethyl-4-oxa-7-azaspiro[2.5]octan-7-yl, and 7,7-dimethyl-5-azaspiro[2.5]octan-5-yl. Compounds containing oxygen and / or sulfur atoms in adjacent rings are specifically excluded from the scope of this term. A heterocyclic group may be connected to the parent group through any ring atom (i.e., point of attachment), including one of the heteroatoms or one of the carbon atoms in the heterocyclic group. Where chemically necessary, e.g., acting as a bridging group, the heterocycle may be bonded to one or more other groups. The term "heterocyclyl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are aromatic or non-aromatic, but at least one ring is non-aromatic and contains an N, O, or S ring atom. Examples of fused polycyclic ring systems include 3,4-dihydroisoquinolin-2(1H)-yl, isoindolinyl, indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. These examples are 9- or 10-membered heterocyclyls, respectively.

[0038] As used herein, the term "heteroaryl" refers to a group containing 5 to 14 ring atoms (preferably 5, 6, 10, 13, or 14 ring atoms), sharing 6, 10, or 14 pi electrons in a ring, and having, in addition to carbon atoms, one to three heteroatoms, each independently N, O, or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are non-aromatic, but at least one ring is aromatic, and at least one ring contains an N, O, or S ring atom. A heteroaryl group can be attached to the parent group through any ring atom (i.e., point of attachment), including one of the heteroatoms or one of the carbon atoms in the heteroaryl group. If chemically necessary, for example, to act as a bridging group, the heteroaryl may be attached to one or more other groups.

[0039] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furanyl, and the like. Zanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazo Allyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclinyl thiazinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0040] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined above, that is positioned between and serves to connect two other chemical groups.

[0041] As used herein, when a moiety name (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without specifying the substituents, this means that the group may optionally have multiple non-hydrogen substituents (e.g., 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 non-hydrogen substituents).

[0042] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0043] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced with a halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0044] The term "hydroxyalkyl" refers to -alkylene-OH.

[0045] It is understood that each atom present in formula (I) and compounds contained in formula (I) may be any of its naturally occurring isotopes, with the most abundant isotope being preferred. Thus, for example, each hydrogen atom contained in formula (I) or the formulas described below may be: 1 H, 2 H (deuterium, D) or 3 It may be present as an atom of H (tritium, T), preferably 1 H. Similarly, by way of example, each carbon atom in formula (I), or any formula set forth below, can be 12 C. 13 C or 14 It may be present as an atom of C, preferably 12 It is C.

[0046] As used herein, an "effective amount" of a compound refers to an amount sufficient to negatively regulate or inhibit the activity of PI3K alpha.

[0047] As used herein, a "therapeutically effective amount" of a compound refers to an amount sufficient to ameliorate or in any way alleviate symptoms, or to slow or stop the progression of a disease state, or to negatively regulate or inhibit the activity of PI3K alpha. Such an amount may be administered singly or according to an effective regimen.

[0048] As used herein, "treatment" means any manner in which the symptoms or pathology of a patient's condition, disorder or disease are ameliorated or beneficially altered.

[0049] As used herein, "amelioration of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0050] compound In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, X is N, O, or S; If X is N, then R 1 is H, C1-C3 alkyl, or C3-C6 cycloalkyl; If X is O or S, then R 1 does not exist; R 2 is phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, —C(O)—(C2-C4 alkyl), —C(O)—(C2-C4 alkenyl), —(C2-C4 alkyl)-C(O)OH, or —(C2-C4 cycloalkyl)-C(O)OH, where each phenyl and heteroaryl is selected from 1 to 5 R 7may be optionally substituted with; R 3 is C1-C3 alkyl or C3-C6 cycloalkyl; R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 5 halogens; R 5 is C1-C3 alkyl, C2-C6 alkenyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, or 3- to 9-membered heterocyclyl, where each alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 1 to 5 R 6 and the heterocyclyl may be optionally unsaturated; R 8 is R A , halogen, or cyano; Y is a bond, NR 10 , S or O; where: Each R 6 independently -R A , -OR A , -C(O)OR A , oxo, cyano, halogen, (C1-C3 alkyl)-OR A , -C(O)N(R A )2, -C(O)R 11 , -N(R A )2, -N(R A )C(O)R A , -SO2R A , -R C or two geminal R 6 together with the carbons to which they are attached form a spirocyclic C3-C6 cycloalkyl or 3- to 12-membered heterocyclyl, or two vicinal R 6 However, they combine with the carbon to which they are attached to form condensed C 10 -C 14 Aryl, C8-C 12 Cycloalkyl or C3-C 12 forming a heterocyclyl; where each spirocyclic group and fused group is R B , -OR B , -C(O)OR B , (C1-C3 alkyl)-OR B , -C(O)N(R B )2, optionally substituted with oxo, cyano, halogen; where each R B are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl(C1-C6)alkyl; R C is C3-C6 cycloalkyl, C3-C 12 Heterocyclyl, C3-C 12 heterocyclyl(C1-C6)alkyl, phenyl, phenyl(C1-C2)alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl(C1-C2)alkyl, wherein each cycloalkyl, heterocyclyl, phenyl, and heteroaryl is selected from 1 to 5 R 9 may be optionally substituted with; Each R 7 are independently cyano, halogen, oxo, C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, -P(O)(OH)R A or two geminal R 7 together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; Each R 9 are independently hydroxy, halogen, cyano, C-C alkyl, C-C alkoxy, halo(C-C) alkyl, or -SON(R 10 )2; Each R 10 are independently hydrogen or C1-C6 alkyl; R 11is C1-C6 alkyl, C3-C6 cycloalkyl(C1-C6)alkyl, C3-C6 cycloalkyl, or phenyl, each group consisting of 1 to 5 R 7 may be optionally substituted with; Each R A are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C6)alkyl, or two geminal R A together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; and Unless otherwise specified herein, each alkyl and cycloalkyl group is unsubstituted, substituted with 1 to 5 halogens, perfluorinated, or substituted with 1 to 3 groups selected from methyl, oxo, and carboxy; and However, if Y is a bond, then R 5 is not unsubstituted morpholinyl] and pharmaceutically acceptable salts thereof, as well as prodrugs, solvates, hydrates, isomers, deuterated compounds, and tautomers thereof.

[0051] In certain embodiments as otherwise described herein, X is N.

[0052] In certain embodiments as otherwise described herein, Y is a bond and R 5 is a 5- to 7-membered heterocyclyl.

[0053] In certain embodiments as otherwise described herein, Y is a bond and R 5 is a 5- to 7-membered heterocyclyl selected from piperidinyl, piperazinyl, azetidinyl, and isoindolinyl, each of which may be optionally substituted. 5 The heterocyclyl group is attached to the pyridopyrimidine ring via a nitrogen atom in the heterocyclyl group.

[0054] In certain embodiments as otherwise described herein, Y is a bond and R 5is a 5- to 6-membered heteroaryl, each of which may be optionally substituted. In other embodiments, Y is a bond and R 5 is thiophene, pyrazinyl, or pyridinyl, each of which may be optionally substituted.

[0055] In certain embodiments as otherwise described herein, R 1 is H or CH. For example, in certain embodiments, R 1 is H. In other embodiments, R 1 is CH3.

[0056] In certain embodiments as otherwise described herein, R 2 is phenyl, pyridinyl, -C(O)-CH=CH2, or -C(O)-CH2-Cl, where each phenyl or pyridinyl is selected from 1 to 5 R 7 may be optionally substituted with

[0057] In certain embodiments as otherwise described herein, R 3 is C1-C3 alkyl, where the alkyl group is unsubstituted, substituted with 1 to 5 halogens, or perfluorinated. For example, in certain embodiments, R 3 is methyl (e.g., unsubstituted methyl).

[0058] In certain embodiments as otherwise described herein, R 4 is H, methyl, ethyl, or cyclopropyl. For example, in certain embodiments, R 4 is methyl, ethyl, or cyclopropyl, each of which is unsubstituted.

[0059] In certain embodiments as otherwise described herein, Y is a bond.

[0060] In certain embodiments as otherwise described herein, R 5 are 6-10 membered aryl, C-C cycloalkyl, or 3-9 membered heterocyclyl, each of which is 1-5 R6 For example, in certain embodiments, R 5 is cyclopropyl, phenyl, piperidinyl, or isoindolinyl, each of which is 1 to 5 R 6 In various embodiments, R 5 is not a morpholino and is not an unsubstituted morpholino.

[0061] In certain embodiments as otherwise described herein, R 8 is hydrogen, methyl, ethyl, or cyano. For example, in certain embodiments, R 8 is methyl (eg, unsubstituted methyl), or H.

[0062] In certain embodiments of formula (I) as otherwise described herein, R 1 is H.

[0063] In certain embodiments of formula (I) as otherwise described herein, R 1 is CH3.

[0064] In certain embodiments of formula (I) as otherwise described herein, R 1 is H or CH3.

[0065] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or 5- to 7-membered heteroaryl, each of which is 1, 2, or 3 R 7 is substituted with a group.

[0066] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or 5- to 7-membered heteroaryl, each of which is 1, 2, or 3 R 7 group and at least one R 7 The group is -C(O)OR A is.

[0067] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or 5- to 7-membered heteroaryl, each of which is 1, 2, or 3 R 7 group and at least one R 7 The group is -C(O)OR A where R A is H, methyl or ethyl.

[0068] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or 5- to 7-membered heteroaryl, each of which is 1, 2, or 3 R 7 group and at least one R 7 The group is -C(O)OR A where R A is H.

[0069] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or 5- to 7-membered heteroaryl, each of which is 1, 2, or 3 R 7 group and at least one R 7 The group is -C(O)OR A where R A is methyl or ethyl.

[0070] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each group consisting of 1 to 5 R 7 may be optionally substituted with

[0071] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or pyridinyl, each group having 1 to 5 R 7 may be optionally substituted with

[0072] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or pyridinyl, each group having 1 to 5 R 7 and optionally substituted with at least one R 7 The group is -C(O)OR A is.

[0073] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or pyridinyl, each group having 1 to 5 R 7 and optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H, methyl or ethyl.

[0074] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or pyridinyl, each group having 1 to 5 R 7 and optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H.

[0075] In certain embodiments of formula (I) as otherwise described herein, R 2 is phenyl or pyridinyl, each group having 1 to 5 R 7 and optionally substituted with at least one R 7 The group is -C(O)OR A where R A is methyl or ethyl.

[0076] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 is phenyl optionally substituted with

[0077] In certain embodiments of formula (I) as otherwise described herein, R2 is 1 to 5 R 7 phenyl optionally substituted with at least one R 7 The group is -C(O)OR A is.

[0078] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 phenyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H, methyl or ethyl.

[0079] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 phenyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H.

[0080] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 phenyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is methyl or ethyl.

[0081] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 and pyridinyl optionally substituted by

[0082] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 pyridinyl optionally substituted with at least one R 7 The group is -C(O)OR Ais.

[0083] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 pyridinyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H, methyl or ethyl.

[0084] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 pyridinyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is H.

[0085] In certain embodiments of formula (I) as otherwise described herein, R 2 is 1 to 5 R 7 pyridinyl optionally substituted with at least one R 7 The group is -C(O)OR A where R A is methyl or ethyl.

[0086] In certain embodiments of formula (I) as otherwise described herein, R 3 is a C1-C3 alkyl, where the alkyl group is unsubstituted, substituted with 1 to 5 halogens, or perfluorinated.

[0087] In certain embodiments of formula (I) as otherwise described herein, R 3 is a C1-C3 alkyl, where the alkyl group is unsubstituted, substituted with 1 to 5 halogens, or perfluorinated.

[0088] In certain embodiments of formula (I) as otherwise described herein, R 3 is C1-C3 alkyl.

[0089] In certain embodiments of formula (I) as otherwise described herein, R 3 is ethyl, or R 3 is methyl.

[0090] In certain embodiments, as otherwise described herein, the compound has the formula (IIa), (IIb), or (IIc): [ka] [In the formula, Q is N or CH; R 1 is H or CH3; R 3 is C1-C3 alkyl; R 4 is H, C1-C3 alkyl, C3-C6 cycloalkyl, cyano, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 5 halogens; Each R 6 independently -R A , -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A )2, oxo, cyano, halogen, or two geminal R 6 together with the carbons to which they are attached form a C3-C6 cycloalkyl or heterocyclyl, or two vicinal R 6 However, they combine with the carbon to which they are attached to form condensed C 10 -C 14 Aryl or C8-C 12 Forming a cycloalkyl; each m is 0, 1, 2, 3, or 4; Each R 7 are independently C1-C4 alkyl, -OR A , -C(O)OR A , (C1-C3 alkyl)-OR A , -C(O)N(R A)2, cyano, halogen, or two geminal R 7 together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; each n is 0, 1, 2, 3, or 4; R 8 is methyl, ethyl or cyano; Each R A are independently H, C1-C3 alkyl, C3-C6 cycloalkyl, or two geminal R A together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 3- to 9-membered heterocyclyl; and wherein each alkyl and cycloalkyl group is unsubstituted, substituted with 1 to 5 halogens, perfluorinated, or substituted with 1 to 3 groups selected from methyl, oxo, or carboxy. or a pharmaceutically acceptable salt thereof.

[0091] In certain embodiments, as otherwise described herein, with respect to examples of compounds of Formula (IIa), (IIb), and / or (IIc), Q is CH. In other embodiments, Q is N.

[0092] In certain embodiments, as otherwise described herein, with respect to example compounds of Formula (IIa), (IIb), and / or (IIc), m ranges from 1 to 3. For example, in certain embodiments, m is 2 and each R 6 is methyl (e.g., unsubstituted methyl).

[0093] In certain embodiments, as otherwise described herein, with respect to example compounds of Formula (IIa), (IIb), and / or (IIc), n ranges from 1 to 3. For example, in certain embodiments, n is 1 and R 7 is -COOH.

[0094] In certain embodiments, the compound of formula I is [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] or a pharmaceutically acceptable salt of one of the foregoing compounds.

[0095] In another embodiment, the compound of formula I is Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29

Table 30

[0096] In another embodiment, the compound of formula I is [Table 48] [Table 49] [Table 50] Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 [Table 68] [Table 69] [Table 70] [Table 71] or a pharmaceutically acceptable salt of one of the foregoing compounds.

[0097] Pharmaceutical Composition The compounds of formula I may be formulated into pharmaceutical compositions.

[0098] In another aspect, the present invention provides pharmaceutical compositions comprising the PI3K alpha inhibitor of the present invention and pharmaceutically acceptable carriers, excipients or diluents.The compounds of the present invention can be formulated by any method known in the art and prepared for administration by any route, including but not limited to parenteral administration, oral administration, sublingual administration, transdermal administration, topical administration, intranasal administration, intratracheal administration or intrarectal administration.In certain embodiments, the compounds of the present invention are administered intravenously in hospitals.In certain other embodiments, they may be preferably administered orally.

[0099] The characteristics of the carrier vary depending on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic substance that is compatible with a living system, such as a cell, cell culture, tissue, or organism, and does not inhibit the effectiveness of the biological activity of the active ingredient. Therefore, in addition to the inhibitor, the compositions described in the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0100] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the intended biological activity of the compound and exhibits minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). The compounds may be administered as pharmaceutically acceptable quaternary salts known to those of skill in the art, including quaternary ammonium salts of the formula -NRZ-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion such as chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., of benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartarate, ascorbic acid, benzoate, cinnamate, mandelic acid, benzilic acid, and diphenylacetic acid).

[0101] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxic effects to the patient being treated. Dosages of the active compound for all of the above conditions range from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, and more commonly 0.5 to about 25 mg / kg of recipient body weight per day. Typical topical dosages range from 0.01 to 3% wt / wt in a suitable carrier. Effective dosage ranges for pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound delivered. If the derivative itself is active, the effective dosage can be estimated using the weight of the derivative, as described above, or by other methods known to those skilled in the art.

[0102] Pharmaceutical compositions containing the compounds of the present invention may be used in the methods described herein.

[0103] How to use In another aspect, the disclosure generally relates to methods for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutant inhibitor).

[0104] In some embodiments, the PI3K inhibitor (e.g., a PI3K alpha inhibitor or a PI3K alpha H1047R mutant inhibitor) is a compound of Formula (I), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof. In certain embodiments, the PI3K inhibitor includes a compound selected from Table 1.

[0105] In another aspect, the disclosure provides compounds obtained by or obtained by a method of making a compound described herein (e.g., a method comprising one or more steps described in a scheme).

[0106] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (lIa), (IIb), (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0107] In another aspect, the disclosure provides intermediates described herein (e.g., intermediates selected from those described in the Examples) that are suitable for use in the methods of making the compounds described herein.

