STOCK NICHOLAS SIMON (US)
NAGLE ADVAIT (US)
FEINBERG EVAN NATHANIEL (US)
INDARTE MARTIN (US)
| WHAT IS CLAIMED IS: 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R2 is phenyl optionally substituted with 1-3 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC, C1-C6 alkoxy optionally substituted with – C(=O)NRARC or –O(R2B); each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi) (vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or – C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R2B is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or Z is NR3B or O; Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. 2. The compound of Claim 1, wherein Z is O. 3. The compound of Claim 1, wherein Z is NR3B. 4. The compound of any one of Claims 1-3, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A. 5. The compound of any one of Claims 1-3, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A. 6. The compound of any one of Claims 1-5, wherein R2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A. 7. The compound of any one of Claims 1-5, wherein R2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A or –O(R2B). 8. The compound of any one of Claims 1-5, wherein R2 is C1-C6 alkoxy substituted with –C(=O)NRARC. 9. The compound of any one of Claims 1-5, wherein R2 is C1-C6 alkoxy. 10. The compound of any one of Claims 1-5, R2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC. 11. The compound of any one of Claims 1-5, R2 is C1-C6 alkoxyalkyl. 12. The compound of any one of Claims 1-11, wherein X is a bond. 13. The compound of any one of Claims 1-11, wherein X is CH2. 14. The compound of any one of Claims 1-11, wherein X is CH(CH3). 15. The compound of any one of Claims 1-11, wherein X is C(CH3)2. 16. The compound of any one of Claims 1-11, wherein X is . 17. The compound of any one of Claims 1-16, wherein Y is phenyl optionally substituted with 1-3 independently selected RY. 18. The compound of any one of Claims 1-16, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY. 19. The compound of any one of Claims 1-16, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. 20. The compound of any one of Claims 1-19, wherein RY is halogen. 21. The compound of any one of Claims 1-19, wherein RY is is hydroxyl. 22. The compound of any one of Claims 1-19, wherein RY is cyano. 23. The compound of any one of Claims 1-19, wherein RY is C1-C6 haloalkyl. 24. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkoxy. 25. The compound of any one of Claims 1-19, wherein RY is C1-C6 haloalkoxy. 26. The compound of any one of Claims 1-19, wherein RY is C1-C6 hydroxyalkyl. 27. The compound of any one of Claims 1-19, wherein RY is -NHC(=O)RC. 28. The compound of any one of Claims 1-19, wherein RY is -C(=O)NHRY1. 29. The compound of any one of Claims 1-19, wherein RY is –CO2RA. 30. The compound of any one of Claims 1-19, wherein RY is -SO2NRFRG. 31. The compound of any one of Claims 1-19, wherein RY is -NHSO2RF. 32. The compound of any one of Claims 1-19, wherein RY is –S(=O)(=NRF)RG. 33. The compound of any one of Claims 1-19, wherein RY is –SO2(C1-C6 alkyl). 34. The compound of any one of Claims 1-19, wherein RY is -C(=O)NRARB. 35. The compound of any one of Claims 1-19, wherein RY is 4-6 membered heteroaryl. 36. The compound of any one of Claims 1-19, wherein RY is heteroaralkyl. 37. The compound of any one of Claims 1-19, wherein RY is 4-6 membered heterocyclyl. 38. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. 39. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. 40. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl substituted with RY1. 41. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl. 42. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl. 43. The compound of any one of Claims 38-40, wherein RY1 is –SO2(C1-C6 alkyl). 44. The compound of any one of Claims 38-40, wherein RY1 is C1-C6 alkyl optionally substituted with oxo. 45. The compound of any one of Claims 38-40, wherein RY1 is hydroxyl. 46. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof. 47. A pharmaceutical composition comprising a compound of any one of Claims 1- 46, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 48. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47. 49. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47. 50. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47. 51. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof. |
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-B): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-C): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-D): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-E):
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-FF): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G):
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G1): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G2): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G3):
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G4): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G5): or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G6): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-HH): or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-I): or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-II): or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the Compounds 1-1413, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
Table A
Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Methods of Treatment A “PI3Kα inhibitor” as used herein (e.g., compounds of Formula (I) and pharmaceutically acceptable salts thereof) includes any compound exhibiting PI3Kα inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Kα inhibitor can be selective for a PI3Kα having one or more mutations. The ability of test compounds to act as inhibitors of PI3Kα may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands. Potency of a PI3Kα inhibitor as provided herein can be determined by EC 50 value. A compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC 50 value. Potency of a PI3Kα inhibitor as provided herein can also be determined by IC 50 value. A compound with a lower IC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC 50 value. In some embodiments, the substantially similar conditions comprise determining a PI3Kα-dependent phosphorylation level, in vitro or in vivo. The selectivity between wild type PI3Kα and PI3Kα containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Kα activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3Kα kinase activity. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3Kα. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Kα. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3Kα kinase including one or more mutations, for example, the mutations in Table 1. In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα over another kinase or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of PI3Kα containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition of PI3Kα having a combination of mutations described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a PI3Kα inhibitor, such as PI3Kα-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (a PI3Kα-associated cancer), for example, as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Kα -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for preventing diseases as defined herein such as cancer. The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof. The term “PI3Kα-associated disease” as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Kα protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3Kα-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Kα-associated cancer). The term “PI3Kα-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Kα-associated cancer are described herein. The phrase “dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kα that includes a deletion of at least one amino acid as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with one or more point mutations as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with at least one inserted amino acid as compared to a wild type PI3Kα, a gene duplication that results in an increased level of PI3Kα in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3Kα in a cell), an alternative spliced version of PI3Kα mRNA that results in PI3Kα having a deletion of at least one amino acid in the PI3Kα as compared to the wild type PI3Kα), or increased expression (e.g., increased levels) of a wild type PI3Kα in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3Kα that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non- limiting examples of PI3Kα point mutations/substitutions/insertions/deletions are described in Table 1. The term “wild type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Kα mRNA) or protein (e.g., a PI3Kα) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein. The term “wild type PI3Kα” or “wild-type PI3Kα” describes a normal PI3Kα nucleic acid (e.g., a PIK3CA or PI3Kα mRNA) or protein that is found in a subject that does not have a PI3Kα-associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and/or is not suspected of having a PI3Kα-associated disease), or is found in a cell or tissue from a subject that does not have a PI3Kα-associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and/or is not suspected of having a PI3Kα-associated disease). Provided herein is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more a PI3Kα protein substitutions/point mutations/insertions. Non- limiting examples of PI3Kα protein substitutions/insertions/deletions are described in Table 1. In some embodiments, the PI3Kα protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E545X, where X is any amino acid other than E. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Kα mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Kα having at least one residue deleted (as compared to the wild type PI3Kα protein) resulting in a constitutive activity of a PI3Kα protein domain. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity, as compared to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2 + and HER2- breast cancer, ER + breast cancer, and triple negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, hepatocellular carcinoma, prostate cancer, Malignant Peripheral Nerve Sheath Tumor (MPNST), glioblastoma, cholangiocarcinoma, and pancreatic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2 + and HER2- breast cancer, ER + breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.
In some embodiments of any of the methods or uses described herein, the PI3Kα- associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is lung cancer.
In some embodiments of any of the methods or uses described herein, the PI3Kα- associated cancer is selected from the cancers described in Table 1.
Table 1. PI3Kα Protein Amino Acid Substitutions/Insertions/Deletions A
Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN Also provided is a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Kα activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some mebodiments, the PI3Kα is human PI3Kα. In some embodiments, the PI3Kα has one or more point mutations in the PIK3CA gene. In some embodiments, the point mtations include a substitution at amino acid position 1047 of a human PI3Kα protein. In some embodiments, the substitution is H1047R. When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein. Embodiments 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R 2 is phenyl optionally substituted with 1-3 independently selected R 2A , 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R 2A , 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R 2A , 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R 2A , C1-C6 alkoxyalkyl optionally substituted with –C(=O)NR A R C , C1-C6 alkoxy optionally substituted with – C(=O)NR A R C , or –O(R 2B ); each R 2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NR A R B , (v) -C(=O)NR A R B , (vi) (vii) -NHC(=O)R C , (viii) -C(=O)NR D R E , (ix) -C(=O)OR F , (x) -SO 2 R F , (xi) -NHSO 2 R F , (xii) -SO 2 NR F R G , (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NR A R B , (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B , (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO 2 (C1-C6 alkyl), -SO 2 NR F R G , -C(=O)NR A R B , -NHC(=O)C1-C6 alkyl optionally substituted with -NR A R B , or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B , or – C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NR A R B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R 2B is phenyl optionally substituted with 1-4 independently selected R 2A , 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R 2A , 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A , 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R 2A ; each R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO 2 (C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each R C is independently selected from C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl optionally substituted with -NR A R B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each R D and R E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R 3A and R 3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B , together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R 4 is hydrogen, C1-C6 alkyl, or acrylamido; R 5 is hydrogen, C1-C6 alkyl, cyano, -NR 5A R 5B , -NR 5A C(=O)R 5B , or -C(=O)NR 5A R 5B ; R 5A and R 5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R 6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or Z is NR 3B or O; Y is phenyl optionally substituted with 1-3 independently selected R Y , naphthyl optionally substituted with 1-3 independently selected R Y , or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y ; each R Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)R C , -C(=O)NHR Y1 , –CO 2 R A , -SO 2 NR F R G , -NHSO 2 R F , –S(=O)(=NR F )R G , –SO 2 (C1-C6 alkyl), -C(=O)NR A R B , 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R Y1 , and C1-C6 alkyl optionally substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 ; R Y1 is –SO 2 (C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each R F and R G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NR A R B . 2. The compound of Embodiment 1, wherein R 1 is hydrogen. 3. The compound of Embodiment 1, wherein R 1 cyano. 4. The compound of Embodiment 1, wherein R 1 is C3-C6 cycloalkyl. 5. The compound of Embodiment 1, wherein R 1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. 6. The compound of Embodiment 1 or 5, wherein R 1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. 7. The compound of Embodiment 1 or 5-6, wherein R 1 is C1-C6 alkyl substituted with phenyl substituted with halogen. 8. The compound of Embodiment 1 or 5-6, wherein R 1 is C1-C6 alkyl substituted with phenyl. 9. The compound of Embodiment 1 or 5, wherein R 1 is C1-C6 alkyl. 10. The compound of Embodiment 1, wherein R 1 is C1-C6 thioalkyl. 11. The compound of Embodiment 1, wherein R 1 is C1-C6 haloalkyl. 12. The compound of Embodiment 1, wherein R 1 is C1-C6 alkoxy. 13. The compound of Embodiment 1, wherein R 1 is C1-C6 alkoxyalkyl. 14. The compound of any one of Embodiments 1-13, wherein R 2 is phenyl optionally substituted with 1-3 independently selected R 2A . 15. The compound of any one of Embodiments 1-13, wherein R 2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R 2A . 16. The compound of any one of Embodiments 1-13, wherein R 2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R 2A . 17. The compound of any one of Embodiments 1-13, wherein R 2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R 2A or –O(R 2B ). 18. The compound of any one of Embodiments 1-17, wherein 1, 2, 3, or 4 of R 2A are independently halogen. 19. The compound of any one of Embodiments 1-18, wherein 1, 2, 3, or 4 of R 2A are independently cyano. 20. The compound of any one of Embodiments 1-19, wherein 1, 2, 3, or 4 of R 2A are independently hydroxyl. 21. The compound of any one of Embodiments 1-20, wherein 1, 2, 3, or 4 of R 2A are independently -NR A R B . 22. The compound of any one of Embodiments 1-21, wherein 1, 2, 3, or 4 of R 2A are independently -C(=O)NR A R B . 23. The compound of any one of Embodiments 1-22, wherein 1, 2, 3, or 4 of R 2A are independently . 24. The compound of any one of Embodiments 1-23, wherein 1, 2, 3, or 4 of R 2A are independently -NHC(=O)R C . 25. The compound of any one of Embodiments 1-24, wherein 1, 2, 3, or 4 of R 2A are independently -C(=O)NR D R E . 26. The compound of any one of Embodiments 1-25, wherein 1, 2, 3, or 4 of R 2A are independently -C(=O)OR F . 27. The compound of any one of Embodiments 1-26, wherein 1, 2, 3, or 4 of R 2A are independently -SO 2 R F . 28. The compound of any one of Embodiments 1-27, wherein 1, 2, 3, or 4 of R 2A are independently -NHSO 2 R F . 29. The compound of any one of Embodiments 1-28, wherein 1, 2, 3, or 4 of R 2A are independently -SO 2 NR F R G . 30. The compound of any one of Embodiments 1-29, wherein 1, 2, 3, or 4 of R 2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NR A R B . 31. The compound of any one of Embodiments 1-30, wherein 1, 2, 3, or 4 of R 2A are independently -NHC(=O)C1-C6 alkyl substituted with NR A R B . 32. The compound of any one of Embodiments 1-31, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 haloalkyl. 33. The compound of any one of Embodiments 1-32, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 hydroxyalkyl. 34. The compound of any one of Embodiments 1-33, wherein 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B . 35. The compound of any one of Embodiments 1-34, wherein 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B . 36. The compound of any one of Embodiments 1-35, wherein 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl. 37. The compound of any one of Embodiments 1-36, wherein 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO 2 (C1-C6 alkyl), -SO 2 NR F R G , C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NR A R B , or -NHC(=O)C1-C6 alkyl optionally substituted with -NR A R B . 38. The compound of any one of Embodiments 1-37, wherein 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO 2 (C1-C6 alkyl), -SO 2 NR F R G , C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NR A R B , or -NHC(=O)C1-C6 alkyl optionally substituted with -NR A R B . 39. The compound of any one of Embodiments 1-38, wherein 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO 2 (C1-C6 alkyl), -SO 2 NR F R G , C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NR A R B , or -NHC(=O)C1-C6 alkyl substituted with -NR A R B . 40. The compound of any one of Embodiments 1-39, wherein 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO 2 (C1-C6 alkyl), -SO 2 NR F R G , -C(=O)NR A R B , -NHC(=O)C1-C6 alkyl optionally substituted with -NR A R B , or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. 