[0108] In another aspect, the disclosure provides a method for modulating the activity of PI3K (e.g., PI3Kα) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (lIa), (IIb), or (IIc), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[0109] In certain embodiments, the PI3K-related disease or disorder has H1047R mutation. For example, in certain embodiments as otherwise described herein, the compound selectively inhibits H1047R mutant PI3Kα over wild-type PI3Kα. This unexpected finding suggests that certain compounds can target and inhibit PI3Kα through a novel binding mechanism compared with conventional wild-type PI3Kα inhibitors. Without wishing to be bound by theory, the H1047R mutant PI3Kα has a modification site away from the active site of wild-type PI3Kα. Therefore, it is believed that compounds that are selective for H1047R mutant PI3Kα over wild-type PI3Kα do not bind strongly to the PI3Kα active site, but rather target other binding pockets. Because the active site of PI3K proteins is thought to be well conserved among mutants, compounds that effectively bind to positions other than the active site may exhibit more selective PI3Kα inhibition than other PI3K proteins (e.g., PI3Kβ).

[0110] In another aspect, there is provided a method for treating cancer, comprising administering to a patient with cancer a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof.

[0111] The compositions and methods provided herein may be used to treat a wide range of cancers, including tumors of the prostate, breast, brain, and skin, cervical cancer, testicular cancer, and the like. In particular, cancers that may be treated with the compositions and methods of the present invention include, but are not limited to, astrocytoma, breast, cervical, colon, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid cancer, and sarcoma. More specifically, these compounds are useful in treating the following: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, pulmonary hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell tumor, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, splenic carcinoma, bile duct carcinoma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteomalacia (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancer of the meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pineal tumors), glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological: uterus (endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, undifferentiated carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer; Hematological: myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma); It may be used to treat skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, atypical nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0112] In some embodiments, the cancer is selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0113] In another embodiment, the cancer is selected from breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

[0114] Thus, in certain embodiments, the present disclosure provides a method of treating cancer, comprising administering a compound of Formula (I), a pharmaceutical composition thereof, and a KRAS inhibitor to a patient in need of treatment, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

[0115] In other embodiments, the disclosure provides methods of treating cancer, comprising administering a compound of Formula (I), a pharmaceutical composition thereof, or a mutant-selective KRAS inhibitor to a patient in need of treatment, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

[0116] In another embodiment, the disclosure provides a compound of Formula (I) or a pharmaceutical composition thereof in combination with a KRAS inhibitor for treating cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

[0117] The concentration and route of administration to a patient will vary depending on the cancer being treated. The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the compounds and salts may be administered in combination with other anti-cancer compounds (e.g., chemotherapy), or may be used in combination with other treatments (e.g., radiation therapy or surgery) as pre- or post-operative adjuvant therapy.

[0118] The present disclosure provides methods for treating, preventing, or ameliorating a PI3K-mediated disease or disorder by administering a therapeutically effective amount of a PI3K inhibitor to a patient in need thereof. The methods of the present disclosure can be used to treat a variety of PI3K-mediated diseases and disorders.

[0119] In some embodiments, the disease or disorder is cancer (e.g., breast cancer, brain tumor, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal abnormality syndrome) or PIK3Cα-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, These include cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar hepatocellular carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, various neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0120] Details of the present disclosure are set forth in the description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, those described herein are exemplary of the methods and materials. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In the specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0121] General Reaction Schemes, Intermediates and Examples General reaction scheme In the synthetic methods and reaction schemes described herein, the compounds of the invention may be prepared using commercially available reagents and intermediates, or may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0122] Unless otherwise specified, when a "first eluting enantiomer" or a "second eluting enantiomer" is referred to, the specific stereochemistry of that enantiomer has not been determined, and any stereochemistry depicted in the corresponding compound structure has been arbitrarily assigned.

[0123] For example, intermediates for preparing the compounds of the present invention and compounds of formula (I) can be prepared according to General Reaction Schemes I-III.

[0124] General Reaction Scheme I [ka] In General Reaction Scheme I, compound 5 is an example of formula (I). In this General Reaction Scheme I, 1 is reacted with a reducing agent (e.g., sodium borohydride) to give compound 2. Compound 2 then undergoes a halogenation reaction with a reagent (e.g., phosphorus tribromide) to give the halogenated product 3. Compound 3 is then treated with a nucleophilic amine 4. This reaction may be, for example, a nucleophilic substitution reaction in the presence of a suitable base (such as N,N-diisopropylethylamine) or a metal-catalyzed reaction to give the title compound 5.

[0125] General Reaction Scheme II [ka] In General Reaction Scheme II, compound 5 is an example of formula (I). In this General Reaction Scheme II, 1 is reacted with a reducing agent (e.g., sodium cyanoborohydride) in the presence of an ammonium salt (e.g., ammonium acetate) to give compound 6. Compound 6 can then be reacted with a coupling partner (e.g., a halide, compound 7 (XR 4 )) to afford the title compound 5.

[0126] General Reaction Scheme III [ka] In General Reaction Scheme III, compound 5 is an example of formula (I). In this General Reaction Scheme III, 1 is reacted with a substituted amine 8 (NH-R 4 ) to give compound 5.

[0127] Intermediate A [ka]

[0128] Step A: To a solution of 3-bromo-5-methyl-pyridin-2-amine (10.0 g, 53.5 mmol, 1.00 equiv) in dichloromethane (100 mL) was added malonyl chloride (7.91 g, 56.1 mmol, 5.46 mL, 1.05 equiv) dropwise, and the reaction mixture was stirred at 25 °C for 48 h. After stirring was complete, the reaction solution became opaque, and the yellow cake was collected by filtration, washed with dichloromethane (200 mL), and dried under vacuum to give 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.4 g, 31.4 mmol, 58.7% yield, 70.2% purity) as a yellow solid. LCMS [M+1] + =254.9 1 H NMR (400MHz, DMSO-d6)δ=8.72(s, 1H), 8.28(d, J=1.6Hz, 1H), 5.51(s, 1H), 2.34(s, 3H)

[0129] Step B: To a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.4 g, 44.7 mmol, 1.00 equiv) in tetrahydrofuran (110 mL) were added triethylamine (18.1 g, 179 mmol, 24.9 mL, 4.00 equiv) and methanesulfonic anhydride (11.7 g, 67.0 mmol, 1.50 equiv) at 0° C. The mixture was stirred at 25° C. for 1 hour, and then piperidine (11.4 g, 134 mmol, 13.2 mL, 3.00 equiv) was added and heated at 55° C. for 12 hours. After completion of the reaction, the mixture was cooled to 25° C., and the reaction mixture was then concentrated under reduced pressure to provide a residue. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 9-bromo-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.20 g, 13.2 mmol, 29.5% yield, 81.8% purity) as a yellow solid. LCMS [M+1] + =324.0 1 H NMR(400MHz, CDCl3)δ=8.67(s, 1H), 7.80(d, J=2.0Hz, 1H), 5.61(s, 1H), 3.69(br s, 4H), 2.31(d, J=1.0Hz, 3H), 1.70(br d, J=3.6Hz, 2H), 1.65(brd, J=4.8Hz, 4H)

[0130] Step C: A mixture of 9-bromo-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.20 g, 16.1 mmol, 1.00 equiv.), n-butyl vinyl ether (4.85 g, 48.4 mmol, 6.23 mL, 3.00 equiv.), diisopropylethylamine (6.26 g, 48.4 mmol, 8.43 mL, 3.00 equiv.), bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.18 g, 1.61 mmol, 0.10 equiv.) in n-butanol (50.0 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 120° C. under a nitrogen atmosphere for 12 hours. The resulting mixture was then cooled to 25°C, and hydrochloric acid (3N, diluted with water, 40 mL) was added, followed by stirring at 25°C for 1 hour. The mixture was then adjusted to pH 8 with saturated sodium bicarbonate solution, further diluted with water (150 mL), and extracted with dichloromethane (150 mL x 2). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.7 g, 9.40 mmol, 58.2% yield, 99.3% purity) as a yellow solid. 1 H NMR (400MHz, CDCl3-d)δ=8.84(d, J=0.8Hz, 1H), 7.82(d, J=2.4Hz, 1H), 5.72-5.57(m, 1H), 3.67-3.59(m, 4H), 2.79(s, 3H), 2.34(s, 3H), 1.74-1.68(m, 2H), 1.65-1.59(m, 4H)

[0131] Intermediate B [ka]

[0132] Step A: N-Bromosuccinimide (2.98 g, 16.8 mmol, 1.50 equiv) was added to a solution of 5-cyclopropylpyridin-2-amine (1.50 g, 11.2 mmol, 1.00 equiv) in acetonitrile (30 mL) and stirred at 40 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give 3-bromo-5-cyclopropylpyridin-2-amine (0.89 g, 4.14 mmol, 37.0% yield, 99% purity) as a yellow solid. LCMS [M+3] + =214.7 1 H NMR (400MHz, DMSO-d6)δ=7.79(d, J=2.0Hz, 1H), 7.39(d, J=2.0Hz, 1H), 5.91(s, 2H), 1.82-1.72(m, 1H), 0.86-0.80(m, 2H), 0.60-0.55(m, 2H)

[0133] Step B: To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (490 mg, 2.30 mmol, 1.00 equiv) in acetone (5.00 mL) was added bis(2,4,6-trichlorophenyl)malonate (1.06 g, 2.30 mmol, 1.00 equiv) and stirred at 25 °C for 12 hours. The reaction mixture was cooled to 20 °C, the resulting precipitate was filtered, and the filter cake was washed with acetone (5.00 mL) to give 9-bromo-7-cyclopropyl-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (440 mg, 1.55 mmol, 67.4% yield, 99% purity) as a yellow solid. LCMS [M+3] + =280.9

[0134] Step C: To a solution of 9-bromo-7-cyclopropyl-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (0.3 g, 1.07 mmol, 1.00 equiv) in tetrahydrofuran (3.00 mL), triethylamine (324 mg, 3.20 mmol, 446 μL, 3.00 equiv) and methanesulfonic anhydride (278.86 mg, 1.60 mmol, 1.50 equiv) were added and stirred for 6 hours at 60° C. The reaction mixture was concentrated under reduced pressure to give 9-bromo-7-cyclopropyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-ylmethanesulfonic acid (385 mg, crude) as a yellow solid.

[0135] The following examples further illustrate some embodiments of the present invention and are not intended to limit the scope of the invention.

[0136] Example 1 7-methyl-9-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [ka] To a solution of 9-acetyl-7-methyl-2-(1-piperidyl)pyrido[1,2-a]pyrimidin-4-one (100 mg, 350 μmol, 1.00 equiv.), aniline (32.6 mg, 350 μmol, 32.0 μL, 1.00 equiv.) in methanol (1.00 mL) was added acetic acid (21.0 mg, 350 μmol, 20.0 μL, 1.00 equiv.), and the mixture was heated to 50°C and stirred at 50°C for 2 hours. The mixture was then cooled to 25°C, sodium cyanoborohydride (66.0 mg, 1.05 mmol, 3.00 equiv.) was added, and the mixture was stirred at 40°C for an additional 2 hours. After completion of the reaction, the mixture was cooled to 25°C, poured into saturated aqueous sodium bicarbonate (10.0 mL), and extracted with ethyl acetate (20.0 mL × 2). The combined organic layer was washed with brine (10.0 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was concentrated to give a residue. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18, 150 x 25 mm x 10 μm; mobile phase: Phase A: 0.225% formic acid in water, Phase B: acetonitrile; B%: 54%-84%) to give 7-methyl-9-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (25 mg, 68.0 μmol, 19.4% yield, 98.6% purity) as a yellow solid. LCMS [M+1] + =363.2 1 H NMR (400MHz, DMSO-d6)δ=8.49(s, 1H), 7.59(d, J=2.0Hz, 1H), 6.99(t, J=7.8Hz, 2H), 6.48(t, J=7.2Hz, 1H), 6.43(d, J=7.6Hz, 2H), 6.25(d, J=6.8Hz, 1H), 5.61(s, 1H), 5.09(quin, J=6.4Hz, 1H), 3.66(br t, J=4.8Hz, 4H), 2.22(s, 3H), 1.68-1.61(m, 2H), 1.56(br d, J=3.6Hz, 4H), 1.46(d, J=6.8Hz, 3H)

[0137] Example 2 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0138] Step A: To a solution of 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (360 mg, 1.26 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added sodium borohydride (95.5 mg, 2.52 mmol, 2.00 equiv), stirred at 0° C. for 1 hour, and then diluted with saturated ammonium chloride solution (1.00 mL) under a nitrogen atmosphere at 0° C. The solution was further diluted with water (15.0 mL) and extracted with dichloromethane (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The resulting residue was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 9-(1-hydroxyethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (230 mg, 728 μmol, 57.7% yield, 91.0% purity) as a yellow solid. LCMS [M+1] + =288.2

[0139] Step B: To a solution of 9-(1-hydroxyethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (166 mg, 578 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) was added phosphorus tribromide (164 mg, 607 μmol, 1.05 equiv.), and the mixture was stirred at 25° C. for 30 minutes. The mixture was poured into saturated aqueous sodium bicarbonate (10.0 mL) and extracted with dichloromethane (30.0 mL × 2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was concentrated to give 9-(1-bromoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (200 mg, crude) as a yellow oil. This was used as is.

[0140] Step C: To a solution of 9-(1-bromoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (199 mg, 568.16 μmol, 1.00 equiv.), methyl 2-aminobenzoate (258 mg, 1.70 mmol, 220 μL, 3.00 equiv.) in dimethylformamide (2.00 mL), diisopropylethylamine (220 mg, 1.70 mmol, 297 μL, 3.00 equiv.) was added and stirred at 80°C for 12 hours. After completion of the reaction, the mixture was cooled to 25°C and the pH of the mixture was adjusted to pH 5-6 with 1N hydrochloric acid (diluted with water). This solution was then extracted with dichloromethane (60 mL x 2) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (250 mg, crude) as a yellow oil, which was used as is.

[0141] Step D: To a solution of methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (250 mg, 594 μmol, 1.00 equiv.) in a mixture of methanol (1.00 mL), tetrahydrofuran (1.00 mL), and water (0.5 mL), lithium hydroxide (28.5 mg, 1.19 mmol, 2.00 equiv.) was added and stirred at 45°C for 12 hours. The mixture was then cooled to 25°C, and the pH of the mixture was adjusted to pH 5-6 with hydrochloric acid (1N, diluted with water). The solution was then extracted with dichloromethane (60.0 mL × 2), and the combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative HPLC (Phenomenex Synergi C18 150 x 25 mm x 10 μm; mobile phase: Phase A: 0.225% formic acid in water, Phase B: acetonitrile; B%: 51%-81%) to give 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (15.0 mg, 36.6 μmol, 6.16% yield, 99.3% purity) as a yellow solid. LCMS [M+1] + =407.3 1 H NMR(400MHz, CDCl3)δ=8.68(s, 1H), 8.25(s, 1H), 8.05(dd, J=1.2, 8.0Hz, 1H), 7.50(d, J=1.6Hz, 1H), 7.27-7.21(m, 1H), 6.63(t, J=7.6Hz, 1H), 6.33(d, J=8.4Hz, 1H), 5.81(s, 1H), 5.30(quin, J=6.4Hz, 1H), 3.71(s, 4H), 2.26(s, 3H), 1.80-1.67(m, 4H), 1.66(s, 3H), 1.65(s, 2H)

[0142] Examples 3-1 and 3-2 (R)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid and (S)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0143] Step A: A mixture of tert-butyl 2-aminobenzoate (1.03 g, 5.34 mmol, 973 μL, 1.70 equiv.) and 9-(1-bromoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.10 g, 3.14 mmol, 1.00 equiv.) in dimethylformamide (6.00 mL) was stirred at 80° C. for 5 hours. After completion of the reaction, the mixture was cooled to 25°C, and the reaction mixture was then filtered and purified by preparative HPLC (Column: Phenomenex luna C18 150 x 40 mm x 15 um; Mobile phase: Phase A: 0.225% formic acid in water, Phase B: acetonitrile; B%: 87%-100%) to give tert-butyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (500 mg, 1.08 mmol, 34.4% yield) as a pale yellow solid. LCMS [M+Na] + =463.2

[0144] Step B: To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (500 mg, 1.08 mmol, 1.00 equiv) in dichloromethane (3.00 mL) was added trifluoroacetic acid (1.50 mL) dropwise. The mixture was stirred at 20° C. for 16 hours and then concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 40 mm x 15 μm; mobile phase: [Phase A: 0.225% formic acid in water, Phase B: acetonitrile]; B%: 51%-81%) to give 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (320 mg, 787 μmol, 72.8% yield) as a white solid. LCMS [M+1] + =407.1