41. The compound of any one of Embodiments 1-36, wherein 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl. 42. The compound of any one of Embodiments 1-41, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B , or –C(=O)C3-C6 cycloalkyl. 43. The compound of any one of Embodiments 1-42, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B , or –C(=O)C3-C6 cycloalkyl. 44. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B , or –C(=O)C3-C6 cycloalkyl. 45. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy, and 4-10 membered heterocyclyl. 46. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl. 47. The compound of any one of Embodiments 1-46, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy optionally substituted with -NR A R B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 48. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 49. The compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 50. The compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl. 51. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy. 52. The compound of any one of Embodiments 1-51, wherein 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 53. The compound of any one of Embodiments 1-52, wherein 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 54. The compound of any one of Embodiments 1-53, wherein 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. 55. The compound of any one of Embodiments 1-53, wherein 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl. 56. The compound of any one of Embodiments 1-52, wherein 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl. 57. The compound of any one of Embodiments 1-13, wherein R 2 is C1-C6 alkoxy optionally substituted with –C(=O)NR A R C . 58. The compound of any one of Embodiments 1-13 or 57, wherein R 2 is C1-C6 alkoxy substituted with –C(=O)NR A R C . 59. The compound of any one of Embodiments 1-13 or 57, wherein R 2 is C1-C6 alkoxy. 60. The compound of any one of Embodiments 1-13, R 2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NR A R C . 61. The compound of any one of Embodiments 1-13, R 2 is C1-C6 alkoxyalkyl. 62. The compound of any one of Embodiments 1-61, wherein X is a bond. 63. The compound of any one of Embodiments 1-61, wherein X is CH 2 . 64. The compound of any one of Embodiments 1-61, wherein X is CH(CH 3 ). 65. The compound of any one of Embodiments 1-61, wherein X is C(CH 3 ) 2 . 66. The compound of any one of Embodiments 1-61, wherein X is . 67. The compound of any one of Embodiments 1-66, wherein Z is O. 68. The compound of any one of Embodiments 1-66, wherein R 3A is hydrogen. 69. The compound of any one of Embodiments 1-66, wherein R 3A is C1-C6 alkyl. 70. The compound of any one of Embodiments 1-67, wherein R 3A is methyl. 71. The compound of any one of Embodiments 1-66, wherein R 3A is C1-C6 alkoxy. 72. The compound of any one of Embodiments 1-66, R 3A is C1-C6 haloalkyl. 73. The compound of any one of Embodiments 1-66, wherein Z is NR 3B . 74. The compound of Embodiment 73, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkyl. 75. The compound of Embodiment 73-74, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is methyl. 76. The compound of Embodiment 73, wherein each of R 3A and R 3B is hydrogen. 77. The compound of Embodiment 73, wherein each of R 3A and R 3B is an independently selected C1-C6 alkyl. 78. The compound of Embodiment 73 or 77, wherein each of R 3A and R 3B is methyl. 79. The compound of Embodiment 73, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkoxy. 80. The compound of Embodiment 73, wherein one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 alkoxy. 81. The compound of Embodiment 73, wherein each of R 3A and R 3B is C1-C6 alkoxy. 82. The compound of Embodiment 73, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 haloalkyl. 83. The compound of Embodiment 73, wherein one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 haloalkyl. 84. The compound of Embodiment 73, wherein each of R 3A and R 3B is C1-C6 haloalkyl. 85. The compound of Embodiment 73, wherein R 3A and R 3B , together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. 86. The compound of any one of Embodiments 1-85, wherein Y is phenyl optionally substituted with 1-3 independently selected R Y . 87. The compound of any one of Embodiments 1-85, wherein Y is naphthyl optionally substituted with 1-3 independently selected R Y . 88. The compound of any one of Embodiments 1-85, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y . 89. The compound of any one of Embodiments 1-88, wherein 1, 2, or 3 of R Y is independently halogen. 90. The compound of any one of Embodiments 1-89, wherein 1, 2, or 3 of R Y is hydroxyl. 91. The compound of any one of Embodiments 1-90, wherein 1, 2, or 3 of R Y is cyano. 92. The compound of any one of Embodiments 1-91, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkyl. 93. The compound of any one of Embodiments 1-92, wherein 1, 2, or 3 of R Y is independently C1-C6 alkoxy. 94. The compound of any one of Embodiments 1-93, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkoxy. 95. The compound of any one of Embodiments 1-94, wherein 1, 2, or 3 of R Y is independently C1-C6 hydroxyalkyl. 96. The compound of any one of Embodiments 1-95, wherein 1, 2, or 3 of R Y is independently -NHC(=O)R C . 97. The compound of any one of Embodiments 1-96, wherein 1, 2, or 3 of R Y is independently -C(=O)NHR Y1 . 98. The compound of any one of Embodiments 1-97, wherein 1, 2, or 3 of R Y is independently –CO 2 R A . 99. The compound of any one of Embodiments 1-98, wherein 1, 2, or 3 of R Y is independently -SO 2 NR F R G . 100. The compound of any one of Embodiments 1-99, wherein 1, 2, or 3 of R Y is independently -NHSO 2 R F . 101. The compound of any one of Embodiments 1-100, wherein 1, 2, or 3 of R Y is independently –S(=O)(=NR F )R G . 102. The compound of any one of Embodiments 1-101, wherein 1, 2, or 3 of R Y is independently –SO 2 (C1-C6 alkyl). 103. The compound of any one of Embodiments 1-102, wherein 1, 2, or 3 of R Y is independently -C(=O)NR A R B . 104. The compound of any one of Embodiments 1-103, wherein 1, 2, or 3 of R Y is independently 4-6 membered heteroaryl. 105. The compound of any one of Embodiments 1-104, wherein 1, 2, or 3 of R Y is independently heteroaralkyl. 106. The compound of any one of Embodiments 1-105, wherein 1, 2, or 3 of R Y is independently 4-6 membered heterocyclyl. 107. The compound of any one of Embodiments 1-106, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl optionally substituted with –CO 2 R A or 5-6 membered heteroaryl optionally substituted with R Y1 . 108. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 5-6 membered heteroaryl optionally substituted with R Y1 . 109. The compound of any one of Embodiments 1-108, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 5-6 membered heteroaryl substituted with R Y1 . 110. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 5-6 membered heteroaryl. 111. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl. 112. The compound of any one of Embodiments 1-88 or 107-109, wherein R Y1 is – SO 2 (C1-C6 alkyl). 113. The compound of any one of Embodiments 1-88 or 107-109, wherein R Y1 is C1- C6 alkyl optionally substituted with oxo. 114. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R Y1 is hydroxyl. 115. The compound of any one of Embodiments 1-10114, wherein R 4 is hydrogen. 116. The compound of any one of Embodiments 1-114, wherein R 4 is C1-C6 alkyl. 117. The compound of any one of Embodiments 1-114, wherein R 4 is acrylamido. 118. The compound of any one of Embodiments 1-117, wherein R 5 is hydrogen. 119. The compound of any one of Embodiments 1-117, wherein R 5 is C1-C6 alkyl. 120. The compound of any one of Embodiments 1-117, wherein R 5 is cyano. 121. The compound of any one of Embodiments 1-117, wherein R 5 is -NR 5A R 5B . 122. The compound of any one of Embodiments 1-117, wherein R 5 is -C(=O)NR 5A R 5B . 123. The compound of any one of Embodiments 1-117, wherein R 5 is -NR 5A C(=O)R 5B . 124. The compound of any one of Embodiments 1-117 or 121-123, wherein one of R 5A and R 5B is hydrogen and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. 125. The compound of any one of Embodiments 1-117 or 121-123, wherein one of R 5A and R 5B is C1-C6 alkyl and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. 126. The compound of any one of Embodiments 1-103 or 121-123, wherein each of R 5A and R 5B is hydrogen. 127. The compound of any one of Embodiments 1-117 or 121-123, wherein each of R 5A and R 5B is an independently selected C1-C6 alkyl. 128. The compound of any one of Embodiments 1-127, wherein R 6 is hydrogen. 129. The compound of any one of Embodiments 1-127, wherein R 6 is halogen. 130. The compound of any one of Embodiments 1-127, wherein R 6 is C1-C6 alkyl. 131. The compound of any one of Embodiments 1-130, wherein each of R A and R B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 132. The compound of any one of Embodiments 1-131, wherein one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 133. The compound of any one of Embodiments 1-132, wherein one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy. 134. The compound of any one of Embodiments 1-132, wherein one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl. 135. The compound of any one of Embodiments 1-130, wherein R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl. 136. The compound of any one of Embodiments 1-130 or 135, wherein R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and – C(=O)C1-C6 alkyl. 137. The compound of any one of Embodiments 1-130 or 135, wherein R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. 138. The compound of any one of Embodiments 1-125, wherein each R C is independently C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl substituted with -NR A R B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. 139. The compound of any one of Embodiments 1-138, wherein each R C is independently C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl substituted with -NR A R B or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. 140. The compound of any one of Embodiments 1-139, wherein each R C is independently C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl substituted with -NR A R B or with 4-10 membered heterocyclyl. 141. The compound of any one of Embodiments 1-138, wherein each R C is independently C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl. 142. The compound of any one of Embodiments 1-141, wherein one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. 143. The compound of any one of Embodiments 1-141, wherein each of R D and R E is hydrogen. 144. The compound of any one of Embodiments 1-141, wherein each of R D and R E is an independently selected C1-C6 alkyl. 145. The compound of any one of Embodiments 1-144, wherein one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl optionally substituted with oxo or –NR A R B . 146. The compound of any one of Embodiments 1-144, wherein one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl substituted with oxo or –NR A R B . 147. The compound of any one of Embodiments 1-144, wherein one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl. 148. The compound of any one of Embodiments 1-144, wherein each of R F and R G is hydrogen. 149. The compound of any one of Embodiments 1-144, wherein each of R F and R G is an independently selected C1-C6 alkyl. 150. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof. 151. A pharmaceutical composition comprising a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 152. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 153. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 154. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-150 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 155. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof. EXAMPLES Compound Preparation The general methods for the preparation of the compounds of Formula (I) have been described in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof. The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. Example 1: Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1- (7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid (Compound 269) Step 1: Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2 - a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1-(7-methyl-4-oxo- 2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino) benzoic acid (Compound 269) 2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrim idin-9- yl)ethyl)amino)benzoic acid (70 mg) was isolated by Prep-chiral-HPLC with the following conditions : Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B (isocratic) in 12 min; Wave Length: 205/254 nm; RT1(min): 5.37; RT2(min): 8.8; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 5. The 1 st eluting fraction was concentrated and lyophilized to afford rel-(R)-2-((1-(7-methyl-4-oxo-2- (pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid (Compound 268; 21.9 mg, 31.28%, ee=99.86%) as a white solid, and the 2 nd eluting fraction was concentrated and lyophilized to afford rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2 -a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (Compound 269; 19.8 mg, 28.28%, ee=99.71%) as a white solid. Compound 268: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.86 – 8.67 (m, 3H), 8.57 (s, 1H), 8.28 – 8.16 (m, 2H), 7.88 – 7.77 (m, 2H), 7.28 – 7.11 (m, 2H), 6.61 – 6.49 (m, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 7.0 Hz, 1H), 2.37 (s, 3H), 1.69 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 401.1 Compound 269: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.89 – 8.71 (m, 3H), 8.53 (d, J = 6.4 Hz, 1H), 8.26 – 8.14 (m, 2H), 7.90 – 7.76 (m, 2H), 7.27 – 7.10 (m, 2H), 6.55 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.64 – 5.47 (m, 1H), 2.37 (s, 3H), 1.70 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 401.1 Example 2: Preparation of rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin- 1-yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyri midin-9- yl)ethyl]amino}benzoic acid (Compound 420) and rel-2-{[(1R)-1-(2-{4-[(4- cyclopropanecarbonylpiperazin-1-yl)methyl]-3-fluorophenyl}-7 -methyl-4-oxopyrido[1,2- a]pyrimidin-9-yl)ethyl]amino}benzoic acid (Compound 421) 2-{[1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1-yl)methyl]-3 -fluorophenyl}-7-methyl- 4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino}benzoic acid (140 mg, 0.240 mmol, 1 equiv) was isolated by prep-chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose- SB, 3*25 cm, 5 μm; Mobile Phase A: CO 2 , Mobile Phase B: IPA(0.1% 2M NH 3 -MEOH); Flow rate: 100 mL/min; Gradient: isocratic 50% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Wave Length: 220/278 nm; RT1(min): 4.85; RT2(min): 6, 2(min): ; Sample Solvent: IPA; Injection Volume: 2 mL; Number Of Runs: 8. The 1 st eluting fraction was concentrated and lyophilized to afford (isomer 1) rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1- yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyrimi din-9-yl)ethyl]amino}benzoic acid (Compound 420; 40.8 mg, 29.08%, ee=100%). The 2 nd eluting fraction was concentrated and lyophilized to afford (isomer 2) rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1- yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyrimi din-9-yl)ethyl]amino}benzoic acid (Compound 421; 35.1 mg, 24.87%, ee=97.2%) Compound 420: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.75 (s, 2H), 8.17 – 8.02 (m, 2H), 7.90 – 7.81 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 14.0 Hz, 2H), 6.54 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.56 (q, J = 7.5 Hz, 1H), 3.65 (d, J = 12.1 Hz, 4H), 3.47 (s, 2H), 2.49 – 2.26 (m, 7H), 2.02-1.88 (m, 1H), 1.66 (d, J = 6.5 Hz, 3H), 0.87-0.59 (m, 4H). LC-MS: (ES+H, m/z): [M+H] + = 584.2 Compound 421: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.74 (s, 2H), 8.19 – 7.99 (m, 2H), 7.96-7.87 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.09 (s, 2H), 6.52 (t, J = 7.5 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.54 (q, J = 6.4 Hz, 1H), 3.64 (d, J = 13.0 Hz, 4H), 3.47 (s, 2H), 2.48 – 2.22 (m, 7H), 2.00-1.84 (m, 1H), 1.64 (d, J = 6.5 Hz, 3H), 0.79-0.61 (m, 4H). LC- MS: (ES+H, m/z): [M+H] + = 584.2 Example 3: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 739) and (S)-2- ((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyri do[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 740) Step 1: Synthesis of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one A solution of 3-bromo-5-methylpyridin-2-amine (20 g, 108 mmol) in acetone (200 mL) was added bis(2,4,6-trichlorophenyl) malonate (55 g, 119 mmol). The reaction mixture was heated to 60 °C for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered to give the title compound (19.5 g, 72%) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.74 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 5.50 (s, 1H), 2.34 (s, 3H). MS: m/z 254.8 (M+H + ). Step 2: Synthesis of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-o ne A solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12.5 g, 49 mmol), K 2 CO 3 (13.5 g, 98 mmol) and TBAI (1.8 mg, 4.9 mmol) in DMF (120 mL) was added BnBr (6.71 g, 39.2 mmol). The reaction was heated to 65 ºC for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was added water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (4 g, 23%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.86 (s, 1H), 7.98 (s, 1H), 7.57 - 7.49 (m, 2H), 7.40 - 7.30 (m, 3H), 5.85 (s, 1H), 5.52 (s, 2H), 2.40 (s, 3H) MS: m/z 345.0 (M+H + ). Step 3: Synthesis of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4- one A mixture of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (3 g, 8.7 mmol), tributyl(1-ethoxyvinyl)stannane (7.85 g, 21.7 mmol) and Pd(dppf)Cl 2 (509 mg, 0.7 mmol) in dioxane (30 mL) was degassed and purged with N 2 for 3 times. The reaction mixture was stirred at 90 °C for 16 h under N 2 atmosphere. After cooling to room temperature, HCl (3 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 50 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.39 g, 51%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.94 (s, 1H), 8.07 (s, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.30 (m, 3H), 5.77 (s, 1H), 5.41 (s, 2H), 2.70 (s, 3H), 2.41 (s, 3H). MS: m/z 309.2 (M+H + ). Step 4: Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4- one (1 g, 3.2 mmol), NH 4 OAc (3.75 g, 48.6 mmol) in MeOH (10 mL), NaBH 3 CN (610 mg, 9.7 mmol) was added. The reaction was heated to 40 ºC for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (200 mL), extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (510 mg, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.79 (s, 1H), 8.02 (s, 1H), 7.54 - 7.26 (m, 5H), 6.42 - 6.09 (m, 2H), 5.77 (s, 1H), 5.54 - 5.38 (m, 2H), 4.99 - 4.75 (m, 1H), 2.41 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). MS: m/z 310.2 (M+H + ). Step 5: Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyri midin-4-one (500 mg, 1.6 mmol), tert-butyl 2-bromobenzoate (540 mg, 2.1 mmol), Cs 2 CO 3 (1.05 g, 3.2 mmol) , Pd 2 (dba) 3 (148 mg, 0.16 mmol) and Xantphos (140 mg, 0.24 mmol) in dioxane (8 mL), the reaction mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (250 mg, 31%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 8.73 (s, 1H), 8.30 - 8.15 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 7.21 - 7.13 (m, 1H), 6.61 - 6.51 (m, 1H), 6.31 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 5.58 - 5.45 (m, 2H), 5.33 - 5.24 (m, 1H), 2.32 (s, 3H), 1.56 (s, 9H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 486.3 (M+H + ). Step 6: Synthesis of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (2.7 g, 5.6 mmol) in MeOH (30 mL) was added wet Pd/C (3 g, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 0.5 h under H 2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (1.7 g, 77%) as yellow oil that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.74 - 8.59 (m, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.71 - 7.65 (m, 1H), 7.26 - 7.14 (m, 1H), 6.59 - 6.50 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.53 (s, 1H), 5.35 - 5.24 (m, 1H), 2.27 (s, 3H), 1.61 - 1.49 (m, 12H). MS: m/z 396.2 (M+H + ). Step 7: Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (500 mg, 1.3 mmol) in DCM (10 mL) was added pyridine (300 mg, 3.8 mmol) and Tf 2 O (535 mg, 1.9 mmol).The mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (510 mg, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.85 - 8.22 (m, 1H), 8.21 (d, J = 6.6 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.79 - 7.78 (m, 1H), 7.19 - 7.15 (m, 1H), 6.59 - 6.56 (m, 1H), 6.52 (s, 1H), 6.29 (d, J = 8.8 Hz, 1H), 5.23 - 5.17 (m, 1H), 2.40 (s, 3H), 1.59 - 1.57 (m, 12H). MS: m/z 528.1 (M+H + ). Step 8: Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (300 mg, 569 umol), K 2 CO 3 (236 mg, 1.7 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (217 mg, 796 umol) (prepared according to the procedure in WO201755305) in dioxane (5 mL) and water (0.5 mL), Pd(PPh 3 ) 4 (66 mg, 57 umol) was added. The reaction mixture was heated to 100 °C and stirred for 2 h under N 2 atmosphere. The reaction was diluted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with (3% MeOH in DCM) to afford the title compound (290 mg, 97%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.76 (s, 1H), 8.70 (s, 1H), 8.27 - 8.38 (m, 2H), 7.85 - 7.79 (m, 1H), 7.75 - 7.66 (m, 1H) , 7.23 - 7.19 (m, 1H), 7.16 (s, 1H), 6.58 - 6.53 (m, 1H), 6.52 - 6.48 (m, 1H), 5.60 - 5.55 (m, 1H), 4.00 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.74 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 524.2 (M+H + ). Step 9: Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, 95 umol) in DCM (3 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 51% - 81% / 0.225% formic acid in water) to give the title compound (5 mg, 11%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.70 ( s, 1H), 8.76 (s, 1H), 8.69 (s, 1H), 8.56 - 8.48 (m, 1H), 8.40 - 8.32 (m, 1H), 7.86 - 7.82 (m, 1H), 7.79 - 7.76 (m, 1H), 7.69 - 7.65 (m, 1H), 7.24 – 7.20 (m, 1H), 7.15 (s, 1H), 6.57 - 6.54 (m, 1H), 6.50 - 6.47 (m, 1H), 5.63 - 5.58 (m, 1H), 4.00 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H). MS: m/z 468.1 (M+H + ). Step 10: Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 739) and (S)-2-((1-(2-(1,3- dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoic acid (Compound 740) 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-py rido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (200 mg, 428 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 30/30; 70 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (66 mg, first peak) as a white solid and (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4 H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (61 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 740: 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.75 (s, 1H), 8.69 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 7.86 - 7.79 (m, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.15 (s, 1H), 6.58 - 6.49 (m, 1H), 6.45 - 6.40 (m, 1H), 5.61 - 5.55 (m, 1H), 4.00 (s, 3H), 2.55 (s, 3H), 2.34 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H). MS: m/z 468.1 (M+H + ) Example 4: Preparation of 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin- 1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)am ino)benzoic acid (Compound 711) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-y l)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712) Step 1: Synthesis of tert-butyl 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (120 mg, 0.31 mmol) in DMF (5 mL) was added PyBOP (189.5 mg, 0.36 mmol), DIEA (0.16 mL, 0.91 mmol). The mixture was stirred at room temperature for 30 min, cis-4,4-difluoro-3,5-dimethylpiperidine (90 mg, 0.61 mmol, prepared according to the procedure in WO2017125) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 80 mL), brine (80 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (80 mg, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.56 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.70 - 7.59 (m, 1H), 7.27 - 7.21 (m, 1H), 6.57 - 6.54 (m, 1H), 6.42 - 6.40 (m, 1H), 5.86 (s, 1H), 5.23 - 5.20 (m, 1H), 2.88 - 2.70 (m, 2H), 2.38 - 2.31 (m, 2H), 2.25 (s, 3H), 2.13 - 2.01 (m, 2H), 1.61 - 1.59 (m, 3H), 1.56 (s, 9H), 1.03 - 0.98 (m, 6H). MS: m/z 527.3 (M+H + ). Step 2: Synthesis of 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7 - methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid To a mixture of tert-butyl 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7 - methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oate (140 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL), then the mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give the title compound (80 mg, 63%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.72 (s, 1H), 8.55 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.61 (s, 1H), 7.24 - 7.21 (m, 1H), 6.57 - 6.53 (m, 1H), 6.39 - 6.37 (m, 1H), 5.86 (s, 1H), 5.25 - 5.22 (m, 2H), 4.56 - 4.42 (m, 2H), 2.79 - 2.73 (m, 2H), 2.24 (s, 3H), 2.11 - 2.05 (m, 2H), 1.58 (d, J = 8.0 Hz, 3H), 1.02 - 0.99 (m, 6H). MS: m/z 471.2 (M+H + ). Step 3: Synthesis of 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-y l)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid (Compound 711) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-y l)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712) 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7 -methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (70 mg, 0.15 mmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250mm*30mm,5um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 65/35; 60 ml/min) to afford 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrim idin-9-yl)ethyl)amino)benzoic acid (Compound 711; 8 mg, first peak) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrim idin-9-yl)ethyl)amino)benzoic acid (Compound 712; 10 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 711: 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.55 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.24 - 7.10 (m, 1H), 6.57 - 6.48 (m, 1H), 6.32 - 6.27 (m, 1H), 5.86 (s, 1H), 5.21 - 5.19 (m, 2H), 4.52 - 4.47 (m, 2H), 2.79 - 2.76 (m, 2H), 2.23 (s, 3H), 2.11 - 2.04 (m, 2H), 1.55 (d, J = 4.0 Hz, 3H), 1.02 - 0.99 (m, 6H). MS: m/z 471.6 (M+H + ). Example 5: Preparation of 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 691) Step 1: Synthesis of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne To a mixture of 3-bromo-5-methyl-pyridin-2-amine (12.3 g, 65.7 mmol) in acetone (200 mL) was heated to 40 °C for 0.5 h, and then bis(2,4,6-trichlorophenyl) 2-methylpropanedioate (34.5 g, 72.3 mmol) (prepared according to the procedure in Bioorg. Med. Chem. Lett., 2021, 47, 128208) was added dropwise at 40 °C. The final mixture was stirred at 65 °C for 4 h. After cooling to room temperature, the reaction mixture was filtrate to give the title compound (15 g, crude) as a yellow solid that required no further purification. 1 H NMR (400MHz, DMSO-d 6 ): δ 11.66 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 2.34 (s, 3H), 1.96 (s, 3H). MS: m/z 268.8 (M+H + ). Step 2: Synthesis of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin -4- one A mixture of 9-bromo-2-hydroxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 37.2 mmol), K 2 CO 3 (10.3 g, 74.3 mmol) and TBAI (1.37 g, 3.72 mmol) in DMF (100 mL) was added (bromomethyl)benzene (3.53 mL, 29.7 mmol). The mixture was stirred at 65 °C for 4 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was added water (1 L) and yellow solid was precipitated, filtrated. The residue was dissolve in ethyl acetate (1 L), washed with brine (500 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (12.7 g, crude) as a yellow solid that required no further purification. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.74 (d, J = 1.6 Hz,, 1H), 8.28 (s, J = 1.6 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.29-7.41 (m, 3H), 5.55 (s, 2H), 2.37 (s, 3H), 2.02 (s, 3H) MS: m/z 359.0 (M+H + ). Step 3: Synthesis of 9-acetyl-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4- one A mixture of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin -4-one (20 g, 55.7 mmol) and Pd(dppf)Cl 2 (2.04 g, 2.78 mmol) in dioxane (200 mL) was degassed and purged with N 2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (40.2 g, 111 mmol) was added, the final mixture was stirred at 90 °C for 16 h under N 2 atmosphere. After cooling to room temperature, HCl (1 M, 20 mL) was added, the mixture was stirred at room temperature for 0.5 h. To the mixture was added 10% KF solution (300 mL), stirred at room temperature for 2 h. The mixture was filtered and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (200 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified with silica gel chromatography (solvent gradient: 0 - 100% EtOAc in petroleum ether) to give the title compound (13.5 g, 75%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.90 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.45 - 7.32 (m, 5H), 5.48 (s, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H). MS: m/z 323.0 (M+H + ). Step 4: Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-acetyl-2-benzyloxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-o ne (8 g, 24.8 mmol), NH 4 OAc (28.7 g, 372 mmol), NaBH 3 CN (4.68 g, 74.45 mmol) and AcOH (1.42 mL, 24.82 mmol) in MeOH (100 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 50 °C for 4 h under N 2 atmosphere. After cooling to room temperature, MeOH (100 mL) was removed in vacuo, EtOAc (300 mL) was added, and the mixture was washed with sat. aq. NaHCO 3 (200 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (5 g, 62%) as yellow oil. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.69 (s, 1H), 7.92 (s, 1H), 7.46-7.44 (m, 2H), 7.40 - 7.36 (m, 2H), 7.32 - 7.29 (m, 1H), 5.52 (s, 2H), 4.68 - 4.63 (m, 3H),2.39 (s, 3H), 2.05 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). MS: m/z 324.4 (M+H + ). Step 5: Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a] pyrimidin- 4-one (15.1 g, 46.7 mmol), tert-butyl 2-bromobenzoate (18.0 g, 70.0 mmol), Cs 2 CO 3 (30.4 g, 93.4 mmol), Pd 2 (dba) 3 (2.05 g, 2.24 mmol) and Xantphos (2.70 g, 4.67 mmol) in dioxane (200 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, dioxane was removed in vacuo to give the crude residue. The crude residue was purified with silica gel chromatography (solvent gradient: 0 - 100% DCM in petroleum ether) to give the title compound (13.9 g, 60%) as yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.69 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.32-7.26 (m, 1H), 7.15 - 7.10 (m, 1H), 6.56 - 6.54 (m, 1H), 6.29 (d, J = 8.8 Hz, 1H), 5.63-5.60 (m, 2H), 5.31 - 5.28 (m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.56 (s, 9H), 1.52 (d, J = 6.4 Hz, 3H). MS: m/z 500.3 (M+H + ). Step 6: Synthesis of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (5 g, 10.0 mmol), Pd/C (2.72 g, 2.00 mmol, 10% purity) in MeOH (15 mL) was degassed and purged with H 2 (15 psi) for 3 times, and then the mixture was stirred at room temperature for 1 h under H 2 atmosphere. After the reaction was completed, the reaction mixture was filtrated. The filtrate was concentrated to give the tilte compound (4 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.47 (s, 1H), 8.63 (s, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.78 – 7.76 (m, 1H), 7.60 (s, 1H), 7.22-7.18 (m, 1H), 6.57 – 6.53 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.38 – 5.32 (m, 1H), 2.27 (s, 3H), 1.99 (s, 3H), 1.58 (s, 9H), 1.57 (d, J = 6.8 Hz, 3H). MS: m/z 410.2 (M+H + ). Step 7: Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (0.6 g, 1.47 mmol) in DCM (15 mL) was added pyridine (355 uL, 4.40 mmol) and Tf 2 O (363 uL, 2.20 mmol).The mixture was stirred at 0 °C for 2 h. The mixture was diluted with DCM (50 mL), washed with 1M HCl (20 mL), brine (20 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated to give the crude which was purified with silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (0.72 g, 90%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.46 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.57 (s, 1H), 7.21 – 7.17 (m, 1H), 6.56 – 6.53 (m, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.36 – 5.33 (m, 1H), 2.26 (s, 3H), 1.98 (s, 3H), 1.59 (s, 9H), 1.56 (d, J = 6.4 Hz, 3H). MS: m/z 542.2 (M+H + ). Step 8: Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 0.19 mmol), K 2 CO 3 (77 mg, 0.55 mmol) and (4-fluorophenyl)boronic acid (78 mg, 0.55 mmol) in dioxane (3 mL) and water (1 mL) was added Pd(PPh 3 ) 4 (43 mg, 0.03 mmol). The reaction was stirred at 100 ºC for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (50 mg, 56%) as yellow oil. MS: m/z 488.2 (M+H + ). Step 9: Synthesis of 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 721) To a solution of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 0.13 mmol) in DCM (3 mL) was added TFA(0.2 mL, 26 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The crude residue was purified by reverse phase chromatography (acetonitrile 65-95% / 0.225% formic acid in water) to afford the title compound (15 mg, 28%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 8.61 (s, 1H), 7.82 - 7.79 (m, 3H), 7.66 (s, 1H), 7.39 - 7.34 (m, 2H), 7.16 - 7.13 (m, 1H), 6.53 - 6.52 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.38 - 5.39 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 432.0 (M+H + ). Example 6: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 605) and (S)-2- ((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyri midin-9- yl)ethyl)amino)benzenesulfonamide (Compound 606) Step 1: Synthesis of 2-(benzyloxy)-9-(1-hydroxyethyl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-benzyloxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one (5 g, 16.2 mmol) in MeOH (50 mL) was added NaBH 4 (950 mg, 25 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h under N 2 atmosphere. The mixture was quenched with sat. aq. NH 4 Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.88 g, 77%) as a yellow solid. MS: m/z 311.2 (M+H + ). Step 2: Synthesis of 2-(benzyloxy)-9-(1-bromoethyl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 2-benzyloxy-9-(1-hydroxyethyl)-7-methyl-pyrido[1,2-a]pyrimid in-4-one (3.88 g, 12.5 mmol) in DCM (40 mL) was added PBr 3 (6.77 g, 25 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h under N 2 atmosphere. The mixture was quenched with sat. aq. NaHCO 3 (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (2.25 g, 48%) as a yellow solid. MS: m/z 375.1 (M+2+H + ). Step 3: Synthesis of 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidi n-9- yl)ethyl)amino)benzenesulfonamide To a solution of 2-benzyloxy-9-(1-bromoethyl)-7-methyl-pyrido[1,2-a]pyrimidin -4-one (500 mg, 1.34 mmol) in dioxane (6 mL) was added 2-aminobenzenesulfonamide (1.38 g, 8 mmol) at room temperature. The reaction was stirred at 100 ºC for 2 h under N 2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (370 mg, 59%) as colorless oil. NMR (400 MHz, DMSO-d 6 ): δ 8.73 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 1.2, 8.0 Hz, 1H), 7.55 (s, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.40 - 7.35 (m, 2H), 7.33 - 7.29 (m, 1H), 7.24 - 7.19 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.68 - 6.57 (m, 2H), 6.43 (d, J = 6.0 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 5.52 (s, 2H), 5.33 (t, J = 6.4 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 2.30 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H). MS: m/z 465.1 (M+H + ). Step 4: Synthesis of 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide: To a solution of 2-[1-(2-benzyloxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (370 mg, 796 umol) in MeOH (5 mL) was added palladium on carbon (250 mg, 239 umol). The reaction was stirred at room temperature for 2 h under a hydrogen atmosphere. The reaction was filtrated and concentrated in vacuo to give the title compound (160 mg, crude) as a white solid. MS: m/z 375.1 (M+H + ). Step 5: Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide To a solution of 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (100 mg, 267 umol) in DMF (5 mL) was added PyBOP (167 mg, 320 umol), DIEA (0.23 mL, 1.34 mmol). The mixture was stirred at room temperature for 30 min, isoindoline (96 mg, 800 umol) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 100 mL) and brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give the title compound (100 mg, 78%) as a yellow solid. MS: m/z 476.0 (M+H + ). Step 6: Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide & (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfon amide 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9- yl)ethyl)amino)benzenesulfonamide (100 mg, 0.21 mmol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 35/65; 60 ml/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 605; 30 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (Compound 606; 30 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 605: 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.59 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.52 (s, 2H), 7.42 (d, J = 3.6 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.48 - 6.44 (m, 2H), 5.44 (s, 1H), 5.42 - 5.38 (m, 1H), 5.00 (s, 2H), 4.74 (s, 2H), 2.25 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). MS: m/z 476.1 (M+H + ). Example 7: Preparation of 2-(((R)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-ox o-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 582) and 2-(((S)-1-(2-((3aR,6aS)- 5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl- 4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 583)