[0145] Step C: 2-((1-(7-Methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (320 mg) was purified by preparative HPLC (Column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 um); Mobile phase: Phase A: acetonitrile, Phase B: 0.1% ammonium hydroxide / isopropanol; B%: 50%) to give the first eluting enantiomer (130 mg, 307 μmol, 39.1% yield, 96.5% purity) as a white solid. SFC: Rt=1.573 min, LCMS [M+1] + =407.2 1H NMR(400MHz, CDCl3)δ=8.67(s, 1H), 8.21(br d, J=1.2Hz, 1H), 8.04(dd, J=1.6, 8.0Hz, 1H), 7.49(d, J=1.6Hz, 1H), 7.27-7.20(m, 1H), 6.63(t, J=7.6Hz, 1H), 6.33(d, J=8.8Hz, 1H), 5.78(s, 1H), 5.33(br d, J=6.4Hz, 1H), 3.70(br s, 4H), 2.26(s, 3H), 1.77-1.70(m, 2H), 1.69-1.61(m, 7H) SFC column: IC-3 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A: CO2, Phase B: Methanol (0.05% DEA); Gradient: Methanol (0.05% DEA) / CO2 = 5% to 40%, Flow rate: 3 mL / min; Detection: PDA, Column temperature: 35 °C; Back pressure: 100 Bar The second eluting enantiomer (125.9 mg, 308 μmol, 39.1% yield, 99.4% purity) was obtained as an off-white solid. SFC: Rt=2.20 min, LCMS [M+1] + =407.2 1 H NMR(400MHz, CDCl3)δ=8.66(s, 1H), 8.32-8.07(m, 1H), 8.03(d, J=8.0Hz, 1H), 7.49(d, J=1.6Hz, 1H), 7.26-7.22(m, 1H), 6.63(t, J=7.6Hz, 1H), 6.33(d, J=8.8Hz, 1H), 5.78(s, 1H), 5.32(br d, J=6.4Hz, 1H), 3.70(br s, 4H), 2.26(s, 3H), 1.77-1.70(m, 2H), 1.70-1.60(m, 7H) Identification by SFC: Column: IC-3 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A: CO2, Phase B: Methanol (0.05% DEA); Gradient: Methanol (0.05% DEA) / CO2 = 5% to 40%, Flow rate: 3 mL / min; Detection: PDA, Column temperature: 35 °C; Back pressure: 100 Bar

[0146] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77]

[0147] Example 4-1 N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acrylamide [ka]

[0148] Step A: To a solution of 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (400 mg, 1.40 mmol, 1.00 equiv) in methanol (4.00 mL) was added ammonium acetate (1.08 g, 14.0 mmol, 10.0 equiv) and acetic acid (84.18 mg, 1.40 mmol, 80.17 μL, 1.00 equiv) and heated at 65° C. for 1 hour. Sodium cyanoborohydride (106 mg, 1.68 mmol, 1.20 equiv) was then added in one portion to the mixture and heated at 65° C. for 1 hour. After heating was complete, the mixture was cooled to 25° C., quenched with saturated aqueous ammonium chloride (1.00 mL), and diluted with water (5.00 mL). The mixture was then extracted with dichloromethane (20.0 mL x 2), and the combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (conditions: Welch Ultimate XB-C18 20-35 μm; 100 Å, mobile phase: Phase A: 0.225% formic acid in water, Phase B: acetonitrile; B%: 5-100%) to give 9-(1-aminoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (80.0 mg, 279 μmol, 19.9% ​​yield) as a green solid. LCMS [M+1]+: 287.2

[0149] Step B: To a solution of 9-(1-aminoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (50.0 mg, 175 μmol, 1.00 equiv.), triethylamine (35.3 mg, 349 μmol, 48.6 μL, 2.00 equiv.) in dichloromethane (1.00 mL) was added acryloyl chloride (17.4 mg, 192 μmol, 15.7 μL, 1.10 equiv.) dropwise at 0° C., and the mixture was then warmed to 20° C. and stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative HPLC (basic conditions: column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: Phase A: 0.1% aqueous ammonium hydroxide solution (v / v), Phase B: acetonitrile; B%: 25% to 55%) to obtain N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acrylamide (5.64 mg, 16.4 μmol, yield 9.38%, purity 98.9%) as a white solid. LCMS [M+1] + : 341.0 1 H NMR (400MHz, DMSO-d6)δ=8.56(d, J=7.6Hz, 1H), 8.52(s, 1H), 7.51(d, J=2.0Hz, 1H), 6.32(dd, J=10.0, 17.2Hz, 1H), 6.09(dd, J=2.0, 17.2Hz, 1H), 5.64-5.60(m, 1H), 5.59(s, 1H), 5.52(quin, J=7.2Hz, 1H), 3.63(br s, 4H), 2.29(d, J=0.8Hz, 3H), 1.67-1.59(m, 2H), 1.53(br d, J=4.4Hz, 4H), 1.42(d, J=7.2Hz, 3H) 1H NMR (400MHz, DMSO-d6, T=80℃)δ=8.52(s, 1H), 8.26(br d, J=5.6Hz, 1H), 7.55(s, 1H), 6.36-6.26(m, 1H), 6.10(dd, J=1.6, 17.2Hz, 1H), 5.62-5.53(m, 3H), 3.66-3.61(m, 4H), 2.30(s, 3H), 1.70-1.62(m, 2H), 1.61-1.53(m, 4H), 1.46(d, J=6.8Hz, 3H)

[0150] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 78]

[0151] Examples 5-1 and 5-2 (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid and (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0152] Preparation of 2-methylmalonyl dichloride: To a solution of 2-methylmalonic acid (10.0 g, 84.7 mmol, 6.85 mL, 1.00 equiv) in dichloromethane (10.0 mL), N,N-dimethylformamide (309 mg, 4.23 mmol, 326 μL, 0.05 equiv) and oxalyl chloride (16.1 g, 127 mmol, 11.1 mL, 1.50 equiv) were added and stirred for 2 hours at 25° C. The reaction mixture was concentrated under reduced pressure to give 2-methylmalonyl dichloride (13.26 g, crude) as a yellow solid.

[0153] Step A: To a solution of 2-methylmalonyl dichloride (13.3 g, 85.5 mmol, 1.00 equiv.) in dichloromethane (20.0 mL) was added 3-bromo-5-methylpyridin-2-amine (16.0 g, 85.5 mmol, 1.00 equiv.) at 0° C. and stirred at 25° C. for 12 hours. The reaction mixture was then cooled to 20° C., and the resulting precipitate was filtered. The filter cake was washed with dichloromethane (50.0 mL), and the resulting crude product was triturated with dichloromethane at 25° C. for 1 hour and dried under vacuum to give 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (7.00 g, 25.8 mmol, 30.1% yield, 99.0% purity) as a white solid. LCMS [M+3] + =270.8 1 H NMR (400MHz, DMSO-d6)δ=8.70(s, 1H), 8.21(d, J=1.6Hz, 1H), 2.34(s, 3H), 1.96(s, 3H)

[0154] Step B: To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.00 g, 7.43 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL), methanesulfonic anhydride (2.59 g, 14.9 mmol, 2.00 equiv) and triethylamine (2.26 g, 22.3 mmol, 3.10 mL, 3.00 equiv) were added and stirred at 60° C. for 12 hours. The resulting mixture was then treated with saturated aqueous sodium bicarbonate (10.0 mL), and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 9-bromo-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-ylmethanesulfonic acid (2.10 g, 5.99 mmol, 80.6% yield, 99.0% purity) as a yellow solid. LCMS [M+3] + =348.8

[0155] Step C: A solution of 9-bromo-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-ylmethanesulfonic acid (2.1 g, 6.05 mmol, 1.00 equiv.) in N,N-dimethylformamide (15.0 mL) was added to 4,4-dimethylpiperidine (1.37 g, 12.1 mmol, 2.00 equiv.), 4 Å molecular sieves (5.00 mg, 6.05 mmol, 1.00 equiv.), and triethylamine (1.84 g, 18.1 mmol, 2.53 mL, 3.00 equiv.) and stirred at 40 °C for 12 h. The mixture was diluted with water (15.0 mL) and extracted with dichloromethane (15.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase flash column chromatography (0.1% aqueous formic acid / acetonitrile). The desired fractions were collected, neutralized with solid sodium bicarbonate, and concentrated under vacuum. This aqueous mixture was then extracted with ethyl acetate (10.0 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.97 g, 2.64 mmol, 43.6% yield, 99.0% purity) as a yellow solid. LCMS [M+3] + =365.8 1 H NMR (400MHz, DMSO-d6)δ=8.61(s, 1H), 8.13(d, J=1.6Hz, 1H), 3.47-3.41(m, 4H), 2.31(s, 3H), 2.04(s, 3H), 1.45-1.41(m, 4H), 0.98(s, 6H)

[0156] Step D: A mixture of 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 1.37 mmol, 1.00 equiv), tributyl(1-ethoxyvinyl)tin (991 mg, 2.75 mmol, 927 μL, 2.00 equiv), and bis(triphenylphosphine)palladium(II) dichloride (96.3 mg, 137 μmol, 0.10 equiv) was evacuated and refilled with nitrogen three times, then toluene (5.00 mL) was added and the mixture was stirred under a nitrogen atmosphere at 90° C. for 12 hours. The reaction mixture was quenched with water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(4,4-dimethylpiperidin-1-yl)-9-(1-ethoxyvinyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.5 g, crude) as a yellow solid.

[0157] Step E: To a solution of 2-(4,4-dimethylpiperidin-1-yl)-9-(1-ethoxyvinyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (490 mg, 1.38 mmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added hydrochloric acid (4 M, dioxane solution, 1.00 mL, 2.90 equiv), and the mixture was stirred at 25° C. for 1 hour. The mixture was then treated with saturated aqueous sodium bicarbonate (10.0 mL), and the aqueous layer was extracted with ethyl acetate (3×10.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (190 mg, 516 μmol, 37.5% yield, 89% purity) as a yellow solid. LCMS [M+1] + =327.9

[0158] Step F: To a solution of 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (360 mg, 1.10 mmol, 1.00 equiv) in dichloromethane (3.00 mL) and ethanol (3.00 mL) was added sodium borohydride (52.2 mg, 1.38 mmol, 1.25 equiv) at −10° C. and stirred for 1 hour at −10° C. The mixture was quenched with saturated aqueous ammonium chloride (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(4,4-dimethylpiperidin-1-yl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (320 mg, crude) as a yellow solid. LCMS [M+1] + =330.3

[0159] Step G: To a solution of 2-(4,4-dimethylpiperidin-1-yl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 304 μmol, 1.00 equivalents) in dichloromethane (1.00 mL), phosphorus tribromide (164 mg, 607 μmol, 2.00 equivalents) was added at 0° C. and stirred at 25° C. for 5 hours to give 9-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (120 mg, crude) as a yellow liquid.

[0160] Step H: To a solution of tert-butyl 2-aminobenzoate (98.5 mg, 510 μmol, 92.9 μL, 2.00 equiv.) in dimethylformamide (0.50 mL), diisopropylethylamine (98.8 mg, 765 μmol, 133 μL, 3.00 equiv.) and 9-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 254.89 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) were added at 0° C. The pH of the reaction was adjusted to pH 3-4 and stirred at 60° C. for 12 hours. Diisopropylethylamine (329 mg, 2.54 mmol, 443 μL, 10.0 equiv.) was then added to the reaction mixture, and the pH was adjusted to pH 8-9. The reaction was stirred at 60°C for 3 hours, and the mixture was stirred at 60°C for 12 hours. The resulting residue was purified by preparative HPLC (column: Waters XBridge 150 × 25 mm 10 μm; mobile phase: Phase A: 0.1% aqueous ammonium carbonate, Phase B: acetonitrile; B%: 28%-58%). The desired fractions were collected and the aqueous layer was lyophilized to give 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (20 mg, 42.8 μmol, 16.8% yield, 96% purity) as a yellow solid. LCMS [M+1] + =449.0 The resulting residue was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: Phase A: acetonitrile, Phase B: ammonium hydroxide / isopropyl alcohol; B%: 40%) to obtain the first eluted enantiomer (4.14 mg, 8.68 μmol, 19.5% yield, purity 94.0%) as a yellow solid, and the second eluted enantiomer (5.07 mg, 10.62 μmol, 23.8% yield, purity 94.0%) as a yellow solid. Spectral data for the first eluting enantiomer: 1H NMR(400MHz, CD3OD)δ=8.60(s, 1H), 7.91(d, J=7.6Hz, 1H), 7.59(s, 1H), 7.15(t, J=8.0Hz, 1H), 6.54(t, J=7.6Hz, 1H), 6.33(d, J=8.4Hz, 1H), 5.41(q, J=6.4Hz, 1H), 3.55(br t, J=5.6Hz, 4H), 2.29(s, 3H), 2.18(s, 3H), 1.64(d, J=6.4Hz, 3H), 1.54(q, J=5.2Hz, 4H), 1.05(s, 6H); LCMS[M+1] + =449.4 Spectral data for the second eluting enantiomer: 1 H NMR (400MHz, methanol-d4)δ=8.60(s, 1H), 7.91(dd, J=1.6, 8.0Hz, 1H), 7.60(d, J=1.8Hz, 1H), 7.17-7.11(m, 1H), 6.54(t, J=7.2Hz, 1H), 6.32(d, J=8.4Hz, 1H), 5.43-5.37(m, 1H), 3.55(br t, J=5.6Hz, 4H), 2.29(s, 3H), 2.18(s, 3H), 1.64(d, J=6.4Hz, 3H), 1.54(br d, J=5.2Hz, 4H), 1.05(s, 6H); LCMS[M+1] + =449.3

[0161] Example 5-3 2-((1-(7-cyclopropyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0162] Step A: A solution of 9-bromo-7-cyclopropyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl methanesulfonic acid (385 mg, 1.07 mmol, 1.00 equiv) in dimethylformamide (4.00 mL) was added to diisopropylethylamine (416 mg, 3.22 mmol, 560 μL, 3.00 equiv), piperidine (183 mg, 2.14 mmol, 212 μL, 2.00 equiv), and 4 Å molecular sieves (5.00 mg, 1.07 mmol, 1.00 equiv) and stirred at 40 °C for 1 h. The mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-bromo-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (290 mg, 816.11 μmol, 76.14% yield, 98% purity) as a yellow solid. LCMS [M+3] + =350.0 1 H NMR (400MHz, DMSO-d6)δ=8.55(d, J=1.8Hz, 1H), 7.95(d, J=2.0Hz, 1H), 5.59(s, 1H), 3.66(br s, 4H), 2.10-2.01(m, 1H), 1.67-1.61(m, 2H), 1.55(m, 4H), 0.98-0.92(m, 2H), 0.80-0.73(m, 2H)

[0163] Step B: A mixture of 9-bromo-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (290 mg, 833 μmol, 1.00 equiv.), tributyl(1-ethoxyvinyl)tin (610 mg, 1.69 mmol, 570 μL, 2.03 equiv.), and bis(triphenylphosphine)palladium(II) dichloride (58.5 mg, 83.3 μmol, 0.10 equiv.) was evacuated and refilled with nitrogen three times, then toluene (3.00 mL) was added and stirred under a nitrogen atmosphere at 90° C. for 12 hours. The mixture was then diluted with water (3.00 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-cyclopropyl-9-(1-ethoxyvinyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (300 mg, crude) as a yellow solid.

[0164] Step C: To a solution of 7-cyclopropyl-9-(1-ethoxyvinyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (300 mg, 884 μmol, 1.00 equiv.) in tetrahydrofuran (3.00 mL), HCl (4 M, 0.60 mL, 2.72 equiv.) was added and stirred at 25° C. for 1 hour. The mixture was treated with saturated aqueous sodium bicarbonate (5.00 mL), and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1, 1 / 1) to give 9-acetyl-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (120 mg, 382 μmol, 43.2% yield, 99% purity) as a green solid. LCMS [M+1] + =312.0

[0165] Step D: To a solution of 9-acetyl-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (80 mg, 257 μmol, 1.00 equiv.) in dichloromethane (0.20 mL) and ethanol (0.20 mL), sodium borohydride (12.2 mg, 321 μmol, 1.25 equiv.) was added at 0° C. and stirred at 0° C. for 30 minutes. The mixture was then treated with saturated aqueous ammonium chloride (5.00 mL) and extracted with ethyl acetate (5.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-cyclopropyl-9-(1-hydroxyethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (72 mg, crude) as a yellow solid. LCMS [M+1] + =314.2

[0166] Step E: To a solution of 7-cyclopropyl-9-(1-hydroxyethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (72 mg, 230 μmol, 1.00 equiv) in dichloromethane (0.50 mL) was added thionyl chloride (82.0 mg, 689 μmol, 50.0 μL, 3.00 equiv) at 0° C. and stirred for 3 hours at 25° C. The reaction mixture was then concentrated under reduced pressure to give crude 9-(1-chloroethyl)-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (76 mg) as a yellow solid.