Step 1: Synthesis of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate To a solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (500 mg, 2.22 mmol) in DCM (10 mL) was added DAST (1.43 g, 8.88 mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 16 h under N 2 atmosphere. The mixture was quenched with sat. aq. NaHCO 3 (10 mL), diluted with water (20 mL), extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (450 mg, 82%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.58 - 3.43 (m, 2H), 3.19 - 3.03 (m, 2H), 2.85 - 2.77 (m, 2H), 2.44 - 2.25 (m, 2H), 2.11 - 1.90 (m, 2H), 1.39 (s, 9H). Step 2: Synthesis of (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole trifluoroacetate To a solution of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (450 mg, 1.82 mmol) in DCM (10 mL) was added TFA (1.04 g, 9 mmol). The reaction mixture was stirred at room temperature for 2 h under N 2 atmosphere. The mixture was concentrated in vacuo to give the title compound (450 mg, 82%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.56 - 3.42 (m, 2H), 2.76 - 2.72 (m, 2H), 2.62 - 2.55 (m, 2H), 2.30 - 2.13 (m, 2H), 1.92 - 1.71 (m, 2H). Step 3: Synthesis of tert-butyl 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c] pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate To a solution of tert-butyl 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzoate (180 mg, 45 umol) in DMF (5 mL) was added PyBOP (280 mg, 543 umol), DIEA (0.24 mL, 1.81 mmol). The mixture was stirred at room temperature for 30 min, (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole trifluoroacetate (200 mg, 1.36 mmol) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 100 mL) and brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (120 mg, 50%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.55 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 5.6, 1H), 7.62 (s, 1H), 7.24 ( t, J = 7.6 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.23 (q, J = 6.8 Hz, 1H), 3.95 - 3.65 (m, 2H), 3.57 - 3.41 (m, 2H), 3.18 - 3.15 (m, 1H), 3.01 - 2.96 ( s, 2H), 2.46 - 2.36 (m, 2H), 2.24 (s, 3H), 2.19 - 1.99 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H). MS: m/z 525.3 (M+H + ). Step 4: 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol -2(1H)-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid To a mixture of tert-butyl 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol - 2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethy l)amino)benzoate (120 mg, 228 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then dulited with MeOH (2mL). The mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 10-33% / 0.225% formic acid in water) to give the title compound (40 mg, 37%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.72 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.22 - 7.20 (m, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.27 - 5.15 (m, 1H), 3.91 - 3.64 (m, 2H), 3.54 - 3.39 (m, 2H), 2.96 (s, 2H), 2.44 - 2.36 (m, 2H), 2.23 (s, 3H), 2.17 - 2.04 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 469.0 (M+H + ). Step 5: Synthesis of 2-(((R)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]py rrol- 2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethy l)amino)benzoic acid (Compound 582) and 2-(((S)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]py rrol-2(1H)- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (Compound 583) 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol -2(1H)-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (40 mg, 85 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 30/70; 60 ml/min) to afford 2-(((R)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-ox o-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (15 mg, first peak) and 2-(((S)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-ox o-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (11 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 583: 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.70 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.22 - 7.20 (m, 1H), 6.54 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.27 - 5.15 (m, 1H), 3.91 - 3.64 (m, 2H), 3.54 - 3.39 (m, 2H), 2.96 (s, 2H), 2.44 - 2.36 (m, 2H), 2.23 (s, 3H), 2.17 - 2.04 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 469.0 (M+H + ). Example 8: Preparation of (S)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid (Compound 536) Step 1: Synthesis of tert-butyl 2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)inda zol-3- amine (155 mg, 569 umol, prepared according to the procedure in WO2015140054), tert-butyl 2- [1-[7-methyl-4-oxo-2-(trifluoromethylsulfonyloxy)pyrido[1,2- a]pyrimidin-9- yl]ethylamino]benzoate (150 mg, 284 umol), K 2 CO 3 (118 mg, 853 umol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh 3 ) 4 (33 mg, 28 umol). The reaction mixture was stirred at 100 °C for 2 h under N 2 atmosphere. After cooling to room temperature, EtOAc (30 mL) was added, and the mixture was washed with brine (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (125 mg, 84%) as a brown solid. MS: m/z 525.1 (M+H + ). Step 2: Synthesis of tert-butyl (R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oate & tert-butyl (S)-2-((1-(2- (3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4 H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (125 mg, 238 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 65/35; 60 ml/min) to afford tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)- 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate (60 mg, first peak) and tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4 H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, second peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. Step 3: Synthesis of (S)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-o xo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536) To a mixture of tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 114 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 3-33% / 0.225% formic acid in water) to give the title compound (Compound 536; 18 mg, 33%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.76 (s, 1H), 8.72 (s, 1H), 8.67 - 8.57 (m, 1H), 8.23 - 8.21 (m, 1H), 7.83 - 7.81 (m, 1H), 7.73 - 7.72 (m, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.19 - 7.15 (m, 1H), 6.95 (s, 1H), 6.53 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.63 (s, 1H), 3.77 (s, 3H), 2.33 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 468.5 (M+H + ). Example 9: Preparation of rel-(R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid (Compound 535) and rel-(R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl -4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536) 2-({1-[2-(3-amino-1-methylindazol-5-yl)-7-methyl-4-oxopyrido [1,2-a]pyrimidin-9- yl]ethyl}amino)benzoic acid (100 mg, 0.213 mmol, 1 equiv) was isolated by prep-chiral-HPLC with the following conditions : Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B (isocratic) in 18 min; Wave Length: 220/203 nm; RT1(min): 9.69; RT2(min): 14.55; Sample Solvent: HFIP; Injection Volume: 0.5 mL; Number Of Runs: 8. The 1 st eluting fraction was concentrated under vacuum and lyophilized to afford rel-(R)-2-((1-(2-(3- amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2 -a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 535; 26.3 mg, 25.98%) as an yellow solid. The 2 nd eluting fraction was concentrated under vacuum and lyophilized to afford rel-(R)-2-((1-(2-(3- amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2 -a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 536; 13.4 mg, 13.28%) as a yellow solid. Compound 535: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 – 8.72 (m, 2H), 8.71 – 8.33 (m, 1H), 8.23 (dd, J = 8.9, 1.6 Hz, 1H), 7.84 (dd, J = 8.0, 1.7 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.20 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.97 (s, 1H), 6.55 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.66 (s, 1H), 3.78 (s, 3H), 2.33 (d, J = 1.2 Hz, 3H), 1.70 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 469.2. Compound 536: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.91 – 8.68 (m, 2H), 8.52 (s, 1H), 8.23 (dd, J = 8.9, 1.7 Hz, 1H), 7.83 (dd, J = 8.0, 1.8 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.20 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.96 (s, 1H), 6.55 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.65 (s, 1H), 3.78 (s, 3H), 2.44 – 2.22 (m, 3H), 1.70 (d, J = 6.5 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 469.2. Example 10: Preparation of rel-2-{[(1R)-1-[7-methyl-4-oxo-2-(pyridin-4- yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 439) and rel-2-{[(1R)- 1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin-9-y l]ethyl]amino}benzamide (Compound 440) 2-({1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin -9- yl]ethyl}amino)benzamide (76 mg, 0.190 mmol, 1 equiv) was isolated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B (isocratic)in 37 min; Wave Length: 206/256 nm; RT1(min): 18.85; RT2(min): 26.65; Sample Solvent: MeOH: DCM=1: 2; Injection Volume: 0.7 mL; Number Of Runs: 5; The 1 st eluting fraction was concentrated under reduced pressure to afford rel-2-{[(1R)- 1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin-9-y l]ethyl]amino}benzamide (Compound 439; 26.9 mg, 35.39%,ee=100%) as a white solid. The 2nd eluting fraction was concentrated under reduced pressure to afford rel-2-{[(1R)-1-[7-methyl-4-oxo-2-(pyridin-4- yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 440; 34.1 mg, 44.87%, ee=99.59%) as a white solid. Compound 439: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.85 (d, J = 6.4 Hz, 1H), 8.81 – 8.75 (m, 3H), 8.25 – 8.20 (m, 2H), 7.93 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.67-7.61(m, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 7.15 – 7.06 (m, 1H), 6.56-6.43(m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.56-5.44(m, 1H), 2.40 – 2.31 (m, 3H), 1.64 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 400.1 Compound 440: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.85 (d, J = 6.3 Hz, 1H), 8.81 – 8.72 (m, 3H), 8.25 – 8.20 (m, 2H), 7.93 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.67-7.61(m, 1H), 7.28 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.15 – 7.06 (m, 1H), 6.56-6.43(m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.56-5.44(m, 1H), 2.40 – 2.31 (m, 3H), 1.64 (d, J = 6.5 Hz, 3H). LC-MS: (ES+H, m/z): [M+H] + = 400.1 Example 11: Preparation of 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (Compound 1413) Step 1: Synthesis of 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]oxazol-2(3H)-one To a solution of 5-chloro-7-methyl-3H-1,3-benzoxazol-2-one (0.3 g, 1.63 mmol) (prepared according to the procedure in US2015210655) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (830 mg, 3.27 mmol) in dioxane (10 mL) was added Xphos-Pd-G2 (128 mg, 163 umol) and KOAc (401 mg, 4.09 mmol). The reaction mixture was stirred at 110 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 7- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[ d]oxazol-2(3H)-one (200 mg, 45%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 7.44 (s, 1H), 7.33 (s, 1H), 2.39 (s, 3H), 1.35 (s, 12H). MS: m/z 276.1 (M+H + ). Step 2 - Synthesis of tert-butyl 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 132 umol) and 7-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (73 mg, 265 umol) in dioxane (6 mL) and water (1.5 mL) was added Pd(PPh 3 ) 4 (15 mg, 13 umol) and K 2 CO 3 (55 mg, 398 umol). The mixture was stirred at 100 °C for 4 h under N 2 atmosphere. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to tert-butyl 2-((1-(7- methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-4-o xo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (40 mg, 58%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 8.75 (s, 1H), 8.34 (d, J = 4.8 Hz, 1H), 7.90 (s, 1H), 7.82 - 7.80 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.46 ( d, J = 8.4 Hz, 1H), 5.57 - 5.44 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 527.2 (M+H + ). Step 3 - Synthesis of 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol- 5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzo ic acid (Compound 319) To a mixture of tert-butyl 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (30 mg, 57 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. The residue was adjusted pH to 6 with NH 3 •H 2 O (25% w/w) solution. The resulting mixture was purified by Prep-TLC (10% MeOH in DCM) to give 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol- 5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (7 mg, 23%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.72 (s, 1H), 11.73 (s, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 7.90 (s, 1H), 7.85 - 7.75 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.58 - 5.49 (m, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H). MS: m/z 471.2 (M+H + ). Example 12: Preparation of (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 393) Step 1 - tert-butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 379 umol) in DMF (2 mL) was added DIEA (198 uL, 1.14 mmol) and PyBOP (236 mg, 455 umol). The reaction mixture was stirred at room temperature for 10 minutes, then isoindoline (135 mg, 1.14 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 30 mL) and brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert- butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9- yl)ethyl)amino)benzoate (150 mg, 79%) as a white solid. MS: m/z 497.2 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 302 umol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-TLC (10% MeOH in DCM) to give 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9-yl)ethyl)amino)benzoic acid (100 mg, 68%) as a yellow solid. MS: m/z 441.2 (M+H + ). Step 3 - (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-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 (Compound 403) 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9- yl)ethyl)amino)benzoic acid (100 mg, 227 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ-H (250mm*30mm,5um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 70/30; 60 ml/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (41 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (34 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 403: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (s, 2H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J =1.6 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.35 - 7.29 (m, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.42 (s, 1H), 5.38 - 5.31 (m, 1H), 5.11 - 4.86 (m, 2H), 4.78 - 4.68 (m, 2H), 2.25 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). MS: m/z 441.1 (M+H + ). Example 13: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide (Compound 620) Step 1 - Synthesis of 9-bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one: To a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (5 g, 20 mmol) in DMF (100 mL) was added PyBOP (12 g, 23 mmol) and DIEA (10.2 mL, 59 mmol). The mixture was stirred at room temperature for 20 minutes, isoindoline hydrochloride (4.7 g, 30 mmol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 200 mL), brine (200 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 9- bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin -4-one (6.5 g, 93%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.36 - 7.32 (m, 2H), 5.42 (s, 1H), 4.99 - 4.92 (m, 2H), 4.78 - 4.69 (m, 2H), 2.25 (s, 3H). MS: m/z 358.0 (M+H + ). Step 2 - Synthesis of 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2 - a]pyrimidin-4-one: A mixture of 9-bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimid in-4-one (6.5 g, 18 mmol), tributyl(1-ethoxyvinyl)stannane (14 g, 39 mmol), Pd(dppf)Cl 2 (668 mg, 912 umol) in dioxane (100 mL) was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, the mixture was quenched with 100 mL of 10% KF aqueous solution, stirred for 30 min. The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2 -a]pyrimidin-4-one (4.1 g, 64%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.37 - 7.30 (m, 2H), 5.65 (s, 1H), 5.42 (s, 1H), 4.89 (s, 2H), 4.80 (s, 1H), 4.72 (s, 2H), 3.96 (q, J = 6.8 Hz, 2H), 2.34 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H). MS: m/z 348.2 (M+H + ). Step 3 - Synthesis of 9-acetyl-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2 - a]pyrimidin-4-one (1 g, 2.88 mmol) in THF (10 mL) was added 1M HCl (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 7 with sat. aq. NaHCO 3 , then extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 9-acetyl-2- (isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.9 g, crude) as a brown solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.37 - 7.30 (m, 2H), 5.43 (s, 1H), 4.93 (s, 2H), 4.73 (s, 2H), 2.84 (s, 3H), 2.35 (s, 3H). Step 4 - Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1, 2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimi din-4-one (1 g, 3.13 mmol) in MeOH (20 mL) was added NaBH 4 (142 mg, 3.76 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N 2 atmosphere. The mixture was quenched with 1M HCl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1- hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]p yrimidin-4-one (0.97 g, 96%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.42 (s, 2H), 7.35 - 7.29 (m, 2H), 5.42 - 5.27 (m, 3H), 4.99 - 4.65 (m, 4H), 2.33 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H). MS: m/z 322.2 (M+H + ). Step 5 - Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1, 2- a]pyrimidin-4-one (957 mg, 2.98 mmol) in DCM (10 mL) was added PBr 3 (1.6 g, 5.91 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N 2 atmosphere. The mixture was quenched with sat. aq. NaHCO 3 (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7- methyl-4H-pyrido[1,2-a]pyrimidin-4-one (455 mg, 40%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.41 - 7.32 (m, 4H), 6.16 - 6.09 (m, 1H), 5.58 (s, 1H), 5.19 - 4.95 (m, 2H), 4.75 - 4.68 (m, 2H), 2.39 (s, 3H), 2.14 (d, J = 6.8 Hz, 3H). Step 6 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin- 4-one (100 mg, 260 umol) and 2-aminobenzamide (71 mg, 520 umol) in dioxane (1 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 55% - 85% / 0.225% formic acid in water) to give 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide (30 mg, 26%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (d, J = 6.8 Hz, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.64 - 7.57 (m, 2H), 7.45 - 7.41 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 (s, 1H), 7.16 - 7.12 (m, 1H), 6.53 - 6.49 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 5.36 - 5.25 (m, 1H), 5.12 - 4.87 (m, 2H), 4.76 - 4.70 (m, 2H), 2.25 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). MS: m/z 440.2 (M+H + ). Step 7 - Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide (Compound 37) & (S)-2-((1-(2-(isoindolin-2-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz amide 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9- yl)ethyl)amino)benzamide (20 mg, 45 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 55/45; 60 mL/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin- 9-yl)ethyl)amino)benzamide (7 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 646: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (d, J = 6.4 Hz, 1H), 8.58 (s, 1H), 7.89 (s, 1H), 7.63 - 7.58 (m, 2H), 7.46 - 7.40 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 (s, 1H), 7.15 - 7.11 (m, 1H), 6.52 - 6.48 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 5.33 - 5.27 (m, 1H), 5.09 - 4.88 (m, 2H), 4.78 - 4.68 (m, 2H), 2.25 (s, 3H), 1.61 (d, J = 6.4 Hz, 3H). MS: m/z 440.1 (M+H + ). Example 14: Preparation of 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 416) Step 1 - Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 284 umol), 3-pyridylboronic acid (87 mg, 711 umol), Pd(PPh 3 ) 4 (66 mg, 57 umol), K 2 CO 3 (118 mg, 853 umol) in dioxane (1.5 mL) and water (0.15 mL) was stirred at 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 77%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.45 (s, 1H), 8.79 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.74 - 7.79 (m, 1H), 7.22 - 7.18 (m, 1H), 7.16 (s, 1H), 6.57 - 7.53 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.55 - 5.49 (m, 1H), 2.37 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 457.1 (M+H + ). Step 2 - Synthesis of 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 219 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 27% - 57% / 0.225% formic acid in water) to give 2-((1-(7-methyl- 4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl) amino)benzoic acid trifluoroacetate (Compound 426) (70 mg, 80%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 9.45 (d, J = 1.6 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 6.4 Hz, 1H), 7.79 - 7.83 (m, 2H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 - 7.23 (m, 1H), 7.17 (s, 1H), 6.57 - 6.53 (m, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.58 - 5.52 (m, 1H), 2.36 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 401.0 (M+H + ). Example 15: Preparation of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 1412) Step 1 - Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 366 umol) in DMF (3 mL) was added DIEA (447 uL, 2.56 mmol) and PyBOP (248 mg, 476 umol). The mixture was stirred at room temperature for 20 min, isoindoline hydrochloride (257 mg, 1.65 mmol) was added. The final mixture was stirred at 50 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was poured into 1M aq. HCl (30 mL). The suspension solution was filtered, the filter cake was dissolved in EtOAc (100 mL). The mixture was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimid in-9-yl)ethyl)amino)benzoate (110 mg, 32%) as a white solid. MS: m/z 511.2 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 764) To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (30 mg, 59 umol) in DCM (1.5 mL) was added TFA (0.5 ml). The mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 54% - 84% / 0.225% formic acid in water) to give 2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimid in-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 764) (11 mg, 41%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.73 (s, 1H), 8.56 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 - 7.59 (m, 1H), 7.36 - 7.43 (m, 2H), 7.27 - 7.34 (m, 2H), 7.26 - 7.20 (m, 1H), 6.56 - 6.52 (m, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.38 - 5.32 (m, 1H), 5.23 - 5.13 (m, 4H), 2.42 (s, 3H), 2.26 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). MS: m/z 455.0 (M+H + ). Example 16: Preparation of (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 431) Step 1 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 506 umol) in DMF (4 mL) was added DIEA (440 uL, 2.53 mmol) and PyBOP (316 mg, 607 umol). The mixture was stirred at room temperature for 30 minutes, 4,4-dimethyl-1,4-azasilinane hydrochloride (252 mg, 1.52 mmol) was added. The final mixture was stirred at 40 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (30 mL x 3) and brine (30 mL), dried over anhydrous Na 2 SO 4 , concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4,4-dimethyl- 1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidi n-9-yl)ethyl)amino)benzoate (200 mg, 78%) as a white solid. MS: m/z 507.3 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 296 umol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 3% - 33% / 0.225% formic acid in water) to give 2- ((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 67%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.52 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.25 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.59 (s, 1H), 5.26 - 5.19 (m, 1H), 3.89 - 3.83 (m, 4H), 2.23 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 0.86 - 0.74 (m, 4H), 0.10 (s, 6H). MS: m/z 451.2 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-o xo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 446) and (S)-2-((1- (2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyri do[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4 H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (85 mg, 189 umol) was separated by using chiral SFC (REGIS (S, S) WHELK-O1 (250mm*25mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 70/30; 80 mL/min) to afford (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-o xo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (16 mg, first peak) and (S)-2-((1-(2-(4,4- dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)benzoic acid (25 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 446: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 - 8.43 (m, 2H), 7.81 (dd, J = 8.0, 4.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.59 (s, 1H), 5.27 - 5.17 (m, 1H), 3.90 - 3.84 (m, 4H), 2.22 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 0.84 - 0.73 (m, 4H), 0.10 (s, 6H). MS: m/z 451.2 (M+H + ). Example 17: Preparation of 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 652) Step 1 - Synthesis of tert-butyl 2-((1-(7-methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 506 umol) in DMF (2 mL) was added PyBOP (316 mg, 607 umol) and DIEA (440 uL, 2.53 mmol). The reaction mixture was stirred at room temperature for 10 min, then 1-methylisoindoline hydrochloride (129 mg, 759 umol) was added. The reaction mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 30 mL) and brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 70% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7- methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoate (200 mg, 77%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, J = 0.8 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.67 - 7.62 (m, 1H), 7.42 - 7.37 (m, 2H), 7.34 - 7.31 (m, 2H), 7.27 - 7.20 (m, 1H), 6.60 - 6.51 (m, 1H), 6.50 - 6.29 (m, 1H), 5.71 - 5.40 (m, 2H), 5.39 - 5.29 (m, 1H), 4.95 - 4.57 (m, 2H), 2.26 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.62 (s, 3H), 1.57 - 1.52 (m, 9H). MS: m/z 511.2 (M+H + ). Step 2 - Synthesis of tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((S)-1-(7-methyl-2- ((S)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidi n-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((R)-1-(7-methyl-2-((R)-1-methylisoindolin-2-yl)-4-oxo-4H -pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((S)-1-(7-methyl-2-((R)-1- methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate tert-butyl 2-((1-(7-methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[ 1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 392 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 75/25; 80 mL/min) to afford tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, first peak), tert-butyl 2-(((S)- 1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (33 mg, second peak), tert-butyl 2-(((R)-1-(7-methyl-2-((R)-1- methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate (32 mg, third peak) and tert-butyl 2-(((S)-1-(7-methyl-2-((R)-1-methylisoindolin-2-yl)-4-oxo-4H - pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (33 mg, fourth peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.2 (M+H + ). Step 3 - Synthesis of 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H - pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H - pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, 69 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give 2- (((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H-p yrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 680) (13 mg, 40%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.63 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.63 (s, 1H), 7.43 - 7.37 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 - 7.19 (m, 1H), 6.56 - 6.52 (m, 1H), 6.40 (s, 1H), 5.74 - 5.30 (m, 3H), 5.02 - 4.56 (m, 2H), 2.26 (s, 3H), 1.65 - 1.51 (m, 6H). MS: m/z 455.2 (M+H + ). Example 18: Preparation of (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoic acid (Compound 593) Step 1 - Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiaz ol- 2(3H)-one To a solution of 5-chloro-3H-1,3-benzothiazol-2-one (1 g, 5.39 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (4.1 g, 16.16 mmol) in dioxane (10 mL) was added Xphos-Pd-G2 (424 mg, 539 umol) and KOAc (1.59 g, 16.16 mmol). The reaction mixture was stirred at 110 °C for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiaz ol-2(3H)- one (1.4 g, 93%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 7.6, 1.2 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 1.29 (s, 12H). MS: m/z 277.8 (M+H + ). Step 2 - Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 284 umol) and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-on e (158 mg, 569 umol) in dioxane (2 mL) and water (0.2 mL) was added K 2 CO 3 (118 mg, 853 umol) and Pd(PPh 3 ) 4 (33 mg, 29 umol). The mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 40% EtOAc in petroleum ether) to give tert- butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5- yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (36 mg, 24%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.76 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 8.4, 1.6 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.71 (m, 2H), 7.22 - 7.18 (m, 1H), 7.01 (s, 1H), 6.59 - 6.52 (m, 2H), 6.45 (d, J = 8.4 Hz, 1H), 5.56 - 5.50 (m, 1H), 2.36 (s, 3H), 1.71 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 529.2 (M+H + ). Step 3 - Synthesis of tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate & tert- butyl (S)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazo l-5-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5- yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (94 mg, 178 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 50/50; 60 ml/min) to afford tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate (12 mg, first peak) and tert-butyl (S)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazo l-5-yl)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (12 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 529.2 (M+H + ). Step 4 - Synthesis of (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazo l- 5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl) ethyl)amino)benzoate (12 mg, 23 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then dissolved in MeOH (2 mL). The mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 45 - 75% / 0.225% formic acid in water) to give (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazo l-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 613) (4 mg, 35%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 8.70 - 8.57 (m, 1H), 8.08 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.01 (s, 1H), 6.56 - 6.52 (m, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.60 - 5.49 (m, 1H), 2.35 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H). MS: m/z 473.0 (M+H + ). Example 19: Preparation of (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 424) Step 1 - Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 189 umol), K 2 CO 3 (79 mg, 0.56 mmol) and (4-fluorophenyl)boronic acid (53 mg, 379 umol) in dioxane (3 mL) and water (0.3 mL), Pd(PPh 3 ) 4 (22 mg, 19 umol) was added. The reaction mixture was heated to 100 °C and stirred for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL) and EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (72 mg, 80%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 8.76 (s, 1H), 8.41 - 8.27 (m, 3H), 7.85 - 7.73 (m, 2H), 7.41 - 7.33 (m, 2H), 7.25 - 7.16 (m, 1H), 7.05 (s, 1H), 6.58 - 6.51 (m, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.55 - 5.48 (m, 1H), 2.35 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.54 (s, 9H). MS: m/z 474.2 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 148 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 3% MeOH in DCM) to give 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (57 mg, 35%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.76 (s, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.39 - 8.32 (m, 2H), 7.85 - 7.75 (m, 2H), 7.41 - 7.33 (m, 2H), 7.24 - 7.15 (m, 1H), 7.06 (s, 1H), 6.58 - 6.51 (m, 1H), 6.41 (d, J = 8.8 Hz, 1H), 5.60 - 5.51 (m, 1H), 2.34 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H). MS: m/z 418.0 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 438) and (S)-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-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoic acid (30 mg, 72 umol) was separated by using chiral SFC (DAICEL CHIRALCEL IC (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 50/50; 70 mL/min) to afford (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin- 9-yl)ethyl)amino)benzoic acid (10 mg, first peak) and (S)-2-((1-(2-(4-fluorophenyl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (4 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 438: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.80 (s, 1H), 8.75 (s, 1H), 8.57 - 8.47 (m, 1H), 8.38 - 8.32 (m, 2H), 7.84 - 7.79 (m, 1H), 7.77 (s, 1H), 7.41 - 7.33 (m, 2H), 7.22 - 7.16 (m, 1H), 7.06 (s, 1H), 6.58 - 6.50 (m, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.59 - 5.50 (m, 1H), 2.34 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H). MS: m/z 418.0 (M+H + ). Example 20: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (Compound 696) Step 1 - Synthesis of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1H-pyrazolo[3,4-b]pyridine A mixture of 5-bromo-1,3-dimethyl-pyrazolo[3,4-b]pyridine (710 mg, 3.14 mmol) (prepared according to the procedure in WO2016123629), Pd(dppf)Cl 2 (230 mg, 314 umol), KOAc (925 mg, 9.42 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n- 2-yl)-1,3,2-dioxaborolane (2.39 g, 9.42 mmol) in dioxane (8 mL) was stirred at 100 ºC for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (700 mg, 82%) as a brown solid. MS: m/z 274.1 (M+H + ). Step 2 - Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (193 mg, 366 umol), 1,3-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyrid ine (200 mg, 732 umol), K 2 CO 3 (152 mg, 1.10 mmol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh 3 ) 4 (42 mg, 37 umol). The reaction mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by column chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-met hyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (90 mg, 47%) as a brown solid. MS: m/z 525.1 (M+H + ). Step 3 - Synthesis of tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin- 5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)am ino)benzoate & tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7 -methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-met hyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 133 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,5um); Supercritical CO 2 / i-PrOH + 0.1% NH 3 •H 2 O = 70/30; 60 ml/min) to afford tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H- pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate (20 mg, first peak) and tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H- pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate (25 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 525.1 (M+H + ). Step 4 - Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7 - methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid To a mixture of tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7 - methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oate (20 mg, 38 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 30 - 70% / 0.225% formic acid in water) to give (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7 -methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 726) (7 mg, 23%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (d, J = 2.0 Hz, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.71 - 8.59 (m, 1H), 7.84 - 7.79 (m, 2H), 7.24 (s, 1H), 7.21 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.62 - 5.53 (m, 1H), 4.03 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H), 1.71 (d, J = 6.4 Hz, 3H). MS: m/z 469.1 (M+H + ). Example 21: Preparation of 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (Compound 1411) Step 1 - Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl) amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 185 umol), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3, 4-b]pyridine (101 mg, 369 umol) and K 2 CO 3 (77 mg, 554 umol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh 3 ) 4 (21 mg, 18 umol). The reaction mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by column chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (34 mg, 34%) as a brown solid. MS: m/z 539.1 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate (34 mg, 63 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7-d imethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 752) (11 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.51 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.55 - 7.51 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.48 - 5.34 (m, 1H), 4.03 (s, 3H), 2.56 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 483.1 (M+H + ). Example 22: Preparation of 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoic acid (Compound 1410) Step 1 - Synthesis of 5-bromo-1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridine To a solution of 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (1.11 g, 4.93 mmol) (prepared according to the procedure in US201182138) in DMF (10 mL) was added NaH (237 mg, 5.92 mmol, 60% purity) and MeI (338 uL, 5.42 mmol) under N 2 atmosphere at 0 ºC. The mixture was stirred at 0 ºC for 2 hours. The reaction was quenched with sat. aq. NH 4 Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 5-bromo-1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 93%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H). MS: m/z 241.0 (M+H + ). Step 2 - Synthesis of 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)- 1H-pyrrolo[2,3-b]pyridine To a solution of 5-bromo-1,2,3-trimethyl-pyrrolo[2,3-b]pyridine (1 g, 4.18 mmol) in 1,4- dioxane (15 mL) was added Pd(dppf)Cl 2 (306 mg, 418.22 μmol), KOAc (1.23 g, 12.55 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (3.19 g, 12.55 mmol). The reaction mixture was stirred at 80 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, EtOAc (100 mL) was added, and the mixture was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give 1,2,3-trimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3 -b]pyridine (1.14 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 3.70 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 1.31 (s, 12H). MS: m/z 287.2 (M+H + ). Step 3 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (190 mg, 349 μmol), K 2 CO 3 (145 mg, 1.05 mmol) and 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrrolo[2,3- b]pyridine (200 mg, 699 μmol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh 3 ) 4 (40 mg, 35 μmol). The reaction was stirred at 100 ºC for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (190 mg, 98%) as a white solid. MS: m/z 552.2 (M+H + ). Step 4 - Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)b enzoic acid To a mixture of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)b enzoate (13 mg, 24 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 798) (3 mg, 25%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 6.4 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.46 - 5.40 (m, 1H), 3.75 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 496.2 (M+H + ). Example 23: Preaparation of 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 665) Step 1 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7- methyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin- 4-one (50 mg, 0.13 mmol) and 2-bromoaniline (112 mg, 0.65 mmol) in dioxane (1 mL) was heated to 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 9-(1-((2- bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyr ido[1,2-a]pyrimidin-4-one (370 mg, 59%) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (s, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.03 - 6.98 (m, 1H), 6.59 - 6.52 (m, 1H), 6.34 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 5.38 - 5.25 (m, 1H), 5.17 - 4.97 (m, 2H), 4.83 - 4.67 (m, 2H), 4.16 - 4.10 (m, 1H), 2.30 (s, 3H), 1.73 (br d, J = 6.8 Hz, 3H). MS: m/z 475.2(M+H + ). Step 2 - Synthesis of 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7-meth yl-4H- pyrido[1,2-a]pyrimidin-4-one (200 mg, 0.42 mmol), Na 2 CO 3 (134 mg, 1.26 mmol) and 4- (tributylstannyl)pyridazine (163 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl 2 (31 mg, 0.04 mmol). The reaction was stirred at 100 ºC for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 55 - 85% / formic acid in water) to give 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4-yl)phenyl )amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 694) (16 mg, 8%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.40 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.40 (m, 1H), 7.34 - 7.32 (m, 1H), 7.14 - 7.10 (m, 1H), 6.81 - 6.79 (m, 1H), 6.55 - 6.50 (m, 1H), 5.84 (d, J = 7.6 Hz, 1H), 5.40 (s, 1H), 5.27 - 5.25 (m, 1H), 4.89 - 4.85 (m, 2H), 4.72 - 4.58 (m, 3H), 2.26 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H). MS: m/z 475.0 (M+H + ). Example 24: Preparation of 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7- methyl-4-oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzene sulfonamide (Compound 730) Step 1 - Synthesis of 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo- pyrido[1,2-a]pyrimidin-9-yl]ethylamino]benzenesulfonamide To a solution of 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (200 mg, 534 umol) in DMF (1 mL) was added PyBOP (334 mg, 641 umol) and DIEA (465 uL, 2.67 mmol). The mixture was stirred at room temperature for 20 min, (2S,6R)-2,6-dimethylmorpholine (92 mg, 801 umol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with aq. HCl (1 M, 20 mL) and brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resulting residue was purified by Prep-TLC (10% MeOH in DCM) to give 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo- pyrido[1,2- a]pyrimidin-9-yl]ethylamino]benzenesulfonamide (80 mg, 32%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.23 - 7.20 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.43 - 6.36 (m, 2H), 5.83 (s, 1H), 5.76 (s, 1H), 5.29 - 5.22 (m, 1H), 3.63 - 3.58 (m, 2H), 2.60 - 2.55 (m, 4H), 2.23 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.27 - 1.21 (m, 6H). MS: m/z 472.2 (M+H + ). Step 2 - Synthesis of 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl- 4- oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzenesulfonami de & 2-[[(1S)-1-[2-[(2S,6R)- 2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo-pyrido[1,2-a]pyri midin-9- yl]ethyl]amino]benzenesulfonamide 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo- pyrido[1,2-a]pyrimidin-9- yl]ethylamino]benzenesulfonamide (60 mg, 127 umol) was separated by using chiral SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um); Supercritical CO 2 / EtOH+ 0.1% NH 3 •H 2 O = 50/50; 80 mL/min) to afford 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl- 4- oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzenesulfonami de (30 mg, first peak) and 2- [[(1S)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4- oxo-pyrido[1,2-a]pyrimidin-9- yl]ethyl]amino]benzenesulfonamide (30 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 25: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.51 (s, 2H), 7.26 - 7.19 (m, 1H), 6.71 - 6.60 (m, 1H), 6.43 - 6.34 (m, 2H), 5.70 (s, 1H), 5.33 - 5.17 (m, 1H), 4.45 - 4.19 (m, 2H), 3.64 - 3.57 (m, 2H), 3.49 - 3.42 (m, 2H), 2.23 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.17 - 1.12 (m, 6H). MS: m/z 472.2 (M+H + ). Example 25: Preparation of (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 623) Step 1 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1-en-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (220 mg, 417 umol), 2-(4,4- dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro lane (148 mg, 625.58 umol), Pd(PPh 3 ) 4 (48 mg, 42 umol), K 2 CO 3 (173 mg, 1.25 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 100 °C for 2 hours under N 2 atmosphere. The mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1- en-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl )amino)benzoate (190 mg, 93%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.74 - 7.71 (m, 1H), 7.24 - 7.20 (m, 1H), 7.15 (s, 1H), 6.57 - 6.53 (m, 1H), 6.48 - 6.39 (m, 2H), 5.45 - 5.24 (m, 1H), 2.32 (s, 3H), 2.09 (s, 2H), 1.65 (d, J = 6.8 Hz, 3H), 1.55 (s, 9H), 1.52 (t, J = 6.0 Hz, 2H), 1.31 - 1.22 (m, 4H), 0.97 - 0.94 (m, 6H). MS: m/z 488.1 (M+H + ). Step 2 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1-en-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 300 umol) in MeOH (10 mL) was added wet Pd/C (0.2 g, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 2 h under H 2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to afford tert-butyl 2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin -9-yl)ethyl)amino)benzoate (150 mg, crude) as yellow oil that required no further purification. MS: m/z 490.2 (M+H + ). Step 3 - Synthesis of 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 204 umol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 80% - 100% / 0.225% formic acid in water) to give 2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin -9-yl)ethyl)amino)benzoic acid (45 mg, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.71 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.71 (s, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.41 - 6.36 (m, 1H), 6.35 - 6.31 (m, 1H), 5.47 - 5.36 (m, 1H), 2.32 (s, 3H), 1.83 - 1.73 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H), 1.53 - 1.45 (m, 2H), 1.39 - 1.30 (m, 2H), 0.98 - 0.93 (m, 6H). MS: m/z 434.1 (M+H + ). Step 4 - Synthesis of (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin -9-yl)ethyl)amino)benzoic acid 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 85 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO 2 / i-PrOH+0.1% NH 3 •H 2 O = 65/35; 80 mL/min) to afford (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyri do[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5 mg, first peak) and (S)-2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin -9-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 649: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.73 (s, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.41 - 6.36 (m, 1H), 6.33 (s, 1H), 5.47 - 5.36 (m, 1H), 2.32 (s, 3H), 1.83 - 1.73 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H), 1.53 - 1.45 (m, 2H), 1.39 - 1.30 (m, 2H), 0.98 - 0.93 (m, 6H). MS: m/z 434.1 (M+H + ). Example 26: Preparation of 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oic acid (Compound 512) Step 1 - Synthesis of tert-butyl 2-((1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (100 mg, 0.25 mmol) in DMF (2 mL) was added PyBOP (158 mg, 0.30 mmol), DIEA (0.18 mL, 1.01 mmol). The mixture was stirred at room temperature for 30 minutes, (3R,5S)-3,5-dimethylpiperidine (114 mg, 1.01 mmol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with aq. HCl (1 M, 20 mL) and brine (20 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-((3R,5S)-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrim idin-9-yl)ethyl)amino)benzoate (80 mg, 64%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.31 - 7.15 (m, 1H), 6.55 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.23 - 5.16 (m, 1H), 4.46 - 4.36 (m, 2H), 2.47 - 2.34 (m, 4H), 2.23 (s, 3H), 1.80 - 1.75 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.57 (s, 9H), 0.89 (t, J = 6.4 Hz, 6H), 0.86 - 0.81 (m, 1H) MS: m/z 491.2 (M+H + ). Step 2 - Synthesis of tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benz oate and tert-butyl 2-(((S)- 1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo -4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (80 mg, 137 umol) was separated by prep SFC (REGIS(S,S)WHELK-O1(250mm*25mm,10um), Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 55/45, 80 mL/min) to give tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, first peak) and tert-butyl 2-(((S)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4 -oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (35 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 491.2 (M+H + ). Step 3 – Synthesis of 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4 - oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4 - oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, 71 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4 -oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 529) (10 mg, 33%) as a white solid. Compound 529: 1 H NMR (400MHz, DMSO-d 6 ) δ 12.73 (s, 1H), 8.51 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.56 (s, 1H), 7.25-7.21 (m, 1H), 6.57 - 6.53 (m, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.23 - 5.19 (m, 1H), 4.55 - 4.25 (m, 2H), 2.44 - 2.36 (m, 2H), 2.22 (s, 3H), 1.82 - 1.78 (m, 1H), 1.61 - 1.55 (m, 5H), 0.90 - 0.88 (m, 6H), 0.87 - 0.79 (m, 1H). MS: m/z 435.1 (M+H + ). Example 27: Preparation of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoic acid (Compound 804) Step 1 - Synthesis of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoate & tert- butyl (S)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[ 2,3-b]pyridin-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-[1-[3,7-dimethyl-4-oxo-2-(1,2,3-trimethylpyrrolo[2,3-b]pyr idin-5- yl)pyrido[1,2-a]pyrimidin-9-yl]ethylamino]benzoate (190 mg, 344 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 80/20; 80 ml/min) to afford tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3- trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyr imidin-9-yl)ethyl)amino)benzoate (75 mg, first peak) and tert-butyl (S)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoate (83 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 552.3 (M+H + ). Step 2 - Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoic acid To a mixture of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)e thyl)amino)benzoate (75 mg, 136 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 60 - 90% / 0.225% formic acid in water) to give (R)- 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 850) (50 mg, 74%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 8.71 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.22 - 7.18 (m, 1H), 6.54 (s, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.47 - 5.40 (m, 1H), 3.76 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 496.1 (M+H + ). Example 28: Preparation of (S)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin- 4-yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 848) Step 1 - Synthesis of 9-bromo-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 37.2 mmol) in DMF (100 mL) was added PyBOP (25.1 g, 48.3 mmol) and DIEA (25.9 mL, 148.7 mmol). The mixture was stirred at room temperature for 30 minutes, isoindoline hydrochloride (6.9 g, 44.6 mmol) was added. The reaction was stirred at 90 °C for 16 hours. After cooling to room temperature, 1M aq. HCl (200 mL) solution was added and the suspension solution was filtered and the filter cake was dried in vacuo to give 9-bromo-2-(isoindolin-2-yl)- 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (9.1 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.14 (s, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.29 (m, 2H), 5.16 (s, 4H), 2.40 - 2.37 (s, 3H), 2.33 - 2.31 (s, 3H). MS: m/z 371.8 (M+H + ). Step 2 - Synthesis of 9-acetyl-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-bromo-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimidi n-4-one (5.2 g, 14.0 mmol) in dioxane (60 mL) was added Pd(dppf)Cl 2 (514 mg, 702 umol) and tributyl(1-ethoxyvinyl)stannane (9.5 mL, 28.0 mmol). The mixture was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, HCl (15 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was added 100 mL 10% KF aqueous solution, stirred at room temperature for 2 hours. The suspension solution was filtered and the filter cake was washed with DCM (20 mL x 2) and MeOH (20 mL), dried in vacuo to give 9-acetyl-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]py rimidin-4-one (3.5 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 1H), 7.86 (s, 1H), 7.36 - 7.30 (m, 4H), 5.17 (s, 4H), 2.92 (s, 3H), 2.52 (s, 3H), 2.39 (s, 3H). MS: m/z 334.0 (M+H + ). Step 3 - Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-acetyl-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimid in-4-one (3.5 g, 10.5 mmol) in MeOH (40 mL) was added NaBH 4 (1.2 g, 31.5 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N 2 atmosphere. The reaction was quenched with 1M HCl (10 mL) at 0°C. Then the suspension solution was filtered and the filter cake was washed with EtOAc (20 mL x 2) to give 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (3.5 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (s, 1H), 7.40 (s, 1H), 7.31 - 7.37 (m, 4H), 5.20 - 5.25 (m, 1H), 5.12 - 5.19 (m, 4H), 2.52 (s, 3H), 2.37 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H). MS: m/z 336.1 (M+H + ). Step 4 - Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrid o[1,2- a]pyrimidin-4-one (1 g, 2.98 mmol) in DCM (20 mL) was added PBr 3 (847 mg, 3.13 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour under N 2 atmosphere. The mixture was quenched with sat. aq. NaHCO 3 (20 mL), extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[ 1,2- a]pyrimidin-4-one (1.2 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 7.95 (s, 1H), 7.43 - 7.37 (m, 4H), 5.89 - 6.08 (m, 1H), 5.33 - 5.45 (m, 4H), 2.90 (s, 3H), 2.52 (s, 3H), 2.17 (d, J = 6.4 Hz, 3H). Step 5 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[ 1,2- a]pyrimidin-4-one (100 mg, 251 umol) and 2-bromoaniline (86 mg, 502 umol) in dioxane (1 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1-((2-bromophenyl)amino)ethyl)-2- (isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (80 mg, 80%) as a yellow solid. MS: m/z 491.2 (M+H + ). Step 6 - Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino) ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7-di methyl- 4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 266 μmol) in dioxane (2 mL) was added Pd(dppf)Cl 2 (19 mg, 27 μmol), Na 2 CO 3 (84 mg, 797 μmol) and tributyl(pyridazin-4-yl)stannane (103 mg, 279 μmol). The mixture was stirred at 100 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 62 - 92% / 0.05% NH 3 •H 2 O+10 mM NH 4 HCO 3 in water) to give 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)ph enyl)amino) ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (60 mg, 46%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.42 (s, 1H), 9.24 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 7.88 (dd, J = 5.2, 2.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.29 - 7.34 (m, 2H), 7.09 - 7.15 (m, 2H), 6.73 - 6.68 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.84 (d, J = 7.2 Hz, 1H), 5.29 - 5.25 (m, 1H), 5.19 - 5.12 (m, 2H), 5.01 - 5.09 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H). MS: m/z 489.2 (M+H + ). Step 7 - Synthesis of (R)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one & (S)-2-(isoindolin-2-yl)-3,7- dimethyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino)ethyl)-4H-pyr ido[1,2-a]pyrimidin-4-one (Compound 909) 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)ph enyl)amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (50 mg, 102 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO 2 / EtOH + 0.1% NH 4 OH = 55/45;100 mL/min) to give (R)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (22 mg, first peak) and (S)-2- (isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)phen yl)amino)ethyl)-4H-pyrido[1,2- a]pyrimidin-4-one (23 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 909: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.41 (s, 1H), 9.24 (d, J = 5.6 Hz, 1H), 8.55 (s, 1H), 7.87 (dd, J = 5.2, 2.4 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.33 - 7.28 (m, 2H), 7.08 - 7.13 (m, 2H), 6.73 - 6.69 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.83 (d, J = 7.2 Hz, 1H), 5.29 - 5.23 (m, 1H), 5.11 - 5.19 (m, 2H), 4.99 - 5.09 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H). MS: m/z 489.2 (M+H + ). Example 29: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 856) Step 1 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[ 1,2- a]pyrimidin-4-one (500 mg, 1.26 mmol) and 2-aminobenzenesulfonamide (432 mg, 2.51 mmol) in dioxane (5 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 58 - 88% / 0.225% formic acid in water) to give 2-((1-(2-(isoindolin-2-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzenesulfonamide (100 mg, 16%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (s, 2H), 7.41 (dd, J = 5.6, 3.2 Hz, 2H), 7.34 - 7.29 (m, 2H), 7.23 - 7.19 (m, 1H), 6.67 - 6.61 (m, 1H), 6.43 (d, J = 5.