[0167] Step F: To a solution of tert-butyl 2-aminobenzoate (88.5 mg, 458 μmol, 83.5 μL, 2.00 equiv.) and diisopropylethylamine (88.8 mg, 687 μmol, 120 μL, 3.00 equiv.) in dimethylformamide (1.00 mL), potassium iodide (1.90 mg, 11.5 μmol, 0.05 equiv.) and 9-(1-chloroethyl)-7-cyclopropyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (76 mg, 229 μmol, 1.00 equiv.) in dimethylformamide (1.00 mL) was added at 0 ° C. and stirred at 80 ° C. for 12 hours. The resulting residue was purified by reverse-phase column chromatography [water (0.1% formic acid) / acetonitrile]. The desired fractions were collected, neutralized with solid sodium bicarbonate, and concentrated under reduced pressure to remove any volatiles. The aqueous layer was extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2-((1-(7-cyclopropyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (45 mg, 80.1 μmol, 35.0% yield, 87% purity) as a yellow solid. LCMS [M+1] + =489.3

[0168] Step G: A mixture of tert-butyl 2-((1-(7-cyclopropyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35.0 mg, 71.6 μmol, 1.00 equiv) and trifluoroacetic acid (770 mg, 6.75 mmol, 0.50 mL, 94.3 equiv) was stirred at 25° C. for 6 hours. The reaction mixture was then concentrated under reduced pressure and treated with saturated aqueous sodium bicarbonate (5.00 mL). The aqueous layer was extracted with ethyl acetate (3×5.00 mL), and the combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 um; mobile phase: Phase A: 0.1% aqueous ammonium bicarbonate, Phase B: acetonitrile; B%: 23%-53%). The desired fractions were collected and lyophilized to give 2-((1-(7-cyclopropyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (9.45 mg, 20.7 μmol, 28.9% yield, 94.8% purity) as a yellow solid. LCMS [M+1] + =433.2 1 H NMR(400MHz, CD3OD)δ=8.49(d, J=1.6Hz, 1H), 7.92(dd, J=1.6, 8.0Hz, 1H), 7.45(s, 1H), 7.21-7.13(m, 1H), 6.56(t, J=7.6Hz, 1H), 6.30(br d, J=7.6Hz, 1H), 5.73(s, 1H), 5.30(q, J=7.2Hz, 1H), 3.78-3.73(m, 4H), 1.89(m, 1H), 1.80-1.72(m, 2H), 1.67(br d, J=4.0Hz, 4H), 1.62(d, J=6.4Hz, 3H), 0.98-0.89(m, 2H), 0.69-0.60(m, 1H), 0.56-0.45(m, 1H)

[0169] Examples 5-4 and 5-5 (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid and (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka] To a solution of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (237 mg, 474 μmol, 98.0% purity, 1.00 equiv) in dichloromethane (2.00 mL) was added trifluoroacetic acid (54.0 mg, 474 μmol, 35.1 μL, 1.00 equiv) and stirred at 25° C. for 4 hours. After purging with nitrogen, the mixture was concentrated to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: Phase A: 0.1% formic acid in water, Phase B: acetonitrile; B%: 56%-86%) to give 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (60.0 mg, 137 μmol, 28.8% yield, 98.9% purity) as a white solid. LCMS [M+1] + =435.2

[0170] The enantiomers were separated by the following procedure. 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (60.0 mg) was purified by chiral preparative HPLC (Column: REGIS(S,S)WHELK-O1 (250 mm × 25 mm, 10 μm); Mobile phase: Phase A: acetonitrile, Phase B: 0.1% ammonium hydroxide / methanol; B%: 40% to 40%, 5.2 min), and the first eluting enantiomer (22.9 mg, 51.1 μmol, 37.7% yield, 96.8% purity) was obtained as a white solid (SFC, R t = 1.246 min), the second eluting isomer (23.9 mg, 54.4 μmol, 40.2% yield, 98.7% purity) was obtained as a pale yellow solid (SFC, R t = 1.505 min).

[0171] Identification of the first eluting isomer (Example 5-4): LCMS [M+1] + =435.2 1 H NMR (400MHz, DMSO-d6)δ=8.65-8.45(m, 2H), 7.81(dd, J=1.2, 7.6Hz, 1H), 7.56(d, J=1.6Hz, 1H), 7.20(br t, J=7.2Hz, 1H), 6.53(t, J=7.2Hz, 1H), 6.33(br d, J=8.4Hz, 1H), 5.64(s, 1H), 5.21(br d, J=6.4Hz, 1H), 3.66(br s, 4H), 2.23(s, 3H), 1.57(d, J=6.4Hz, 3H), 1.40-1.35(m, 4H), 0.99(s, 6H) Analytical SFC conditions: Column: Kromasil (S,S) Whelk-O1 50 x 4.6 mm ID, 3.5 um; Mobile phase: Phase A: CO2, Phase B: Methanol + Acetonitrile (0.05% DEA); 40% B / CO2; Flow rate: 3 mL / min; Detection: PDA; Column temperature: 35 °C; Back pressure: 100 Bar (SFC R t =1.246 minutes)

[0172] Identification of the second eluting isomer (Example 5-5): LCMS [M+1] + =435.2 1 H NMR (400MHz, DMSO-d6)δ=8.52(s, 1H), 8.45(br s, 1H), 7.81(dd, J=1.2, 8.0Hz, 1H), 7.56(d, J=1.6Hz, 1H), 7.22(br t, J=7.6Hz, 1H), 6.54(t, J=7.6Hz, 1H), 6.34(br d, J=8.4Hz, 1H), 5.64(s, 1H), 5.28-5.13(br d, J=4.4Hz, 1H), 3.66(br s, 4H), 2.23(s, 3H), 1.57(d, J=6.4Hz, 3H), 1.37(br t, J=5.6Hz, 4H), 0.98(s, 6H) Analytical SFC conditions: Column: Kromasil (S,S) Whelk-O1 50 x 4.6 mm ID, 3.5 um; Mobile phase: Phase A: CO2, and Phase B: methanol + acetonitrile (0.05% DEA); 40% B / CO2; Flow rate: 3 mL / min; Detection: PDA; Column temperature: 35 °C; Back pressure: 100 Bar (SFC R t =1.505 minutes)

[0173] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 79] [Table 80] [Table 81]

[0174] Example 6-1 2-((1-(2,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0175] Step A: A mixture of 3-bromo-5-methyl-pyridin-2-amine (2.42 g, 12.9 mmol, 0.500 equiv.), methyl 3-oxobutanoate (3.00 g, 25.8 mmol, 2.78 mL, 1.00 equiv.), and bismuth(III) chloride (204 mg, 646 μmol, 42.9 μL, 0.03 equiv.) was stirred at 120° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to 25° C., and ethanol (3.00 mL) was added to the solution. A brown precipitate formed, which was collected by filtration and dried under vacuum to give 9-bromo-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.85 g, 7.31 mmol, 28.3% yield) as a brown solid. LCMS [M+3] + =254.9 1 H NMR (400MHz, DMSO-d6)δ=8.77(s, 1H), 8.31(d, J=1.6Hz, 1H), 6.34(s, 1H), 2.39(s, 3H), 2.37(s, 3H)

[0176] Step B: A mixture of 9-bromo-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (400 mg, 1.58 mmol, 1.00 equiv.), n-butyl vinyl ether (475 mg, 4.74 mmol, 610 μL, 3.00 equiv.), diisopropylethylamine (613 mg, 4.74 mmol, 826 μL, 3.00 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (129 mg, 158 μmol, 0.100 equiv.) was evacuated and refilled with nitrogen three times. n-Butanol (5.00 mL) was then added, and the mixture was stirred at 120 °C for 12 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to 25° C. to give crude 9-(1-ethoxyvinyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (380 mg, 1.56 mmol, 98.4% yield) as a brown oil, which was used as is.

[0177] Step C: A mixture of 9-(1-ethoxyvinyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (380 mg, 1.56 mmol, 1.00 equiv.) in hydrochloric acid (3 M, diluted with water, 2.59 mL, 5.00 equiv.) was stirred at 25 °C for 1 h. The mixture was then diluted with water (30.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layers were washed with water (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 9-acetyl-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (180 mg, 821 μmol, 52.8% yield, 98.6% purity) as a yellow solid. LCMS[M+1] + =217.1

[0178] Step D: To a solution of 9-acetyl-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (180 mg, 832 μmol, 1.00 equiv.) in a mixture of dichloromethane (1.00 mL) and methanol (1.00 mL) was added sodium borohydride (63.0 mg, 1.66 mmol, 2.00 equiv.) at −20°C under a nitrogen atmosphere, and the mixture was stirred at −20°C for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution (20.0 mL) was added dropwise at 0°C to quench the reaction. The resulting solution was then diluted with water (30.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 to 3 / 1) to give 9-(1-hydroxyethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 596 μmol, 71.6% yield) as a white solid. LCMS [M+H] + =219.2

[0179] Step E: To a solution of 9-(1-hydroxyethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 596 μmol, 1.00 equiv.) in dichloromethane (1.50 mL) was added phosphorus tribromide (242 mg, 893 μmol, 1.50 equiv.) at 25°C, and the mixture was stirred at 40°C for 3 hours. The mixture was then cooled to 25°C and adjusted to pH 8 with saturated aqueous sodium bicarbonate. The solution was extracted with dichloromethane (10.0 mL × 3), and the combined organic layers were washed with brine (5.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-(1-bromoethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (160 mg, 569 μmol, 95.5% yield) as a white solid. This was used directly in the next step.

[0180] Step F: To a solution of 9-(1-bromoethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (160 mg, 569 μmol, 1.00 equiv) in dimethylformamide (2.00 mL) was added 2-aminobenzoic acid (370 mg, 2.70 mmol, 4.74 equiv) at 25° C., followed by stirring at 80° C. for 1 hour. The mixture was then cooled to 25° C., diluted with ethyl acetate (60.0 mL), and the organic solvent was washed with brine (20.0 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (column: Waters X bridge 150 x 25 mm x 5 μm; mobile phase: Phase A: 0.1% aqueous ammonium hydroxide, Phase B: acetonitrile; B%: 1% to 31%) to give 2-((1-(2,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (30.8 mg, 88.1 μmol, 15.5% yield, 96.4% purity) as a white solid. LCMS [M+1] + =338.1 1H NMR (400MHz, DMSO-d6)δ=9.08-8.77(m, 1H), 8.69(s, 1H), 7.81(dd, J=8.0, 1.6Hz, 1H), 7.71(d, J=2.0Hz, 1H), 7.16-7.08(m, 1H), 6.49(t, J=7.2Hz, 1H), 6.36-6.26(m, 2H), 5.35(q, J=6.4Hz, 1H), 2.44(s, 3H), 2.30(s, 3H), 1.57(d, J=6.8Hz, 3H)

[0181] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 82]

[0182] Example 7-1 2-((1-(7-methyl-4-oxo-2-phenyl-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0183] Step A: To a solution of 3-bromo-5-methylpyridin-2-amine (1.00 g, 5.35 mmol, 1.00 equiv) in glycol (10.00 mL) was added methyl 3-phenylpropiolate (1.28 g, 8.02 mmol, 1.50 equiv) at 25° C. and stirred at 100° C. for 5 hours. The mixture was then cooled to 25° C., and ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 9-bromo-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.20 g, 3.74 mmol, 70.0% yield, 98.3% purity) as a yellow solid. LCMS [M+1] + =315.0 1 H NMR (400MHz, DMSO-d6)δ=8.13(d, J=1.6Hz, 1H), 7.65-7.58(m, 5H), 7.51 (s, 1H), 6.27(s, 1H), 2.09(s, 3H)

[0184] Step B: A mixture of 9-bromo-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (830 mg, 2.63 mmol, 1.00 equiv.), 1-vinyloxybutane (791 mg, 7.90 mmol, 1.02 mL, 3.00 equiv.), N,N-diisopropylethylamine (1.02 g, 7.90 mmol, 1.38 mL, 3.00 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (193 mg, 263 μmol, 0.10 equiv.) was evacuated and refilled with nitrogen three times. n-Butanol (1.00 mL) was then added, and the mixture was stirred at 120 °C for 12 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to 25°C, and HCl (3M, diluted with water, 1.00 mL) was added. The mixture was then stirred at 25°C for 1 hour. The mixture was further diluted with water (30.0 mL) and then extracted with dichloromethane (30.0 mL x 3). The combined organic layers were washed with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 9-acetyl-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (135 mg, 485 μmol, 18.4% yield) as a yellow solid. LCMS [M+1] + =279.1

[0185] Step C: To a solution of 9-acetyl-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 467 μmol, 1.00 equiv.) in a mixture of dichloromethane (1.00 mL) and methanol (1.00 mL) was added sodium borohydride (87.2 mg, 934 μmol, 2.00 equiv.) at −20°C under a nitrogen atmosphere and stirred at −20°C for 1 hour. Ammonium chloride solution (saturated aqueous solution, 50.0 mL) was then added dropwise at 0°C. The resulting mixture was diluted with water (30.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layer was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 9-(1-hydroxyethyl)-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (90.0 mg, 321 μmol, 68.7% yield) as a yellow solid. LCMS [M+1] + =281.1

[0186] Step D: To a solution of 9-(1-hydroxyethyl)-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (90.0 mg, 321 μmol, 1.00 equivalents) in dichloromethane (1.00 mL) was added phosphorus tribromide (130 mg, 482 μmol, 1.50 equivalents) at 25° C., and the mixture was then stirred, warmed to 40° C., and stirred at 40° C. for 3 hours. The pH of the mixture was then adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (15.0 mL×3). The combined organic layers were washed with brine (5.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-(1-bromoethyl)-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (110 mg, 321 μmol, 99.8% yield) as a yellow solid.

[0187] Step E: A solution of 9-(1-bromoethyl)-7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (110 mg, 321 μmol, 1.00 equiv) and 2-aminobenzoic acid (87.0 mg, 634 μmol, 1.98 equiv) in dimethylformamide (1.00 mL) was stirred at 70° C. for 1 hour. The mixture was then cooled to 25° C., diluted with ethyl acetate (60.0 mL), and washed with brine (30.0 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative HPLC (column: Waters X bridge, 150 x 25 mm x 5 μm; mobile phase: Phase A: 0.1% aqueous ammonium hydroxide, Phase B: acetonitrile; B%: 9%-39%) to give 2-((1-(7-methyl-4-oxo-2-phenyl-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (17.6 mg, 43.7 μmol, 13.6% yield, 99.4% purity) as a yellow solid. LCMS [M+1] + =400.3 1 H NMR (400MHz, DMSO-d6)δ=8.75(s, 1H), 8.72-8.61(m, 1H), 8.32-8.24(m, 2H), 7.83(dd, J=8.0, 1.6Hz, 1H), 7.76(d, J=2.0Hz, 1H), 7.59-7.49(m, 3H), 7.19-7.11(m, 1H), 7.04(s, 1H), 6.52(t, J=7.6Hz, 1H), 6.38(d, J=8.4Hz, 1H), 5.55(q, J=6.4Hz, 1H), 2.34(s, 3H), 1.67(d, J=6.4Hz, 3H)

[0188] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 83]

[0189] Example 8-1 2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0190] Step A: To a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (10.0 g, 39.2 mmol, 1.00 equiv) in dimethylformamide (100 mL) was added phosphoryl chloride (18.0 g, 117 mmol, 10.9 mL, 3.00 equiv) at 0 °C, heated to 80 °C, and stirred at 80 °C for 5 hours. The mixture was cooled and concentrated under reduced pressure to give a residue. This residue was diluted with water (50.0 mL) and extracted with dichloromethane (50.0 mL × 3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was triturated with dichloromethane (15.00 mL) to give 9-bromo-2-chloro-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (2.00 g, 3.65 mmol, 4.65% yield, 54.8% purity) as a brown solid. LCMS [M+1] + =302.9

[0191] Step B: To a solution of 9-bromo-2-chloro-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (2.00 g, 6.63 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL), piperidine (1.69 g, 19.9 mmol, 1.97 mL, 3.00 equiv) and diisopropylethylamine (857 mg, 6.63 mmol, 1.16 mL, 1.00 equiv) were added and stirred at 70 °C for 3 hours. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1, 3 / 1) to give 9-bromo-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (1.00 g, 2.68 mmol, 40.5% yield, 94.0% purity) as a yellow solid. LCMS [M+1] + =352.1

[0192] Step C: To a solution of 9-bromo-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (2.00 g, 5.71 mmol, 1.00 equivalents) in acetic acid (2.00 mL) and water (8.00 mL) was added hydroxylamine-O-sulfonic acid (969 mg, 8.57 mmol, 1.50 equivalents) at 0° C. The mixture was heated to 60° C. and stirred at 60° C. for 12 hours. The mixture was filtered to obtain a residue. The residue was triturated with ethyl acetate (3.00 mL) to give 9-bromo-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (1.00 g, 2.76 mmol, 48.4% yield, 90.0% purity) as a yellow solid. LCMS [M+1] + =349.1

[0193] Step D: A mixture of 9-bromo-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (1.00 g, 2.88 mmol, 1.00 equiv.), tributyl(1-ethoxyvinyl)tin (2.08 g, 5.76 mmol, 1.94 mL, 2.00 equiv.), and bis(triphenylphosphine)palladium(II) dichloride (202 mg, 288 μmol, 0.100 equiv.) was evacuated and refilled with nitrogen three times. Toluene (10 mL) was then added, and the mixture was stirred under a nitrogen atmosphere at 95° C. for 20 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 9-(1-ethoxyvinyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (510 mg, crude) as a yellow solid. LCMS [M+1] + =339.0

[0194] Step E: To a solution of 9-(1-ethoxyvinyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (800 mg, 2.36 mmol, 1.00 equiv) in dichloromethane (4.00 mL) was added trifluoroacetic acid (6.16 g, 54.0 mmol, 4.00 mL, 22.9 equiv) and stirred at 0° C. for 2 hours. The mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (3×15.0 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1, 3 / 1) to give 9-acetyl-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (480 mg, 1.50 mmol, 63.5% yield, 97.0% purity) as a yellow solid. LCMS [M+1] + =310.8