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 5.14 - 5.25 (m, 4H), 2.44 (s, 3H), 2.25 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 490.2 (M+H + ). Step 2 - Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 39) & (S)-2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimid in-9- yl)ethyl)amino)benzenesulfonamide 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9- yl)ethyl)amino) benzenesulfonamide (90 mg, 184 umol) was separated by chiral SFC (DAICEL CHIRALCEL Cellulose-4 (250 mm * 30 mm, 5 um), Supercritical CO 2 / MeOH + 0.1% NH 3 •H 2 O = 40/60; 80 mL/min) to give (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (35 mg, first peak) and (S)-2-((1- (2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyri midin-9- yl)ethyl)amino)benzenesulfonamide (29 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 919: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.55 (s, 2H), 7.43 - 7.37 (m, 2H), 7.33 - 7.26 (m, 2H), 7.22 - 7.18 (m, 1H), 6.66 - 6.62 (m, 1H), 6.43 (d, J = 5.6 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.41 - 5.35 (m, 1H), 5.26 - 5.11 (m, 4H), 2.43 (s, 3H), 2.24 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 490.1 (M+H + ). Example 30: Preparation of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)thiophen-3-yl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-on e (Compound 1409) Step 1 - Synthesis of 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2-(isoindolin-2-yl) - 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[ 1,2- a]pyrimidin-4-one (20 mg, 50 μmol) in DMF (2 mL) was added 2-bromothiophen-3-amine hydrobromide (15.6 mg, 60 μmol) (prepared according to the procedure in WO2016144848) and DIEA (26 uL, 150 μmol). The mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting residue was purified by Prep- TLC (50% EtOAc in petroleum ether) to give 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2- (isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (15 mg, 55%) as a yellow solid. MS: m/z 495.0 (M+H + ). Step 2 - Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)thiophen-3-yl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-on e To a solution of 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2-(isoindolin-2-yl) -3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (20 mg, 40 μmol) in dioxane (2 mL) was added Pd(PPh 3 ) 2 Cl 2 (3 mg, 4 μmol), Na 2 CO 3 (13 mg, 120 μmol) and tributyl(pyridazin-4-yl)stannane (30 mg, 81 μmol). The mixture was stirred at 100 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 46 - 76% / 0.225% formic acid in water) to give 2- (isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)thio phen-3-yl)amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 963) (2.5 mg, 12%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (d, J = 1.6 Hz, 1H), 9.08 (d, J = 6.0 Hz, 1H), 8.56 (s, 1H), 7.81 (s, 1H), 7.76 - 7.74 (m, 1H), 7.54 (d, J =5.2 Hz, 1H), 7.41 - 7.47 (m, 1H), 7.32 - 7.30 (m, 2H), 6.53 - 6.61 (m, 2H), 5.30 - 5.43 (m, 1H), 5.04 - 5.21 (m, 4H), 2.42 (s, 3H), 2.28 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H). MS: m/z 495.2 (M+H + ). Example 31: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 902)
Step 1 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (200 mg, 369 μmol ), K 2 CO 3 (153 mg, 1.11 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indole (100 mg, 369 μmol) (prepared according to the procedure in WO201910295) in dioxane (5 mL) and water (1 mL) was added Pd(PPh 3 ) 4 (43 mg, 37 μmol). The reaction was stirred at 100 ºC for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum) to give 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate (150 mg, 76%) as a yellow solid. MS: m/z 537.2 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 280 μmol) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 63% - 93% / 0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-indol- 5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethy l)amino)benzoic acid (90 mg, 67%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.69 (s, 1H), 8.43 ( d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.83 - 7.78 (m, 1H), 7.66 - 7.62 (m, 1H), 7.63 (s, 1H), 7.60 - 7.54 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.54 (t, J = 7.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.47 - 5.42 (m, 1H), 3.77 (s, 3H), 2.34 - 2.24 (m, 9H), 2.07 (s, 1H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 481.2 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 983) & (S)-2-((1-(2- (1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1, 2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 187 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 65/35; 80 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo -4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (25 mg, first peak) and (S)-2-((1-(2-(1,3- dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoic acid (31 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 983: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 8.47 ( s, 1H), 7.89 (s, 1H), 7.82 ( d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.54 (t, J = 7.8 Hz, 1H), 6.39 ( d, J = 8.4 Hz, 1H), 5.46 ( s, 1H), 3.78 (s, 3H), 2.35 - 2.28 (m, 9H), 1.62 ( d, J = 6.4 Hz, 3H). MS: m/z 481.1 (M+H + ). Example 32: Preparation of (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (Compound 892) Step 1 - Synthesis of tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (200 mg, 369 μmol ), K 2 CO 3 (153 mg, 1.11 mmol) and 1-cyclopropyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)-1H- indazole (165 mg, 554 μmol) (prepared according to the procedure of 1-cyclopropyl-3-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole in WO201657834) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh 3 ) 4 (43 mg, 37 μmol). The reaction was stirred at 80 ºC for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum) to give tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H- indazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoate (124 mg, 60%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.85 - 7.80 (m, 1H), 7.70 (s, 1H), 7.24 - 7.18 (m, 1H), 6.54 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.43 - 5.37 (m, 1H), 3.72 - 3.65 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H), 1.09 - 1.13 (m, 4H). MS: m/z 564.3 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimeth yl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate (124 mg, 220 μmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 55% - 85% / 0.225% formic acid in water) to give 2-((1-(2-(1- cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (62 mg, 55%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1 H), 8.71 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.84 - 7.79 (m, 2H), 7.75 - 7.72 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.50 - 5.35 (m, 1H), 3.75 - 3.64 (m, 1H), 2.52 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.17 - 1.06 (m, 4H). MS: m/z 508.3 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid (Compound 969) & (S)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-di methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimeth yl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (62 mg, 122 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 70/30; 80 mL/min) to afford (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (22 mg, first peak) and (S)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-di methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (20 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 969: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.50 - 8.40 (m, 1H), 8.05 (s, 1H), 7.84 - 7.79 (m, 2H), 7.76 - 7.72 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.48 - 5.37 (m, 1H), 3.73 - 3.66 (m, 1H), 2.52 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.13 - 1.08 (m, 4H). MS: m/z 508.2 (M+H + ). Example 33: Preparation of (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 967) Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy) - 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (180 mg, 332 μmol), K 2 CO 3 (138 mg, 997 umol) and (3-cyanophenyl)boronic acid (73 mg, 499 μmol) in dioxane (3 mL) and water (0.3 mL) was added Pd(PPh 3 ) 4 (38 mg, 33 μmol). The reaction was stirred at 100 ºC for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 73%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.27 - 8.26 (m, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.25 - 7.13 (m, 1H), 6.55 - 6.53 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.38 - 5.34 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 495.3 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 121 μmol) in DCM (2 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 58% - 88% / 0.225% formic acid in water) to give 2-((1-(2-(3-cyanophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid (50 mg, 94%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.21 - 7.19 (m 1H), 6.55 - 6.54 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.41 - 5.39 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 439.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1071) & (S)-2-((1-(2-(3- cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 114 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 75/25; 70 mL/min) to afford (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1, 2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (Compound 1071) (4 mg, first peak) and (S)-2-((1-(2-(3- cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.45 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 - 6.54 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.43 - 5.36 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 439.2 (M+H + ). Example 34: Preparation of (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 947) Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-cyano-4-fluoro- phenyl)boronic acid, tert-butyl 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (160 mg, 84%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.36 - 8.27 (m, 2H), 8.21 - 8.11 (m, 1H), 7.79 - 7.65 (m, 3H), 7.20 - 7.18 (m, 1H), 6.53 - 6.51 (m, 1H), 6.46 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H), 2.23 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H). MS: m/z 513.3 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoate, 2-((1- (2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2 -a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 70%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.72 (s, 1H), 8.52 - 8.35 (m, 1H), 8.30 - 8.29 (m, 1H), 8.20 - 8.12 (m, 1H), 7.80 - 7.79 (m, 1H), 7.73 - 7.68 (m, 2H), 7.23 - 7.15 (m, 1H), 6.55 - 6.54 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.44 - 5.35 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 457.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyri do[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 110 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 65/35; 70 mL/min) to afford (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1041) (9 mg, first peak) and (S)-2-((1-(2- (3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoic acid (9 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.53 - 8.43 (m, 1H), 8.30 - 8.29 (m, 1H), 8.19 - 8.11 (m, 1H), 7.80 - 7.79 (m, 1H), 7.74 - 7.67 (m, 2H), 7.18 - 7.16 (m, 1H), 6.55 - 6.53 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.43 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 457.2 (M+H + ). Example 35: Preparation of (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 963) Step 1 – Synthesis of tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (4-chlorophenyl)boronic acid, tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)benzoate (130 mg, 78%) was obtained as a white solid. MS: m/z 504.2 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate, 2-((1-(2-(4- chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid (30 mg, 45%) was obtained as a white solid. MS: m/z 448.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 45) & (S)-2-((1-(2-(4- chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)benzoic acid (20 mg, 45 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 75/25; 70 mL/min) to afford (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1 ,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1067) (2 mg, first peak) and (S)-2-((1-(2- (4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidi n-9-yl)ethyl)amino)benzoic acid (3 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 8.70 (s, 1H), 8.47 (s, 1H), 7.85 - 7.72 (m, 3H), 7.68 - 7.67 (m, 1H), 7.63 - 7.60 (m, 2H), 7.24 - 7.11 (m, 1H), 6.58 - 6.50 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.42 - 5.34 (m, 1H), 2.34 (s, 3H), 2.24 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 448.1 (M+H + ). Example 36: Preparation of (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 965) Step 1 – Synthesis of tert-butyl 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (4-chloro-2-fluoro- phenyl)boronic acid, tert-butyl 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (135 mg, 78%) was obtained as a white solid. MS: m/z 522.2 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chloro-2- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoate, 2-((1- (2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1, 2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (30 mg, 45%) was obtained as a white solid. MS: m/z 466.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H - pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1069) & (S)-2-((1-(2-(4- chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]py rimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyr ido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (30 mg, 65 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 70/30; 60 mL/min) to afford (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H -pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1069) (12 mg, first peak) and (S)-2-((1- (2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1, 2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (7 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.51 - 7.47 (m, 1H), 7.21 - 7.12 (m, 1H), 6.58 - 6.49 (m, 1H), 6.32 (d, J = 8.8 Hz, 1H), 5.48 - 5.18 (m, 1H), 2.34 (s, 3H), 2.06 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H). MS: m/z 466.1 (M+H + ). Example 37: Preparation of (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 975) Step 1 – Synthesis of tert-butyl 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (6-cyano-3-pyridyl)boronic acid, tert-butyl 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (150 mg, 90%) was obtained as a white solid. MS: m/z 496.3 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(6-cyanopyridin-3- yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl) amino)benzoate, 2-((1-(2-(6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9-yl)ethyl)amino)benzoic acid (30 mg, 17%) was obtained as a white solid. MS: m/z 440.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1081) & (S)-2-((1-(2-(6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (20 mg, 46 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 70/30; 60 mL/min) to afford (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyr ido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1081) (6 mg, first peak) and (S)-2-((1-(2- (6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyr imidin-9-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8.74 (s, 1H), 8.51 - 8.45 (m, 1H), 8.44 - 8.40 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.72 (s, 1H), 7.22 - 7.13 (m, 1H), 6.60 - 6.49 (m, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.45 - 5.28 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 440.1 (M+H + ). Example 38: Preparation of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1408) Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with pyridin-4-ylboronic acid, tert- butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoate (130 mg, 83%) was obtained as a white solid. MS: m/z 471.3 (M+H + ). Step 2 - Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate, 2-((1-(3,7-dimethyl-4-oxo- 2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino) benzoic acid (30 mg, 68%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.78 - 8.74 (m, 2H), 8.72 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.76 - 7.72 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.58 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.44 - 5.31 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 415.1 (M+H + ). Example 39: Preparation of (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 969) Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-fluorophenyl) boronic acid, tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)benzoate (120 mg, 67%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 - 7.40 (m, 3H), 7.20 - 7.10 (m, 2H), 6.60 - 6.51 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.58 - 5.39 (m, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.64 (s, 9H). MS: m/z 488.1 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate, 2-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid (60 mg, 54%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.78 (s, 1H), 8.71 (s, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.39 - 7.30 (m, 1H), 7.24 - 7.13 (m, 1H), 6.51 - 6.55 (m, J = 7.6 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1073) & (S)-2-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)benzoic acid (60 mg, 139 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 55/45;100 mL/min) to afford (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1 ,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1073) (10 mg, first peak) and (S)-2-((1- (2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrim idin-9-yl)ethyl)amino)benzoic acid (13 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.45 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.60 - 7.53 (m, 3H), 7.37 - 7.31 (m, 1H), 7.21 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.41 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H + ). Example 40: Preparation of (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 972) Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3- (difluoromethyl)phenyl)boronic acid, tert-butyl 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoate (160 mg, 83%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.63 - 8.15 (m, 1H), 7.87 - 8.01 (m, 1H), 7.86 - 7.81 (m, 2H), 7.65 - 7.58 (m, 3H), 7.19 - 7.10 (m, 1H), 6.91 - 6.61 (m, 1H), 6.60 - 6.54 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.52 - 5.48 (m, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.63 (s, 9H). MS: m/z 520.2 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoate, 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (90 mg, 62%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 8.72 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.81 (d, J = 6.8 Hz, 1H), 7.73 - 7.65 (m, 3H), 7.31 - 7.01 (m, 2H), 6.56 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 464.