[0195] Step F: To a solution of 9-acetyl-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (500 mg, 1.61 mmol, 1.00 equiv) in ethanol (1.00 mL) and dichloromethane (1.00 mL) was added sodium borohydride (487 mg, 12.8 mmol, 8.00 equiv), stirred at −40° C. for 1.5 hours, and quenched by the addition of ammonium chloride (5.00 mL) at 0° C. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3×20.0 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 9-(1-hydroxyethyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (480 mg, crude) as a yellow solid. LCMS [M+1] + =313.1

[0196] Step G: To a solution of 9-(1-hydroxyethyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (480 mg, 1.54 mmol, 1.00 equiv) in dichloromethane (4.00 mL) was added thionyl chloride (548 mg, 4.61 mmol, 3.00 equiv) at 0° C., heated to 25° C., and stirred at 25° C. for 1 hour. The mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (3×5.00 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 9-(1-chloroethyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (480 mg, crude) as a yellow solid. LCMS[M+1] + =331.1

[0197] Step H: To a solution of tert-butyl 2-aminobenzoate (841 mg, 4.35 mmol, 3.00 equiv) in dimethylformamide (4.00 mL) was added 9-(1-chloroethyl)-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (480 mg, 1.45 mmol, 1.00 equiv), diisopropylethylamine (938 mg, 7.25 mmol, 1.26 mL, 5.00 equiv), and potassium iodide (24.1 mg, 145 μmol, 0.100 equiv) and stirred at 40° C. for 12 hours. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1, 3 / 1) to give tert-butyl 2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 106 μmol, 7.29% yield, 86% purity) as a yellow solid. LCMS [M+1] + =488.2

[0198] Step I: To a solution of tert-butyl 2-[1-[3-cyano-7-methyl-4-oxo-2-(1-piperidyl)pyrido[1,2-a]pyrimidin-9-yl]ethylamino]benzoate (45 mg, 92.3 μmol, 1.00 equiv.) was added trifluoroacetic acid (31.6 mg, 277 μmol, 3.00 equiv.) at 0° C., warmed to 25° C., and stirred at 25° C. for 1.5 hours. The resulting mixture was concentrated and neutralized to pH=7 with ammonium hydroxide. This mixture was purified by preparative HPLC (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (NH4HCO3) / acetonitrile]; B%: 20%-50%, 8 min) to give 2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5.91 mg, 13.57 μmol, 14.7% yield, 99.1% purity) as a white solid. LCMS [M+1]+ =432.1 1 H NMR(400MHz, MeOD)δ=8.51(s, 1H), 7.94-7.89(m, 1H), 7.71(d, J=1.6Hz, 1H), 7.17(t, J=6.8Hz, 1H), 6.56(t, J=7.2Hz, 1H), 6.34-6.28(m, 1H), 5.24(q, J=7.2Hz, 1H), 4.04-4.02(m, 4H), 2.26(s, 3H), 1.82-1.72(m, 6H), 1.62(d, J=6.4Hz, 3H)

[0199] Example 9-1 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0200] Step A: To a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (80.0 g, 313 mmol, 1.00 equiv.), (bromomethyl)benzene (80.4 g, 470 mmol, 55.8 mL, 1.50 equiv.) in dimethylformamide (200 mL) was added potassium carbonate (130 g, 940 mmol, 3.00 equiv.) and stirred at 80° C. for 2 hours. After stirring was complete, the reaction mixture was cooled to 25° C., diluted with water (1000 mL), and extracted with ethyl acetate (500 mL × 3). The combined organic layer was washed with brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to give 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (47.0 g, 136 mmol, 54.0% yield, 85.7% purity) as a yellow solid. LCMS [M+1] + =347.1 1 H NMR (400MHz, DMSO-d6)δ=8.78(s, 1H), 8.37(d, J=16Hz, 1H), 7.53(br d, J=6.8Hz, 2H), 7.38(br d, J=7.3Hz, 3H), 5.74(s, 1H), 5.57-5.36(m, 2H), 2.37(s, 3H)

[0201] Step B: To a solution of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (47.0 g, 136 mmol, 1.00 equiv.) and tributyl(1-ethoxyvinyl)tin (59.0 g, 163 mmol, 55.1 mL, 1.20 equiv.), bis(triphenylphosphine)palladium(II) dichloride (4.70 g, 6.81 mmol, 0.05 equiv.) was added, and the reaction was evacuated and refilled with nitrogen three times. Dioxane (250 mL) was then added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. After stirring was complete, the reaction mixture was cooled to 25 °C, diluted with water (500 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(benzyloxy)-9-(1-ethoxyvinyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (36.0 g, 107 mmol, 78.6% yield, 71.5% purity) as a yellow solid. LCMS [M+1] + =337.2

[0202] Step C: To a solution of 2-(benzyloxy)-9-(1-ethoxyvinyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (36.0 g, 107 mmol, 1.00 equiv.) in water (100 mL) and tetrahydrofuran (100 mL) was added hydrochloric acid (4.00 M, diluted with water, 133 mL, 5.00 equiv.) and stirred at 25° C. for 2 hours. After stirring was complete, the reaction mixture was quenched at 25° C. by adding sodium bicarbonate to adjust the pH to 7. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to give 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (32.0 g, 103 mmol, 96.9% yield, 71.3% purity) as a yellow solid. LCMS [M+1] + =309.2

[0203] Step D: To a solution of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (32.0 g, 103 mmol, 1.00 equiv.) in dichloromethane (100 mL) and methanol (100 mL) was added sodium borohydride (7.85 g, 207 mmol, 2.00 equiv.) at 0° C. and stirred under a nitrogen atmosphere for 2 hours at 0° C. After stirring was complete, the reaction mixture was diluted with ammonium chloride (50.0 mL) and extracted three times with a solution (200 mL) of dichloromethane and methanol (10 / 1). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(benzyloxy)-9-(1-hydroxyethyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (32.0 g, 103 mmol, 99.3% yield, 88.0% purity) as a yellow solid. LCMS [M+1] + =311.2

[0204] Step E: To a solution of 2-(benzyloxy)-9-(1-hydroxyethyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (34.0 g, 109 mmol, 1.00 equiv.) in dichloromethane (200 mL) was added phosphorus tribromide (35.5 g, 131 mmol, 1.20 equiv.) at 0 °C, then the mixture was warmed to 25 °C and stirred for 2 h. After stirring was complete, the reaction was quenched by adding sodium bicarbonate solution to pH = 7. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(benzyloxy)-9-(1-bromoethyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (19.0 g, 50.9 mmol, 46.4% yield, 35.3% purity) as a yellow oil. LCMS [M+1] + =375.0

[0205] Step F: To a solution of 2-(benzyloxy)-9-(1-bromoethyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (19.0 g, 50.9 mmol, 1.00 equiv.), methyl 2-aminobenzoate (11.5 g, 76.3 mmol, 9.87 mL, 1.50 equiv.) in dimethylformamide (100 mL), diisopropylethylamine (19.7 g, 152 mmol, 26.6 mL, 3.00 equiv.), and potassium iodide (8.45 g, 50.9 mmol, 1.00 equiv.) were added and stirred at 70° C. for 2 hours. After stirring was complete, the reaction mixture was cooled to 25° C., diluted with water (100 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give methyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (6.00 g, 13.5 mmol, 26.6% yield, 90.2% purity) as a yellow oil. LCMS [M+1] + =444.3 1 H NMR (400MHz, DMSO-d6)δ=8.73(s, 1H), 8.27(d, J=6.8Hz, 1H), 7.82(dt, J=1.6, 4.0Hz, 2H), 7.57-7.44(m, 2H), 7.42-7.34(m, 2H), 7.34-7.28(m, 1H), 7.26-7.17(m, 1H), 6.63-6.49(m, 1H), 6.35(d, J=8.8Hz, 1H), 5.77(s, 1H), 5.52(s, 2H), 5.33(quin, J=6.4Hz, 1H), 3.85(s, 3H), 2.32(d, J=0.8Hz, 3H), 1.54(d, J=6.8Hz, 3H)

[0206] Step G: To a solution of methyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (5.20 g, 11.7 mmol, 1.00 equiv) in ethyl acetate (20.0 mL) was added Pd(OH)2 on carbon (1.65 g, 11.7 mmol, 1.00 equiv) and stirred under a hydrogen atmosphere (15 psi) at 25 °C for 1.5 hours. After stirring was complete, the reaction mixture was filtered and concentrated in vacuo to give methyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (3.60 g, 10.1 mmol, 86.8% yield, 83.1% purity) as a yellow oil. LCMS[M+1] + =354.2

[0207] Step H: To a solution of methyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (3.50 g, 9.90 mmol, 1.00 equiv) and trifluoromethanesulfonic anhydride (5.59 g, 19.8 mmol, 3.27 mL, 2.00 equiv) in dichloromethane (300 mL) was added diisopropylethylamine (6.40 g, 49.5 mmol, 8.63 mL, 5.00 equiv) at 0° C. After the addition was complete, the mixture was warmed to 25° C. and stirred under a nitrogen atmosphere for 2 hours. After stirring was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The resulting residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give methyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (2.00 g, 4.12 mmol, 41.6% yield, 90.3% purity) as a yellow oil. LCMS [M+1] + =486.2

[0208] Step I: Methyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (155 mg, 319 μmol, 1.00 equivalents), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (134 mg To a solution of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (638 μmol, 2.00 equiv.) in dioxane (1.00 mL) and water (0.50 mL), potassium carbonate (132 mg, 957 μmol, 3.00 equiv.) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (20.8 mg, 31.9 μmol, 0.10 equiv.) were added and stirred at 100° C. for 2 hours under a nitrogen atmosphere. After stirring was complete, the reaction mixture was cooled to 25° C., and the solution was filtered and concentrated under reduced pressure to provide a residue. The resulting residue was purified by flash silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give methyl 2-((1-(2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (130 mg, 309 μmol, 97.0% yield, 95.8% purity) as a yellow solid. LCMS [M+1] + =420.2

[0209] Step J: Palladium on carbon (100 mg, 166 μmol, purity 10.0%, 1.00 equivalent) was added to a solution of methyl 2-((1-(2-(3,6-dihydro-2H-pyran-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (70.0 mg, 166 μmol, 1.00 equivalent) in ethyl acetate (5.00 mL), and the mixture was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 5 minutes. After stirring was complete, the reaction mixture was filtered and concentrated under reduced pressure to give methyl 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60.0 mg, 142 μmol, 85.3% yield, 91.9% purity) as a yellow solid. LCMS [M+1] +=422.2

[0210] Step K: To a solution of methyl 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60.0 mg, 142 μmol, 1.00 equivalents) in methanol (1.00 mL) was added sodium hydroxide (2.00 M, 711 μL, 10.0 equivalents), and the mixture was stirred at 40° C. for 2 hours. After stirring was complete, the reaction was quenched by adding hydrochloric acid (4.00 M, diluted with water) at 25° C. to adjust the pH to 3. The reaction mixture was then diluted with water (10.0 mL), filtered, and the solid was dried under vacuum to give 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (20.0 mg, 47.1 μmol, 33.1% yield, 97.4% purity) as a white solid. LCMS [M+1] + =408.2 1 H NMR(400MHz, MeOD)δ=8.65(s, 1H), 7.81(dd, J=1.6, 7.8Hz, 1H), 7.64(d, J=1.6Hz, 1H), 7.11-7.02(m, 1H), 6.45(t, J=7.4Hz, 1H), 6.30(s, 1H), 6.25(d, J=8.4Hz, 1H), 5.44(q, J=6.8Hz, 1H), 4.07-3.89(m, 2H), 3.51(dt, J=2.8, 11.6Hz, 2H), 2.95-2.80(s, 1H), 2.25(d, J=0.8Hz, 3H), 1.99-1.76(m, 4H), 1.57(d, J=6.8Hz, 3H)

[0211] Example 9-2 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0212] Step A: To a solution of 3-bromopyridin-2-amine (10.0 g, 57.8 mmol, 1.00 equiv.) in acetone (100 mL) was added bis(2,4,6-trichlorophenyl)malonate (28.1 g, 60.7 mmol, 1.05 equiv.) and stirred at 25 °C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The resulting residue was triturated with ethyl acetate (20.0 mL) at 25 °C to give 9-bromo-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (10.0 g, 41.5 mmol, 72% yield) as a white solid. LCMS [M+3] + =242.9 1 H NMR (400MHz, DMSO-d6)δ=11.94-11.74(m, 1H), 11.84(br s, 1H), 8.89(dd, J=1.2, 7.2Hz, 1H), 8.34(dd, J=1.2, 7.2Hz, 1H), 7.12(t, J=7.2Hz, 1H), 5.53(s, 1H), 5.62-5.42(m, 1H)

[0213] Step B: To a solution of 9-bromo-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (10.0 g, 41.5 mmol, 1.00 equiv.) and 4,4-dimethylpiperidine (9.93 g, 66.4 mmol, 1.60 equiv., HCl salt) in dimethylformamide (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.3 g, 166 mmol, 25.0 mL, 4.00 equiv.) and benzotriazol-1-yl-oxy-tris-pyrrolizino-phosphonium hexafluorophosphate (34.5 g, 66.4 mmol, 1.60 equiv.). After completion, the mixture was stirred at 25 °C for 12 hours, and the reaction mixture was diluted with ethyl acetate (500 mL). The combined organic layer was washed with water (500 mL × 2) and dried over anhydrous sodium sulfate to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to give 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (10.0 g, 29.7 mmol, 71% yield) as a yellow solid. LCMS [M+3] + =338.0 1 H NMR (400MHz, DMSO-d6)δ=8.72(dd, J=1.2, 7.2Hz, 1H), 8.17(dd, J=1.2, 7.2Hz, 1H), 6.89(t, J=7.2Hz, 1H), 5.58(s, 1H), 3.65(br s, 4H), 1.52-1.21(m, 4H), 0.95(s, 6H)

[0214] Step C: A mixture of 9-bromo-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (8.00 g, 23.8 mmol, 1.00 equiv.), tributyl(1-ethoxyvinyl)tin (22.5 g, 62.2 mmol, 21.0 mL, 2.62 equiv.), and bis(triphenylphosphine)palladium(II) dichloride (1.67 g, 2.38 mmol, 0.10 equiv.) was evacuated and refilled with nitrogen three times. Toluene (80.0 mL) was then added, and the mixture was stirred at 100 °C for 8 h under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to 25 °C and quenched with saturated aqueous potassium fluoride (200 mL). The mixture was then diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 2-(4,4-dimethylpiperidin-1-yl)-9-(1-ethoxyvinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7.50 g, 21.1 mmol, 89% yield, 92% purity) as a yellow oil. LCMS [M+1] + =328.2 1 H NMR (400MHz, DMSO-d6)δ=8.76(dd, J=1.6, 7.2Hz, 1H), 7.87(dd, J=1.6, 7.2Hz, 1H), 7.01(t, J=7.2Hz, 1H), 5.60(s, 1H), 5.01(d, J=1.6Hz, 1H), 4.61(d, J=1.6Hz, 1H), 3.88(q, J=6.8Hz, 2H), 3.62(br s, 4H), 1.37-1.26(m, 7H), 0.96(s, 6H)

[0215] Step D: To a solution of 2-(4,4-dimethylpiperidin-1-yl)-9-(1-ethoxyvinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7.10 g, 21.7 mmol, 1.00 equiv.) in tetrahydrofuran (75.0 mL), hydrochloric acid (2.00 M, diluted with water, 32.5 mL, 3.00 equiv.) was added and stirred at 25° C. for 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (600 mL) and washed with saturated sodium bicarbonate solution (600 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 2) to give 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.80 g, 19.0 mmol, 88% yield, 98% purity) as a yellow solid. LCMS [M+1] + =300.1 1 H NMR (400MHz, DMSO-d6)δ=8.86(dd, J=1.6, 7.2Hz, 1H), 7.94(dd, J=1.6, 7.2Hz, 1H), 7.06(t, J=7.2Hz, 1H), 5.62(s, 1H), 3.60(br s, 4H), 2.66(s, 3H), 1.39-1.28(m, 4H), 0.96(s, 6H)

[0216] Step E: To a solution of 9-acetyl-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.50 g, 18.4 mmol, 1.00 equiv.) in dichloromethane (55.0 mL) and methanol (55.0 mL), sodium borohydride (720 mg, 19.0 mmol, 1.04 equiv.) was added in several portions at −10° C. and stirred for 1 hour at −10° C. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) and extracted with dichloromethane / methanol (150 mL×3, 10 / 1). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(4,4-dimethylpiperidin-1-yl)-9-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.36 g, 17.1 mmol, 93% yield, 96% purity) as a yellow solid. LCMS [M+1] + =302.2 1 H NMR (400MHz, DMSO-d6)δ=8.67(dd, J=1.6, 7.2Hz, 1H), 7.84(d, J=6.4Hz, 1H), 7.05(t, J=6.8Hz, 1H), 5.59(s, 1H), 5.34(d, J=4.4Hz, 1H), 5.25-5.16(m, 1H), 3.62(br s, 4H), 1.39(d, J=6.4Hz, 3H), 1.37-1.31(m, 4H), 0.96(s, 6H)

[0217] Step F: To a solution of 2-(4,4-dimethylpiperidin-1-yl)-9-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 1.66 mmol, 1.00 equiv.) in dichloromethane (5.00 mL) was added thionyl chloride (395 mg, 3.32 mmol, 241 μL, 2.00 equiv.) at 0° C. and stirred at 0° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give 9-(1-chloroethyl)-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, crude) as a yellow solid. LCMS [M+1] + =320.1

[0218] Step G: To a solution of 9-(1-chloroethyl)-2-(4,4-dimethylpiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (200 mg, 375 μmol, 60% purity, 1.00 equiv.) in dimethylformamide (2.00 mL), tert-butyl 2-aminobenzoate (109 mg, 563 μmol, 103 μL, 1.50 equiv.), diisopropylethylamine (97.0 mg, 750 μmol, 131 μL, 2.00 equiv.), and potassium iodide (125 mg, 750 μmol, 2.00 equiv.) were added and stirred at 80° C. for 12 hours. After completion of the reaction, the mixture was cooled to 25° C. and filtered to obtain the filtrate. The filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (formic acid) / acetonitrile]; B%: 90% to 00%, 10 min) to obtain tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (55.0 mg, 113 μmol, 30% yield, 98% purity) as a yellow oil. LCMS [M+1] + =477.3 1 H NMR (400MHz, DMSO-d6)δ=8.67(dd, J=1.2, 7.2Hz, 1H), 8.20-8.14(m, 1H), 7.77(dd, J=1.2, 8.0Hz, 1H), 7.66(d, J=6.0Hz, 1H), 7.31-7.12(m, 1H), 6.97(t, J=6.8Hz, 1H), 6.54(t, J=7.6Hz, 1H), 6.35(d, J=8.4Hz, 1H), 5.20(br t, J=6.8Hz, 1H), 3.68(br s, 4H), 1.65-1.49(m, 12H), 1.44-1.34(m, 4H), 0.98(s, 6H)

[0219] Step H: To a solution of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (40.0 mg, 83.9 μmol, 1.00 equivalents) in dichloromethane (0.50 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 161 equivalents) at 0° C. and stirred at 25° C. for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to provide a residue. The resulting residue was then diluted with dichloromethane (10.0 mL) and concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (formic acid) / acetonitrile]; B%: 51%-81%, 9 min) to give 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (15.7 mg, 37.0 μmol, 44% yield, 99% purity) as a white solid. LCMS [M+1] + =421.2 1 H NMR (400MHz, DMSO-d6)δ=12.75(br s, 1H), 8.67(d, J=7.2Hz, 1H), 8.40(br d, J=5.2Hz, 1H), 7.80(br d, J=8.0Hz, 1H), 7.64(br d, J=6.8Hz, 1H), 7.21(br t, J=8.0Hz, 1H), 6.97(t, J=7.2Hz, 1H), 6.54(t, J=7.6Hz, 1H), 6.32(br d, J=8.4Hz, 1H), 5.65(s, 1H), 5.38-5.02(m, 1H), 3.68(br s, 4H), 1.58(br d, J=6.8Hz, 3H), 1.43-1.30(m, 4H), 0.98(s, 6H)

[0220] Example 9-3 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka] Step A: To a solution of methyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (30.0 mg, 67.6 μmol, 1.00 equivalents) in methanol (1.00 mL) was added sodium hydroxide (2.00 M, diluted with water, 338 μL, 10.0 equivalents), and the mixture was stirred at 25° C. for 1 hour. After stirring was complete, the resulting residue was purified by preparative HPLC (column: Phenomenex C18 75 x 30 mm x 3 um; mobile phase: [water (formic acid) / acetonitrile]; B%: 48%-78%, 7 min) to give 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5.30 mg, 11.8 μmol, 17.5% yield, 99.2% purity) as a yellow oil. LCMS [M+1] + =430.2 1 H NMR (400MHz, DMSO-d6)δ=8.73(s, 1H), 8.66-8.48(m, 1H), 7.82(br d, J=7.6Hz, 1H), 7.78(s, 1H), 7.48(d, J=7.2Hz, 2H), 7.42-7.27(m, 4H), 7.14(br t, J=7.4Hz, 1H), 6.53(t, J=7.5Hz, 1H), 6.26(br d, J=8.3Hz, 1H), 5.77(s, 1H), 5.56-5.46(m, 2H), 5.36-5.22(m, 1H), 2.31(s, 3H), 1.51(br d, J=6.4Hz, 3H)

[0221] The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 84]

[0222] Example 10-1 (R)-2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid [ka]

[0223] Step A: To a solution of 3-bromo-5-methylpyridin-2-amine (400 g, 2.14 mol, 1.00 equiv.) in dichloromethane (3.00 L), 2-methylmalonyl dichloride (365 g, 2.35 mol, 1.10 equiv.) was slowly added dropwise at 25 °C and stirred at 25 °C for 48 hours. After stirring was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (250 mL × 2) and dried under vacuum to give 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (490 g, 1.46 mol, 68.2% yield, 80.1% purity) as a white solid. LCMS [M+3] + =270.9

[0224] Step B: To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (490 g, 1.82 mol, 1.00 equiv.) in dimethylformamide (3.50 L) was added potassium carbonate (755 g, 5.46 mol, 3.00 equiv.) and benzyl bromide (467 g, 2.73 mol, 324 mL, 1.50 equiv.) and stirred at 100 °C for 1 h. The reaction mixture was cooled to 25 °C, diluted with water (7.00 L), filtered, and the filter cake was dried under vacuum to give 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (517 g, 1.36 mol, 74.6% yield, 94.4% purity) as a yellow solid. LCMS [M+3] + =360.9 1H NMR(400MHz, CDCl3)δ=8.72(s, 1H), 7.79(d, J=1.6Hz, 1H), 7.44(d, J=7.2Hz, 2H), 7.31-7.20(m, 3H), 5.49(s, 2H), 2.29(s, 3H), 2.08(s, 3H)

[0225] Step C: A mixture of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (410 g, 1.14 mol, 1.00 equiv.), n-butyl vinyl ether (572 g, 5.71 mol, 734 mL, 5.00 equiv.), Pd(OAc) (12.8 g, 57.1 mmol, 0.05 equiv.), 1,3-bis(diphenylphosphino)propane (47.1 g, 114 mmol, 0.10 equiv.), and N,N-dicyclohexylmethylamine (669 g, 3.42 mol, 726 mL, 3.00 equiv.) in n-butyl alcohol (3.00 L) was evacuated and refilled with nitrogen three times, then stirred under a nitrogen atmosphere at 100 °C for 12 h. After stirring was complete, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was used in the next step without further purification.

[0226] Step D: To a solution of 2-(benzyloxy)-9-(1-butoxyvinyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (420 g, 1.11 mol, 1.00 equiv.) in n-butyl alcohol (2.00 L) was added hydrochloric acid (12 M, 740 mL, 8.00 equiv.) and stirred at 25 °C for 1 hour. After stirring was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (500 mL) and dried under vacuum to give 9-acetyl-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (300 g, 83.6%) as a yellow solid. LCMS [M+1] + =323.3 1H NMR (400MHz, DMSO-d6)δ=8.91(s, 1H), 8.00(d, J=2.0Hz, 1H), 7.49-7.30(m, 5H), 5.48(s, 2H), 2.71(s, 3H), 2.41(s, 3H), 2.05(s, 3H)

[0227] Step E: To a solution of 9-acetyl-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (210 g, 651 mmol, 1.00 equivalents) and (R)-2-methylpropane-2-sulfinamide (103 g, 847 mmol, 1.30 equivalents) in tetrahydrofuran (1.60 L), titanium(IV) ethoxide (297 g, 1.30 mol, 270 mL, 2.00 equivalents) and 1,2-dimethoxyethane (58.7 g, 651 mmol, 67.7 mL, 1.00 equivalents) were added and stirred at 80 ° C. for 16 hours. After stirring was complete, the reaction was slowly quenched with water (60.0 mL) and diluted with ethyl acetate (2.00 L). The resulting mixture was filtered, and the filtrate was washed with brine (2.00 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)—N-(1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (230 g, crude) as a yellow oil, which was used in the next step without further purification.

[0228] Step F: To a solution of (R)—N-(1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (230 g, 540 mmol, 1.00 equiv.) in dichloromethane (2.50 L) was added Schwartz's reagent (167 g, 649 mmol, 1.20 equiv.) under a nitrogen atmosphere at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (2.00 L) and then extracted with dichloromethane (1.50 L × 2). The combined organic layers were washed with brine (3.00 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was triturated with a solution of petroleum ether / ethyl acetate (5 / 1, 300 mL) at 25° C. for 1 hour to give (R)-N-((R)-1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (160 g, 374 mmol, 69.2% yield) as a yellow solid. LCMS [M+1] + =428.4 1 H NMR(400MHz, CDCl3)δ=8.84(s, 1H), 7.56(s, 1H), 7.50-7.44(m, 2H), 7.39(m, 2H), 7.33(br d, J=7.2Hz, 1H), 5.52(s, 2H), 4.93(m, 1H), 4.78(br d, J=7.2Hz, 1H), 2.41(s, 3H), 2.20(s, 3H), 1.59(br d, J=6.8Hz, 3H), 1.22(s, 9H)

[0229] Step G: To a solution of (R)—N—((R)-1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (300 g, 702 mmol, 1.00 equivalents) in dioxane (1.00 L) was added hydrochloric acid (4 M solution in dioxane, 526 mL, 3.00 equivalents) dropwise at 25° C., and the mixture was stirred at 25° C. for 1 hour. After stirring was complete, the reaction was filtered, and the filter cake was triturated with ethyl acetate (2.00 L x 2) at 25 °C for 1 hour, filtered, and the filter cake was dried under vacuum to give (R)-9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (85.0 g, 226 mmol, 47.9% yield, 95.8% purity, hydrochloric acid) as a yellow solid. LCMS [M+1] + =324.1 1 H NMR (400MHz, DMSO-d6)δ=8.78(s, 1H), 8.74(br s, 3H), 8.10(d, J=1.2Hz, 1H), 7.52-7.46(m, 2H), 7.40(t, J=7.2Hz, 2H), 7.35-7.29(m, 1H), 5.63-5.39(m, 2H), 5.04(br s, 1H), 2.40(s, 3H), 2.04(s, 3H), 1.58(d, J=6.8Hz, 3H)

[0230] Step H: (R)-9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (70.0 g, 195 mmol, 1.00 equiv., hydrochloric acid), methyl 2-bromobenzoate (50.2 g, 233 mmol, 32.8 mL, 1.20 equiv.), cesium carbonate (190 g, 584 mmol, 3.00 equiv.), tris(di ... A mixture of (diphenylacetone)dipalladium(0) (17.8 g, 19.5 mmol, 0.10 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22.5 g, 38.9 mmol, 0.20 equiv) was evacuated and refilled with nitrogen three times, then dioxane (1.00 L) was added and the mixture was stirred at 100° C. under a nitrogen atmosphere for 4 hours. After stirring was complete, the reaction mixture was cooled to 25° C., filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give (R)-2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate (77.0 g, 166 mmol, 85.1% yield, 98.4% purity, 99.9% ee) as a yellow oil. LCMS [M+1] + =458.2 1 H NMR(400MHz, CDCl3)δ=8.70(s, 1H), 8.18(br d, J=5.6Hz, 1H), 7.85(dd, J=1.6, 8.0Hz, 1H), 7.48(d, J=1.6Hz, 1H), 7.38(d, J=7.2Hz, 2H), 7.27(t, J=7.6Hz, 2H), 7.22-7.18(m, 1H), 7.04(m, 1H), 6.59-6.41(m, 1H), 6.08(d, J=8.4Hz, 1H), 5.49(d, J=1.6Hz, 2H), 5.37-5.21(m, 1H), 3.84(s, 3H), 2.22(s, 3H), 2.17(s, 3H), 1.48(d, J=6.8Hz, 3H)

[0231] Step I: To a solution of methyl (R)-2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (34.0 g, 74.3 mmol, 1.00 equiv.) in ethyl acetate (350 mL) was added palladium(II) hydroxide on carbon (15.7 g, 22.3 mmol, 20% purity, 0.30 equiv.) under a nitrogen atmosphere, and the suspension was purged with hydrogen three times. The mixture was then stirred at 25° C. under a hydrogen atmosphere (50 psi) for 2 hours. After stirring was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (R)-2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate (25.0 g, 68.1 mmol, 91.6% yield) as a yellow solid. LCMS [M+1] + =368.1

[0232] Step J: To a solution of methyl (R)-2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (25.0 g, 68.1 mmol, 1.00 equiv) and diisopropylethylamine (17.6 g, 136 mmol, 23.7 mL, 2.00 equiv) in dichloromethane (250 mL) was added trifluoromethanesulfonic anhydride (23.0 g, 81.7 mmol, 13.5 mL, 1.20 equiv) dropwise at 0° C. After the addition, the mixture was stirred at 0° C. for 30 minutes, and the reaction was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (R)-2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate (12.0 g, 23.2 mmol, 34.1% yield, 92.2% purity) as a yellow viscous substance. LCMS [M+1] + =500.1 1H NMR(400MHz, CDCl3)δ=8.77(s, 1H), 8.28(br d, J=5.6Hz, 1H), 7.95(dd, J=1.6, 8.0Hz, 1H), 7.75(d, J=1.6Hz, 1H), 7.23-7.14(m, 1H), 6.61(m, 1H), 6.25(d, J=8.4Hz, 1H), 5.36(t, J=6.4Hz, 1H), 3.94(s, 3H), 2.38(s, 3H), 2.30(s, 3H), 1.65(d, J=6.4Hz, 3H)

[0233] Step K: (R)-2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate (70.0 mg, 140 μmol, 1.00 equiv.), 4-(piperazin-1-yl)benzonitrile (39.4 mg, 210 μmol, 1.50 equiv.), (2-dicyclohexylphosphino-2',6' A mixture of 2-(2'-amino-1,1'-biphenyl)-diisopropoxy-1,1'-biphenyl)palladium(II) methanesulfonate (11.7 mg, 14.0 μmol, 0.10 equiv.) and cesium carbonate (137 mg, 420 μmol, 3.00 equiv.) was evacuated and refilled with nitrogen three times, then dioxane (1.00 mL) was added and the mixture was stirred at 100°C under a nitrogen atmosphere for 3 h. After cooling to 25°C, the reaction mixture was diluted with water (3.00 mL) and then extracted with ethyl acetate (15.0 mL, 5.00 mL x 3). The combined organic layers were washed with brine (15.0 mL, 5.00 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 2) to give (R)-2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)methyl benzoate (41.0 mg, 60.7 μmol, 43.3% yield, purity 79.5%) as a yellow oil. LCMS [M+1] + =537.4

[0234] Step L: To a solution of methyl (R)-2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (30.0 mg, 55.9 μmol, 1.00 equiv.) in tetrahydrofuran (0.25 mL), methanol (0.50 mL), and water (0.10 mL) was added lithium hydroxide (11.7 mg, 280 μmol, 5.00 equiv.) and stirred at 40° C. for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then the pH was adjusted to 6 with 1 M hydrochloric acid. The resulting crude product was slurried in water and collected by filtration, and the filter cake was then purified by preparative HPLC (formic acid conditions, column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (formic acid) / acetonitrile]; gradient: 52% to 82% B over 10 min) to give (R)-2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (16.0 mg, 30.6 μmol, 54.7% yield, 99.8% purity) as a white solid. LCMS [M+1] + =523.4 1 H NMR (400MHz, DMSO-d6)δ=8.60(d, J=1.6Hz, 1H), 8.44(br d, J=5.2Hz, 1H), 7.80(dd, J=1.6, 8.0Hz, 1H), 7.65-7.60(m, 2H), 7.59(s, 1H), 7.26-7.16(m, 1H), 7.06(d, J=8.8Hz, 2H), 6.61-6.49(m, 1H), 6.41(d, J=8.8Hz, 1H), 5.32(q, J=6.4Hz, 1H), 3.64-3.58(m, 4H), 3.56-3.51(m, 4H), 2.28(d, J=0.8Hz, 3H), 2.13(s, 3H), 1.61(d, J=6.8Hz, 3H)

[0235] Examples 10-2 to 10-148 The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 85] [Table 86] [Table 87] [Table 88] [Table 89] [Table 90] [Table 91] [Table 92] [Table 93] [Table 94] [Table 95] [Table 96] [Table 97] [Table 98] [Table 99] [Table 100] Table 101 Table 102 Table 103 Table 104 Table 105 Table 106 Table 107 Table 108 Table 109 Table 110 Table 111 Table 112 Table 113 Table 114 Table 115 Table 116 Table 117 Table 118 Table 119 Table 120 Table 121 Table 122 Table 123 Table 124 Table 125 Table 126 Table 127 Table 128 Table 129 Table 130 TIFF2025527747000153.tif220170 Table 131 Table 132 Table 133 Table 134 [Table 135] [Table 136]

[0236] Examples 11-1 to 11-447 The following compounds are prepared essentially according to the procedures set forth in the above schemes and examples. [Table 137] [Table 138] [Table 139] [Table 140] [Table 141] [Table 142] [Table 143] [Table 144] [Table 145] [Table 146] [Table 147] [Table 148] [Table 149] Table 150 Table 151 Table 152 Table 153 Table 154 Table 155 Table 156 Table 157 Table 158 Table 159 Table 160 Table 161 Table 162 Table 163 Table 164 Table 165 Table 166 Table 167 Table 168 Table 169 Table 170 Table 171 Table 172 Table 173 Table 174 Table 175 Table 176 Table 177 Table 178 Table 179 Table 180 Table 181 Table 182 Table 183 Table 184 Table 185 Table 186 Table 187 Table 188 Table 189 Table 190 Table 191 Table 192 Table 193 Table 194 Table 195 Table 196 Table 197 Table 198 Table 199 Table 200 Table 201 Table 202 Table 203 Table 204 Table 205 Table 206 Table 207 Table 208 Table 209 Table 210 Table 211 Table 212 Table 213 Table 214 Table 215 Table 216 Table 217 Table 218 [Table 219] [Table 220] [Table 221] [Table 222] [Table 223] [Table 224] [Table 225]

[0237] Example A This example demonstrates that example compounds of the present invention inhibit the formation of phosphorylated AKT (pAKT) in cells.

[0238] The ability of compounds of formula (I) to inhibit the formation of pAKT was measured using the AlphaLISA Surefire Ultra AKT1 / 2 / 3 (pS473) Assay Kit (Perkin Elmer, Waltham, Mass., #ALSU-PAKT-B50K).

[0239] To prepare plates for the AlphaLISA pAKT assay, cells were trypsinized, resuspended in fresh medium, and viable cells were counted using trypan blue. Prior to seeding, cells were washed with PBS and resuspended in HBSS (Gibco, #14025092). T47D (12,000 / w), SKBR3 (12,000 / w), or MKN1 (24,000 / w) cells were seeded at 12 μL per well into white, flat-bottom, 384-well cell culture plates (Perkin Elmer #6007680).

[0240] Immediately after seeding, cells were treated with compounds at an initial concentration of 10.4 μM using an Echo Liquid Handler (Beckman Coulter), followed by serial dilutions (1:4) for a total of 10 concentrations. Each assay plate contained 14 vehicle (DMSO) wells and 14 positive control (3.125 μM alpelisib) wells. Cells were incubated with compounds (dissolved in DMSO) for approximately 1 or 24 hours at 37°C. After 1 hour (or 24 hours) of treatment, cells were lysed on a microtiter plate shaker using 3 μL of 5-fold diluted lysis buffer and incubated for 15 minutes on a microtiter plate shaker at room temperature. After sufficient cell lysis, 7.5 μL of acceptor bead mixture (prepared using the manufacturer's recommended dilution) was added to each well, placed on the microtiter plate shaker for 1 minute, and then incubated for 1 hour at room temperature in the dark. After 1 hour of incubation with the acceptor bead mixture, 7.5 μL of the donor bead mixture (made using the manufacturer's recommended dilution) was added to each well, placed on a microtiter plate shaker for 1 minute, and incubated overnight at room temperature in the dark. The plates were then imaged the next day using a CLARIOstar microplate reader (BMG Labtech, Germany).

[0241] Percent control values ​​were calculated by subtracting the mean signal from the positive control (alpelisib-treated) wells from all treated wells (including the DMSO control wells) and then dividing by the mean signal from the vehicle control (DMSO-treated) wells. Percent vehicle control values ​​were plotted as log(inhibitor) vs. response—variable slope (fourth parameter) for curve fitting and calculated as IC using XLfit. 50 value was determined. The results are shown in the table below: ND = Not Determined

[0242] Table A pAKT Inhibition in T47D (PI3Kα H1047R Mutant) Cells by Example Compounds of Formula (I) [Table 226] [Table 227] [Table 228]

[0243] Table B pAKT Inhibition in MKN1 (PI3Kα E545K Mutant) Cells by Example Compounds of Formula (I) [Table 229]

[0244] Table C pAKT Inhibition in SKBR3 (PI3Kα Wild Type) Cells by Example Compounds of Formula (I) [Table 230] [Table 231] [Table 232]

[0245] Example B This example demonstrates that example compounds of the present invention reduce cell viability.

[0246] The ability of compounds of formula (I) to reduce cell viability was measured using the CellTiter-Glo 2.0 (CTG) Luminescent Cell Viability Assay (Promega, Madison, Wis., #G9241).

[0247] To prepare plates for viability assays, cells were trypsinized, resuspended in fresh medium, and viable cells were counted using trypan blue. T47D, SKBR3, or MKN1 cells were seeded into white flat-bottom 384-well cell culture plates (Perkin Elmer #6007680) at 1000 cells / 30 μL per well and incubated overnight at 37°C.

[0248] On assay day 1, cells were treated with compounds at an initial concentration of 10 μM using an Echo Liquid Handler (Beckman Coulter) and serially diluted (1:4) to a total of 10 concentrations. Cells were incubated with compounds (dissolved in DMSO) at 37°C for approximately 72 hours. After 72 hours of treatment, the cell plates were returned to room temperature, and 15 μL of CTG was added to each well. The plates were then wrapped in aluminum foil to protect from light and incubated on a microtiter plate shaker for 30 minutes at room temperature. Luminescence values ​​were collected using a CLARIOstar microplate reader (BMG Labtech, Germany). Vehicle control values ​​(%) were plotted as log(inhibitor) vs. response—variable slope (fourth-order parameter) for curve fitting, and IC values ​​were calculated using XLfit. 50 value was determined.

[0249] Table D Viability of T47D (PI3Kα H1047R mutant) cells by example compounds of formula (I) [Table 233] [Table 234] [Table 235] [Table 236] [Table 237] [Table 238] [Table 239] [Table 240] [Table 241] [Table 242] [Table 243] [Table 244] [Table 245] [Table 246] [Table 247]

[0250] Table E Viability of MKN1 (PI3Kα E545K mutant) cells by example compounds of formula (I) [Table 248]

[0251] Table F Viability of SKBR3 (PI3Kα wild type) cells by example compounds of formula (I) [Table 249] [Table 250] [Table 251] [Table 252] [Table 253] [Table 254] [Table 255] [Table 256] [Table 257] [Table 258] [Table 259] [Table 260] [Table 261] [Table 262] [Table 263] [Table 264]

[0252] While the invention has been described with respect to specific embodiments thereof, it is understood that further modifications are possible, and this application is intended to cover, in general, any variation, use, or application of the invention in accordance with the principles of the invention, including any known or conventional developments from this disclosure in the art to which the invention pertains, to the extent applicable to the essential features described above and within the scope of the appended claims.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, X is N, O, or S; If X is N, then R 1 is H, C 1 -C 3 Alkyl, or C 3 -C 6 is cycloalkyl; If X is O or S, then R 1 does not exist; R 2 is phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -C(O)-(C 2 -C 4 alkyl), -C(O)-(C 2 -C 4 alkenyl), -(C 2 -C 4 alkyl)-C(O)OH or -(C 2 -C 4 cycloalkyl)-C(O)OH, where each phenyl and heteroaryl is 1 to 5 R 7 may be optionally substituted with; R 3 is C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; R 4 is H, C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, cyano, or halogen, wherein the C 1 -C 3 The alkyl may be optionally substituted with 1 to 5 halogens; R 5 is C 1 -C 3 Alkyl, C 2 -C 6 Alkenyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, or 3- to 9-membered heterocyclyl, where each alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 1 to 5 R 6 and the heterocyclyl may be optionally unsaturated; R 8 is R A , halogen, or cyano; Y is a bond, NR 10 , S or O; Each R 6 independently -R A , -OR A , -C(O)OR A , oxo, cyano, halogen, (C 1 -C 3 alkyl)-OR A , -C(O)N(R A ) 2 , -C(O)R 11 , -N(R A ) 2 , -N(R A )C(O)R A , -SO 2 R A , -R C or two geminal R 6 However, together with the carbon to which they are attached, they form a spirocyclic C 3 -C 6 Form a cycloalkyl or a 3- to 12-membered heterocyclyl, or two vicinal R 6 However, they combine with the carbon to which they are attached to form condensed C 10 -C 14 Aryl, C 8 -C 12 Cycloalkyl or C 3 -C 12 form a heterocyclyl; where each spirocyclic group and fused group is R B , -OR B , -C(O)OR B , (C 1 -C 3 alkyl)-OR B , -C(O)N(R B ) 2 , optionally substituted with oxo, cyano, halogen; Each R B are independently H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl(C 1 -C 6 ) alkyl; R C is C 3 -C 6 Cycloalkyl, C 3 -C 12 Heterocyclyl, C 3 -C 12 Heterocyclyl(C 1 -C 6 ) alkyl, phenyl, phenyl (C 1 -C 2 ) alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl (C 1 -C 2 ) alkyl, where each cycloalkyl, heterocyclyl, phenyl, and heteroaryl is 1 to 5 R 9 may be optionally substituted with; Each R 7 are independently cyano, halogen, oxo, C 1 -C 4 Alkyl, -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R A ) 2 , -P(O)(OH)R A or two geminal R 7 However, together with the carbon to which they are bonded, C 3 -C 6 forming a cycloalkyl or 3- to 9-membered heterocyclyl; Each R 9 are independently hydroxy, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, Halo(C 1 -C 6 ) alkyl, or -SO 2 N(R 10 ) 2 and; Each R 10 are independently hydrogen or C 1 -C 6 is alkyl; R 11 is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl(C 1 -C 6 ) Alkyl, C 3 -C 6 cycloalkyl, or phenyl, each of which is 1 to 5 R 7 may be optionally substituted with; Each R A are independently H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 3 -C 6 Cycloalkyl(C 1 -C 6 ) alkyl or two geminal R A However, together with the carbon to which they are bonded, C 3 -C 6 forming a cycloalkyl or a 3- to 9-membered heterocyclyl; and Unless otherwise specified herein, each alkyl and cycloalkyl group is unsubstituted, substituted with 1 to 5 halogens, perfluorinated, or substituted with 1 to 3 groups selected from methyl, oxo, and carboxy; and However, if Y is a bond, then R 5 is not unsubstituted morpholinyl] or a pharmaceutically acceptable salt or deuterated compound thereof.

2. 2. The compound of claim 1, wherein X is N.

3. In the formula, R 1 is H or CH 3 3. The compound of claim 1 or claim 2, wherein

4. In the formula, R 2 phenyl, pyridinyl, -C(O)-CH=CH 2 , or -C(O)-CH 2 4. The compound of claim 1, wherein:

5. In the formula, R 3 C 1 -C 3 The compound of any one of claims 1 to 4, wherein the alkyl group is unsubstituted, substituted with 1 to 5 halogens, or perfluorinated.

6. 6. The compound of any one of claims 1 to 5, wherein Y is a bond.

7. In the formula, R 5 6-10 membered aryl, C 3 -C 6 cycloalkyl or 3- to 9-membered heterocyclyl, each of which has 1 to 5 R 6 7. The compound of claim 1, wherein the compound is optionally substituted with

8. In the formula, R 5 is cyclopropyl, phenyl, piperidinyl, or isoindolinyl, each of which has 1 to 5 R 6 8. The compound of claim 1, wherein the compound is optionally substituted with

9. In the formula, R 8 is hydrogen, methyl, ethyl, or cyano, the compound of any one of claims 1 to 8.

10. The compound has formula (IIa), (IIb) or (IIIc): 【Chemistry 2】 [In the formula, Q is N or CH; R 1 is H or CH 3 and; R 3 is C 1 -C 3 is alkyl; R 4 is H, C 1 -C 3 Alkyl, C 3 -C 6 cycloalkyl, cyano, or halogen, wherein the C 1 -C 3 The alkyl may be optionally substituted with 1 to 5 halogens; Each R 6 independently -R A , -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R A ) 2 , oxo, cyano, halogen, or two geminal R 6 However, together with the carbon to which they are bonded, C 3 -C 6 Form a cycloalkyl or a 3- to 9-membered heterocyclyl, or two vicinal R 6 However, they combine with the carbon to which they are attached to form condensed C 10 -C 14 Aryl or C 8 -C 12 Forming a cycloalkyl; each m is 0, 1, 2, 3, or 4; Each R 7 independently C 1 -C 4 Alkyl, -OR A , -C(O)OR A , (C 1 -C 3 alkyl)-OR A , -C(O)N(R A ) 2 , cyano, halogen, or two geminal R 7 However, together with the carbon to which they are bonded, C 3 -C 6 forming a cycloalkyl or 3- to 9-membered heterocyclyl; each n is 0, 1, 2, 3, or 4; R 8 is methyl, ethyl or cyano; and Each R A are independently H, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl or two geminal R A However, together with the carbon to which they are bonded, C 3 -C 6 forming a cycloalkyl or a 3- to 9-membered heterocyclyl; wherein each alkyl and cycloalkyl group is unsubstituted, substituted with 1 to 5 halogens, perfluorinated, or substituted with 1 to 3 groups selected from methyl, oxo, or carboxy.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. 11. The compound of claim 10, wherein Q is CH.

12. In the formula, R 1 12. The compound of claim 10 or claim 11, wherein is H.

13. In the formula, R 3 The compound of any one of claims 10 to 12, wherein is unsubstituted methyl.

14. In the formula, R 4 is H, methyl, ethyl, or cyclopropyl, each of which is unsubstituted.

15. In the formula, R 4 is H or unsubstituted methyl or difluoromethyl.

16. wherein m is 2 and each R 6 The compound of any one of claims 10 to 15, wherein is unsubstituted methyl.

17. wherein n is 1 and R 7 The compound of any one of claims 10 to 16, wherein is -COOH.

18. In the formula, R 8 The compound of any one of claims 10 to 17, wherein is H.

19. below: 7-methyl-9-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-Methoxy-6-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-hydroxy-6-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 5-Methoxy-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 5-hydroxy-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 4-Methoxy-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 4-hydroxy-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethoxy)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)thio)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzonitrile; Methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide; N-methyl-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide; N,N-dimethyl-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide; 9-(1-((2-hydroxyphenyl)amino)ethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 9-(1-((1H-indazol-7-yl)amino)ethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 7-methyl-2-(piperidin-1-yl)-9-(1-((2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; 6-chloro-3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 9-(1-((2-(1,1-difluoro-2-hydroxyethyl)phenyl)amino)ethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-(methyl(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(6-azaspiro[2.5]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acrylamide; N-methyl-N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acrylamide; 2-chloro-N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acetamide; 2-chloro-N-methyl-N-(1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)acetamide; (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-cyclopropyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-ethyl-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-(difluoromethyl)-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-ethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-cyclopropyl-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-phenyl-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(p-tolyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-chlorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(p-tolyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(o-tolyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 3-methyl-3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)butanoic acid; 3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)propanoic acid; 3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)butanoic acid; 3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)cyclobutane-1-carboxylic acid; 2-((1-(7-methyl-2-(4-methyl-3-oxopiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(1-acetylpiperidin-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-2-oxopiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,7-dimethyl-4-oxo-2-phenyl-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-((tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-2-(3-(1-methyl-1H-pyrazol-5-yl)-8-azabicyclo[3.2.1]octan-8-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(2-oxo-[1,4'-bipiperidin]-1'-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(ethoxymethyl)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-3-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-methylpicolinic acid; (R)-2-((1-(2-(4-(2-cyclopropylacetyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(1-hydroxy-6-azaspiro[3.5]nonan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(3-(pyridin-4-yl)pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-ethyl-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-chloro-3-cyano-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-bromo-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3-cyano-2-((cyclopropylmethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(4-methyl-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-methylpicolinic acid; (R)-2-((1-(2-(3,3-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(8-cyanoisoquinolin-5-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-chloro-3-cyano-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3,3-difluoroazetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-4-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-fluoro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-(((R)-1-(3-cyano-2-((S)-3,3-difluoro-2-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-3,3-difluoro-2-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(thiazol-2-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(pyridin-2-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4,6-dicyanonaphthalen-1-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-fluorophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-((3,3-difluorocyclobutyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(pyridin-3-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-fluoro-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(4-fluorophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(3,3-difluoro-4-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-3,3-difluoro-4-methoxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-3,3-difluoro-4-methoxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(3-methylisoxazol-5-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-((3,3-difluorocyclobutyl)(methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3-cyano-2-(5-fluoroisoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-4,4-difluoro-2-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-2-(fluoromethyl)azetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-2-(fluoromethyl)azetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-methoxy-4-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-2-(2-methyl-4-phenylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(((2,2-difluoro-1-methylcyclopropyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-4-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)thiophene-3-carboxylic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid; (R)-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)pyrazine-2-carboxylic acid; (R)-5-chloro-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluorocyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3-cyano-2-(1,1-dioxidothiomorpholino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-carbamoyl-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-3-(trifluoromethyl)-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-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3,3-difluoropyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-cyano-2-methylphenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-methoxy-4-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-fluoro-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-((cyclopropylmethyl)(methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(1,1,2,2-tetrafluoro-6-azaspiro[2.5]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-chlorobenzoyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(2-((cyclopropylmethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3-cyano-2-(4-(2,4-difluorophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(5,6-difluoroisoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(8-azabicyclo[3.2.1]octan-8-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(cyclobutylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2,2-difluoroethyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(5-fluoroisoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-2-((S)-2-methylazetidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-2-((R)-2-methylazetidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2-azabicyclo[2.2.2]octan-2-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(4-cyano-2-methylphenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(1-(4-cyanophenyl)piperidin-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluoropicolinic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-4-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-4-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-3,R 7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(5-cyanopyrimidin-2-yl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-2-methylazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-2-methylazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-chloro-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-3-((1-(3-cyano-2-(cyclobutylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-(((1R)-1-(2-(3,3-difluoro-4-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-benzoylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-3,3-difluoro-4-methoxypyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-3,3-difluoro-4-methoxypyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-(4-cyanophenyl)piperidin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-(((R)-1-(3-cyano-2-((R)-4,4-difluoro-3-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4,4-difluoro-3-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-methoxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4,4-difluoro-3-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4,4-difluoro-3-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5-(difluoromethyl)isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(4-(N-methylsulfamoyl)phenyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(2-oxa-8-azaspiro[4.5]decan-8-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2-cyanopyridin-3-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-2-(2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-2-(octahydro-2H-4,7-ethanoisoindol-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5-fluoroisoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-hydroxy-3-isopropylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-2-(5-methyl-2-azabicyclo[2.2.1]heptan-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5-(hydroxymethyl)isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,6-dimethoxyisoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,6-difluoroisoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(3-(pyridin-2-yl)pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(2-hydroxy-8-azaspiro[4.5]decan-8-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(1-(hydroxymethyl)-6-azabicyclo[3.2.1]octan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6-hydroxy-2-azabicyclo[2.2.2]octan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; or 2-(((R)-1-(2-((3aS,6aS)-1H,3H,4H-3a,6a-(methanooxymethano)furo[3,4-c]pyrrol-5(6H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2. The compound of claim 1, wherein:

20. below: (R)-2-((1-(2-(4-(2-chlorophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(3,4,4-trifluoropiperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(7,7,9,9-tetrafluoro-3-azabicyclo[3.3.1]nonan-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(9,9-difluoro-3-azabicyclo[3.3.1]nonan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(9,9-difluoro-1-(hydroxymethyl)-3-azabicyclo[3.3.1]nonan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((3R,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((3S,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(5,5-difluoro-2-azabicyclo[2.2.2]octan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(7-(tert-butyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(3-phenylpyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-(pyridin-2-yl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(5-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-phenylazetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(1-(hydroxymethyl)isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-cyclobutylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-(pyridin-3-yl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6-hydroxyhexahydro-3,5-methanocyclopenta[b]pyrrol-1(2H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4,4-difluoro-[1,4'-bipiperidin]-1'-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6,6-dimethyl-3-azabicyclo[3.2.0]heptan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-cyclopentylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2-azadispiro[3.1.3 6 .1 4 ]decan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(decahydro-2H-cycloocta[c]pyrrol-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(8-hydroxy-6-azaspiro[3.4]octan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2-azaadamantan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(5-hydroxy-2-azabicyclo[2.2.2]octan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-hydroxyoctahydro-1H-indol-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(5-phenyl-2-azabicyclo[2.2.1]heptan-2-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(8-azatricyclo[4.3.0.0 2,5 ]nonan-8-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6-hydroxy-6-methyl-3-azabicyclo[3.1.1]heptan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(8-hydroxyoctahydro-2H-4,7-methanoisoindol-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(bicyclo[1.1.1]pentan-1-yl-3-d)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-fluoroisoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-methoxyphenyl)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid; 2-(4-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)-7-oxo-1,4-diazepan-1-yl)acetic acid; (R)-2-((1-(3-cyano-2-(4-(2,2-difluoroethyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluoropicolinic acid; (R)-3-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluoropicolinic acid; (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluoropicolinic acid; (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-methylpicolinic acid; 2-(((R)-1-(3-cyano-2-((3R,5R)-3,5-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((3R,5S)-3,5-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-4-oxo-2-((3,3,3-trifluoro-2-methylpropyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(7-chloro-3-cyano-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-(((R)-1-(pyridin-3-yl)ethyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-(((S)-1-(pyridin-3-yl)ethyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(1H-pyrazol-3-yl)piperidin-1-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4,4-difluoro-3-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4,4-difluoro-3-methoxypiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-4-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-4-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(2-oxa-8-azaspiro[4.5]decan-8-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1-oxa-8-azaspiro[4.5]decan-8-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-4,4-difluoro-3-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-3,3-difluoro-4-methoxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(3,3-difluoro-4-methoxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-cyano-4-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-cyano-4-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-cyanopiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-cyanopiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(2-cyano-5-methylphenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4-(2-cyano-5-methylphenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4-(2-cyano-4-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4-(2-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(2-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-4-(3-cyanophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4-(3-cyanophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4-(3-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4-(3-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2,3-difluorobenzoic acid; (R)-3-chloro-6-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-fluorobenzoic acid; (R)-2-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-5-fluorobenzoic acid; (R)-5-chloro-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4,4-difluoro-2-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4,4-difluoro-2-methylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-2-(fluoromethyl)azetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-2-(fluoromethyl)azetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-2-methylazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((S)-2-(trifluoromethyl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((R)-2-(trifluoromethyl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(cyclobutylamino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-2-((R)-2-methylazetidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-2-((S)-2-methylazetidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3-(difluoromethyl)azetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-(difluoromethyl)azetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(3-(trifluoromethyl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-(trifluoromethyl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-((2-cyanoallyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3-cyanoazetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-((2-cyanoallyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3-methoxyazetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-methoxyazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3-fluoroazetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-fluoroazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3,3-difluoroazetidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-3,3-difluoro-4-methoxypyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-4-methoxypyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-4-methoxypyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-4-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-4-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-3,3-difluoro-2-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-3,3-difluoro-2-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((R)-4,4-difluoro-2-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((R)-1-(3-cyano-2-((R)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-(3-cyano-2-((S)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-(3-cyano-2-((S)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((R)-1-(3-cyano-2-((R)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(3-cyano-2-(4-(4-cyano-2-methylphenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(4-(4-cyano-2-methylphenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-(((1R)-1-(3-cyano-2-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4,4-difluorocyclohexyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-4-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)nicotinic acid; 6-chloro-3-(((1R)-1-(3-cyano-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(3-cyano-2-(5,6-difluoroisoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-9-(1-(pyridazin-4-ylamino)ethyl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile; (R)-4-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)pyridazine-3-carboxylic acid; (R)-6-chloro-3-((1-(3-cyano-2-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(3,7-dimethyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(1-methylpiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-cyclopropylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-cyclopropylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(oxetan-3-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(((1-fluorocyclopropyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((((R)-2,2-difluorocyclopropyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((((S)-2,2-difluorocyclopropyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(((2,2-difluorocyclopropyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-(((R)-1-cyclopropyl-2,2,2-trifluoroethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-(((S)-1-cyclopropyl-2,2,2-trifluoroethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-(((R)-1-cyclopropyl-2,2,2-trifluoroethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-(((S)-1-cyclopropyl-2,2,2-trifluoroethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-(((S)-1-cyclopropylethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-(((R)-1-cyclopropylethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-(((S)-1-cyclopropylethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-(((R)-1-cyclopropylethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-(difluoromethyl)-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(3-cyano-7-(difluoromethyl)-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3-cyano-7-(difluoromethyl)-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-(difluoromethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(7-(4-cyanophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((1R,4R)-5-(4-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((1S,4S)-5-(4-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1R,4R)-5-(4-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1S,4S)-5-(4-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(3-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(3-(4-cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-(4-cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(3-cyano-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(3-cyano-1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,6-difluoroisoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(6-(4-cyanophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(6-(4-cyanophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-((((S)-tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-((((R)-tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-4-oxo-2-(((tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((((S)-tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((((R)-tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(((tetrahydrofuran-3-yl)methyl)amino)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(((3,3-difluorocyclobutyl)methyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(((3,3-difluorocyclobutyl)methyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-((cyclopropylmethyl)(methyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-((oxetan-3-ylmethyl)amino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-((oxetan-3-ylmethyl)amino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(3-cyano-2-((cyclopropylmethyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-2-((1-(2-((cyclopropylmethyl)amino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-((R)-3-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-((S)-3-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((R)-3-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((S)-3-(trifluoromethyl)piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,1,2,2-tetrafluoro-6-azaspiro[2.5]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-4-oxo-2-(1,2,3,4-tetrahydro-1,4-epiminonaphthalen-9-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(1,2,3,4-tetrahydro-1,4-epiminonaphthalen-9-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(6-azaspiro[2.5]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(6-azaspiro[2.5]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(3-cyanophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(3-cyanophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1R,4S)-6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-(((1R)-1-(2-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-(((R)-1-(3-cyano-2-((1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-5-ethynyl-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(1-methyl-1H-imidazol-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1H-imidazol-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-(4-cyanophenyl)-1H-imidazol-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-(4-cyanophenyl)-1H-imidazol-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-(2-cyanopropan-2-yl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(3-(2-cyanopropan-2-yl)phenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)prop-2-yn-1-yl)amino)benzoic acid; (R)-2-((1-(2-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-chloro-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-cyclopropyl-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-(((R)-tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-(((S)-tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-(((R)-tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-7-methyl-4-oxo-2-(((S)-tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(4-(methylcarbamoyl)phenyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-carbamoylphenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(3-cyano-1-methyl-1H-indazol-7-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(1H-pyrazol-3-yl)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-((4-cyanophenyl)ethynyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-cyano-6-hydroxynaphthalen-1-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(4-cyano-7-hydroxynaphthalen-1-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-acetylpiperidin-4-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-(4-(aminomethyl)phenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(5-cyanopyrimidin-2-yl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(tetrahydro-1H-thieno[3,4-c]pyrrol-5(3H)-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(2-cyanophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-benzoylpiperazin-1-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(4-(o-tolyl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(o-tolyl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-2-(2-methyl-4-phenylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3-cyano-2-((R)-4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(4-(4-cyanophenyl)-3-methylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(4-cyanophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-phenylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-4-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)nicotinic acid; (R)-4-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)nicotinic acid; (R)-6-chloro-4-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)pyridazine-3-carboxylic acid; (R)-4-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)pyridazine-3-carboxylic acid; (R)-3,7-dimethyl-9-(1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)ethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; (R)-6-chloro-3-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-5-chloro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-5-chloro-2-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-(methylsulfonyl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(3-oxopiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-4-oxo-2-(1-oxa-6-azaspiro[3.4]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(1-(hydroxymethyl)isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-7-methyl-4-oxo-2-(2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-fluoro-2-(isoindolin-2-yl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-chloro-2-(isoindolin-2-yl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-5-((1-(3-cyano-2-(4,4-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)thiazole-4-carboxylic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-5-fluorobenzoic acid; 2-(((R)-1-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-methylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(3,3-difluoropiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 7-methyl-4-oxo-9-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile; (S)-2-(isoindolin-2-yl)-7-methyl-4-oxo-9-(1-(phenylamino)ethyl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile; (R)-2-(isoindolin-2-yl)-7-methyl-4-oxo-9-(1-(phenylamino)ethyl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile; 2-(isoindolin-2-yl)-7-methyl-4-oxo-9-(1-(phenylamino)ethyl)-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile; (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-fluorobenzoic acid; (R)-2-((1-(3-cyano-2-(isobutylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(isobutylamino)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-5-cyano-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(dimethylamino)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-hydroxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(4-(dimethylamino)piperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-2-(4-methylpiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-9-carboxamide)cyclohexane-1-carboxylic acid; 2-(1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-9-carboxamide)cyclobutyl)acetic acid; (R)-1-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)carbamoyl)cyclobutane-1-carboxylic acid; (R)-2-((1-(3-cyano-7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(azepan-1-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-2-(diethylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-3-cyano-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-methyl-4-oxo-2-(2-azaspiro[3.3]heptan-2-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3-cyano-2-(3-hydroxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-chloro-5-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)pyrimidine-4-carboxylic acid; (R)-2-((1-(3-cyano-7-cyclopropyl-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(3-cyano-7-cyclopropyl-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3-cyano-7-ethyl-2-(isoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl 3-amino-6-chloropicolinate; (R)-1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl 3-amino-6-chloropicolinate; (R)-6-chloro-3-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-((1-(3-cyano-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)phenyl)(methyl)phosphinic acid; 2-((1-(2-(4-(4-cyanophenyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-(cyclopropanecarbonyl)piperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-acetylpiperazin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-cyanoisoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-((3-cyanophenyl)amino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-cyanophenoxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-phenoxy-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-hydroxy-3-methylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-hydroxypiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(7-azabicyclo[2.2.1]heptan-7-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-9-carbonyl)proline; 1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-9-carbonyl)piperidine-2-carboxylic acid; 1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)piperidine-4-carboxylic acid; 2-chloro-5-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)isonicotinic acid; 2-((1-(3-cyano-2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 4-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)nicotinic acid; (R)-6-fluoro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-fluoro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (S)-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-(trifluoromethyl)picolinic acid; (R)-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-(trifluoromethyl)picolinic acid; 3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-6-(trifluoromethyl)picolinic acid; 3-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (S)-6-chloro-3-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 6-chloro-3-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid; 2-((1-(3,7-dimethyl-4-oxo-2-(1-oxoisoindolin-2-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 3-Fluoro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 4-Fluoro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-5-Fluoro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-5-Fluoro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 5-Fluoro-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-Fluoro-6-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-((tetrahydrofuran-3-yl)thio)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-((tetrahydrofuran-3-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-methoxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((S)-1-(7-methyl-2-((S)-1-methyl-2-oxopiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((S)-1-(7-methyl-2-((R)-1-methyl-2-oxopiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(7-methyl-2-((S)-1-methyl-2-oxopiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-2-oxopiperidin-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(1-acetylpiperidin-4-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(4-methyl-3-oxopiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)cyclobutane-1-carboxylic acid; 4-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 3-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-methyl-6-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-methoxyphenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(o-tolyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-chlorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-cyanophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(3,7-dimethyl-4-oxo-2-phenyl-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(azetidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(2-(dimethylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidine-9-carbonitrile; 9-(1-hydroxypropyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)propyl)amino)benzoic acid; 2-(((7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)methyl)amino)benzoic acid; 2-((1-(3-cyclopropyl-7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-3-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-3-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(4-oxo-2-(piperidin-1-yl)-7-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(7-cyano-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(7-cyano-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-cyano-2-(4,4-difluoropiperidin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 7-methyl-2-morpholino-9-(1-(phenylamino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one; (R)-2-((1-(4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (S)-2-((1-(4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 6-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)-6-azaspiro[3.4]octane-8-carboxylic acid; 1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)azetidine-3-carboxylic acid; 2-(1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)pyrrolidin-3-yl)acetic acid; 1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)-4-methyl-5-oxopiperazine-2-carboxylic acid; (3aR,5r,6aS)-2-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid; (R)-2-((1-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(1H-pyrazol-1-yl)piperidin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(3,7-dimethyl-4-oxo-2-(1,1,2,2-tetrafluoro-6-azaspiro[3.4]octan-6-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(3-cyano-2-methylphenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(2-(4-(2-fluorophenyl)piperazin-1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(4-(pyridin-4-yl)piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-4-oxo-2-(3-(5-(trifluoromethyl)isoxazol-3-yl)azetidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(2-((1R,4R)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((1R)-1-(2-(5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 2-(((R)-1-(3,7-dimethyl-4-oxo-2-((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; (R)-2-((1-(3,7-dimethyl-2-(4-(4-methylthiazol-2-yl)piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; or 2-(((1R)-1-(2-(7,7-difluoro-2-azaspiro[4.4]nonan-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2. The compound of claim 1, wherein:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a salt thereof together with a pharmaceutically acceptable carrier, excipient or diluent.

22. 20. A method for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 20.

23. The method of claim 22, wherein the PI3K is PI3Kα.

24. 24. The method of claim 22 or claim 23, wherein the PI3K associated with the disease or disorder has an H1047R mutation.

25. The method of any one of claims 22 to 24, wherein the disease or disorder is cancer.

26. 26. The method of claim 25, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

27. The method of any one of claims 22 to 24, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal anomaly syndrome) or PIK3Cα-associated overgrowth syndrome (PROS).

28. 22. A method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

29. 22. A method for treating cancer or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21.

30. 30. The method of claim 29, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colon cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

31. 28. The method of claim 27, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal anomaly syndrome) or PIK3Cα-associated overgrowth syndrome (PROS).

32. 22. A method for treating cancer, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21, and a KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

33. 22. A method for treating cancer, comprising administering to a patient in need thereof a compound of any one of claims 1 to 20 or a pharmaceutical composition of claim 21 and a mutant-selective KRAS inhibitor, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

34. 22. A compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for use in combination with a KRAS inhibitor for the treatment of cancer, wherein the cancer is breast cancer, uterine carcinosarcoma, endometrial carcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, esophageal adenocarcinoma, bladder carcinoma, lung squamous cell carcinoma, glioma, adrenocortical carcinoma, hepatocellular carcinoma, sarcoma, prostate cancer, renal cell carcinoma, lung adenocarcinoma, malignant ovarian cystadenoma, glioblastoma multiforme, or melanoma.

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