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1077) & (S)-2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-py rido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 194 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 55/45;100 mL/min) to give (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1077) (22 mg, first peak) and (S)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4 H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (29 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.44 (s, 1H), 7.94 - 7.89 (m, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.72 - 7.66 (m, 3H), 7.30 - 7.01 (m, 2H), 6.55 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 464.3 (M+H + ). Example 41: Preparation of (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid (Compound 951) Step 1 - Synthesis of tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (5-chloro-6-methylpyridin-3- yl)boronic acid, tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (170 mg, 89%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.33 (d, J = 6.8 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.24 - 7.17 (m, 1H), 6.58 - 6.42 (m, 2H), 5.48 - 5.20 (m, 1H), 2.63 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.51 (s, 9H). MS: m/z 519.1 (M+H + ). Step 2 - Synthesis of 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrim idin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 64%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.44 ( s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.57 - 6.51 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.43 - 5.33 (m, 1H), 2.64 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 463.2 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1052) & (S)-2- ((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H -pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (40 mg, 86 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 40/60; 60 mL/min) to afford (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1052) (12 mg, first peak) and (S)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (11 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.87 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.56 - 6.50 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.42 - 5.33 (m, 1H), 2.64 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 463.0 (M+H + ). Example 42: Preparation of (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 971) Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-cyclopropylphenyl)boronic acid, tert-butyl 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (135 mg, 80%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.68 (s, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.36 (m, 2H), 7.17 (d, J = 7.2 Hz, 2H), 6.56 - 6.54 (m, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.71 - 2.62(m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H), 1.02 - 0.93 (m, 2H), 0.76 - 0.69 (m, 2H). MS: m/z 510.2 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9-yl)ethyl)amino)benzoate, 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 64%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.70 (s, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.43 - 7.37 (m, 2H), 7.23 - 7.15 (m, 2H), 6.57 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.06 - 1.97 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.02 - 0.95 (m, 2H), 0.75 - 0.70 (m, 2H). MS: m/z 454.1 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1075) & (S)-2-((1-(2-(3- cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 88 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 20/80; 60 mL/min) to afford (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyr ido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1075) (11 mg, first peak) and (S)-2-((1- (2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoic acid (21 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (s, 1H), 8.44 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.36 (m, 2H), 7.19 - 7.15 (m, 2H), 6.55 - 6.50 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.44 - 5.35 (m, 1H), 2.32 (s, 3H), 2.21 (s, 3H), 2.06 - 1.95 (m, 1H), 1.59 (d, J = 6.4 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.76 - 0.69 (m, 2H). MS: m/z 454.1 (M+H + ). Example 43: Preparation of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 949) Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with pyridin-3-ylboronic acid, tert- butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoate (165 mg, 95%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.70 - 8.68 (m, 1H), 8.27 (d, J = 6.4 Hz, 1H), 8.18 - 8.15 (m, 1H), 7.78 - 7.70 (m, 2H), 7.59 - 7.56 (m, 1H), 7.23 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.40 - 5.34 (m, 1H), 2.35 (s, 3H), 2.25 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.54 (s, 9H). MS: m/z 471.1 (M+H + ). Step 2 - Synthesis of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(3,7-dimethyl-4- oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)am ino)benzoate tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]p yrimidin-9- yl)ethyl)amino)benzoate (120 mg, 255 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,5um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 70/30; 60 mL/min) to afford tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2 - a]pyrimidin-9-yl)ethyl)amino)benzoate (40 mg, first peak) and tert-butyl (S)-2-((1-(3,7- dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (45 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 471.1 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2 - a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(3,7-dimethyl-4- oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)am ino)benzoate, (R)-2-((1-(3,7- dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (31 mg, 76%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.78 (s, 1H), 8.95 (d, J = 1.6 Hz, 1H), 8.73 - 8.67 (m, 2H), 8.49 - 8.39 (m, 1H), 8.17 - 8.15 (m, 1H), 7.82 - 7.80 (m, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.23 - 7.12 (m, 1H), 6.56 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 415.1 (M+H + ). Example 44: Preparation of (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 973) Step 1 - Synthesis of tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (6-cyclopropylpyridin-3- yl)boronic acid, tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (160 mg, 88%) was obtained as a white solid. MS: m/z 511.2 (M+H + ). Step 2 - Synthesis of tert-butyl (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2-(6- cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-p yrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (130 mg, 254 umol) was separated by using chiral SFC (DAICEL CHIRALCEL IG (250mm*30mm,5um); Supercritical CO 2 / MeOH + 0.1% NH3•H2O = 55/45; 80 mL/min) to afford tert-butyl (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoate (50 mg, first peak) and tert-butyl (S)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.1 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(2-(6- cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate, (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1079) (16 mg, 36%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.13 (s, 1H), 8.03 - 8.00 (m, 1H), 7.81 - 7.79 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.43 - 5.37 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 2.23 - 2.14 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.06 - 0.93 (m, 4H). MS: m/z 455.1 (M+H + ). Example 45: Preparation of (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 953) Step 1 - Synthesis of tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (2-cyclopropyl-4- pyridyl)boronic acid, tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (140 mg, 81%) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 - 7.35 (m, 1H), 7.17 - 7.10 (m, 1H), 6.58 - 6.54 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.51 - 5.41 (m, 1H), 2.36 (s, 6H), 2.25 - 2.15 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H), 1.63 (s, 9H), 1.16 - 1.10 (m, 4H). MS: m/z 511.1 (M+H + ). Step 2 - Synthesis of tert-butyl (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate and tert-butyl (S)-2-((1-(2-(2- cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-p yrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 235 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK IG (250mm*30mm,10μm); Supercritical CO 2 / EtOH+0.1% NH 3 •H 2 O = 65/35; 80 mL/min) to afford tert-butyl (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, first peak) and tert-butyl (S)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (50 mg, second peak) both as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.2 (M+H + ). Step 3 - Synthesis of (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo- 4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(2-(2- cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9- yl)ethyl)amino)benzoate, (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo- 4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1055) (33 mg, 66%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.77 (s, 1H), 8.72 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 7.85 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 7.45 - 7.40 (m, 1H), 7.21 - 7.17 (m, 1H), 6.57 - 6.51 (m, 1H), 6.36 (d, J = 8.6 Hz, 1H), 5.55 - 5.52 (m, 1H), 2.34 (s, 3H), 2.22 - 2.21(m, 4H), 1.60 (d, J = 6.8 Hz, 3H), 1.01 - 0.96 (m, 4H). MS: m/z 455.1 (M+H + ). Example 46: Preparation of (S)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)be nzoic acid (Compound 978) Step 1 – Synthesis of tert-butyl 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with 3-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile, tert-butyl 2-((1-(2-(5-chloro-6-cyanopyridin- 3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethy l)amino)benzoate (120 mg, 76%) was obtained as a white solid. MS: m/z 530.2 (M+H + ). Step 2 – Synthesis of 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4 H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9-yl)ethyl)amino)benzoate, 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4 H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 27%) was obtained as a white solid. MS: m/z 474.1 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-o xo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(5-chloro-6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimi din-9- yl)ethyl)amino)benzoic acid (Compound 1084) 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4 H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (40 mg, 84 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK OD-H (250mm*30mm,5μm); Supercritical CO 2 / MeOH+0.1% NH 3 •H 2 O = 50/50; 60 mL/min) to afford (R)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-o xo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (15 mg, first peak) and (S)-2-((1-(2- (5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 1084) (15 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Second peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (d, J = 2.0 Hz, 1H), 8.74 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 7.85 - 7.86 (m, 1H), 7.67 (s, 1H), 7.02 - 6.99 (m, 1H), 6.47 - 6.43 (m, 1H), 6.22 - 6.19 (m, 1H), 5.34 - 5.31 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H). MS: m/z 474.0 (M+H + ). Example 47: Preparation of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1365) Step 1 – Synthesis of 9-chloro-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one A solution of 3-chloro-5-methylpyridin-2-amine (5 g, 35 mmol) in acetone (60 mL) was added bis(2,4,6-trichlorophenyl) 2-methylmalonate (18.4 g, 38.6 mmol). The reaction mixture was heated to 60 °C for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered to give the title compound (6.7 g, 85%) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.72 (s, 1H), 8.67 (s, 1H), 8.05 (s, 1H), 2.34 (s, 3H), 1.96 (s, 3H). Step 2 – Synthesis of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate To a solution of 9-chloro-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one (2.7 g, 12 mmol) in DCM (30 mL) was added pyridine (2.9 mL, 36 mmol) and Tf 2 O (2.38 mL, 14.4 mmol). The reaction was stirred at 0 ºC for 1 h. The reaction mixture was diluted with DCM (20 mL) and washed with 1M HCl (30 mL), and then the organic layer was washed with NaHCO 3 (40 mL x 2), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to give the title compound (4.2 g, 98%) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.32 (s, 1H), 2.43 (s, 3H), 2.14 (s, 3H). Step 3 – Synthesis of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (6 g, 16.8 mmol), pyridin-3-ylboronic acid (2.27 mg, 18.5 mmol), Pd(PPh 3 ) 4 (972 mg, 841 μmol) and Na 2 CO 3 (5.35 g, 50.5 mmol) in dioxane (100 mL) and H 2 O (10 mL). The mixture was heated to 80 °C for 10 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (4.5 g, 86%) as brown solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.86 (s, 1H), 8.75 (s, 1H), 8.71 - 8.67 (m, 1H), 8.60 (s, 1H), 8.15 - 8.11 (m, 1H), 8.09 - 8.05 (m, 1H), 2.40 (s, 3H), 2.21 (s, 3H). MS: m/z 286.0 (M+H + ). Step 4 – Synthesis of 9-acetyl-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrim idin-4-one (950 mg, 3.32 mmol), tributyl(1-ethoxyvinyl)stannane (3.49 g, 9.66 mmol), SPhos Pd G 3 (129.7 mg, 166 umol) and CsF (1.01 g, 6.65 mmol) in toluene (10 mL) was degassed and purged with N 2 for 3 times. The reaction mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, HCl (6 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 15 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (400 mg, 67%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.94 - 8.83 (m, 2H), 8.70 - 8.67 (m, 1H), 8.11 - 8.06 (m, 1H), 7.58 - 7.54 (m, 1H), 2.73 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). MS: m/z 294.1 (M+H + ). Step 5 – Synthesis of 9-(1-aminoethyl)-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2 - a]pyrimidin-4-one To a solution of 9-acetyl-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrim idin-4-one (200 mg, 681 umol), NH 4 OAc (526 mg, 6.8 mmol) and AcOH (41 mg, 681 umol, 236 μL) in MeOH (4 mL) was added NaBH 3 CN (129 mg, 2.08 mmol). The reaction was heated to 60 °C for 3 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO 3 solution (20 mL x 3), brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% DCM in MeOH) to give the title compound (40 mg, 20%) as yellow oil. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.91 - 8.87 (m, 1H), 8.74 - 8.68 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.61 - 7.54 (m, 1H), 4.72 - 4.65 (m, 1H), 2.43 (s, 3H), 2.22 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). MS: m/z 295.1 (M+H + ). Step 6 – Synthesis of 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benz o[d]isoxazol-3(2H)-one A mixture of 9-(1-aminoethyl)-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2 -a]pyrimidin- 4-one (50 mg, 170 umol), 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one (56 mg, 142 umol) (prepared according to the procedure in Eur. J. Med. Chem. 2018, 150, 930), Pd(OAc) 2 (4 mg, 14 umol), BINAP (11 mg, 17 umol), Cs 2 CO 3 (415 mg, 1.3 mmol) in dioxane (2 mL) was stirred at 110 °C for 5 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (30 mg, 35%) as yellow oil. MS: m/z 608.1 (M+H + ). Step 7 – Synthesis of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]p yrimidin- 9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol -3(2H)-one (30 mg, 49 umol) in DCM (1.5 mL) was added TFA (0.5 mL) and triisopropylsilane (8.60 mg, 54 μmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (5 mg, 24%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.75 - 8.67 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.16 - 7.11 (m, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.38 - 6.33 (m, 1H), 6.01 (d, J = 8.4 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 428.0 (M+H + ). Example 48: Preparation of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one (Compound 1367) Step 1 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one Following the procedure described in Example 47 Step 3 - Step 5 and making non-critical variations as required to replace pyridin-3-ylboronic acid with (3-fluorophenyl) boronic acid, the title compound (2 g, crude) was obtained as a yellow solid. MS: m/z 312.1 (M+H + ). Step 2 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(3-fluorophenyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1 ,2- a]pyrimidin-4-one (1.64 g, 5.3 mmol), 1-bromo-2-iodo-benzene (2.24 g, 7.9 mmol,), Xantphos (610 mg, 1.1 mmol), Pd 2 (dba) 3 (482 mg, 527 μmol) and Cs 2 CO 3 (5.15 g, 15.8 mmol) in dioxane (25 mL) was heated to 100 °C and stirred for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-30% EtOAc in petroleum ether) to give the title compound (1.1 g, 45%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.59 - 7.53 (m, 3H), 7.39 - 7.34 (m, 2H), 7.05 - 7.01 (m, 1H), 6.55 - 6.46 (m, 2H), 5.79 (d, J = 8.0 Hz, 1H), 5.33 - 5.26 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H). MS: m/z 466.1 (M+H + ). Step 3 - Synthesis of methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1 ,2- a]pyrimidin-4-one (300 mg, 643 μmol), methyl prop-2-ynoate (216 mg, 2.6 mmol), Pd(PPh 3 ) 2 Cl 2 (45 mg, 64 μmol), CuI (61 mg, 322 μmol) and K 2 CO 3 (267 mg, 1.9 mmol) in DMF (5 mL) was heated to 100 °C and stirred for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc in petroleum ether) to give the title compound (34 mg, 11%) as yellow oil. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 7.86 (s, 1H), 7.58 - 7.50 (m, 3H), 7.36 (d, J = 7.6 Hz, 2H), 7.19 - 7.15 (m, 1H), 6.61 - 6.43 (m, 1H), 6.44 (d, J = 8.8 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.37 - 5.33 (m, 1H), 3.75 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). MS: m/z 470.3 (M+H + ). Step 4 - Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one To a solution methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1, 2- a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate (34 mg, 72 μmol) in EtOH (2 mL) was added hydroxylamine (10 mg, 144 μmol, 50% in water) slowly. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 54% - 84% / 0.225% formic acid in water) to give the title compound (12 mg, 35%) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ 8.71 (s, 1H), 7.86 (s, 1H), 7.60 - 7.56 (m, 1H), 7.54 - 7.50 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 - 7.31(m, 1H), 7.11 - 7.08 (m, 1H), 6.68 - 6.64 (m, 1H), 6.45 - 6.41 (m, 2H), 5.99 (d, J = 7.2 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 471.1 (M+H + ). Example 49: Preparation of (R)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one & (S)-2-(3- fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phenyl)amino) ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 1368 and Compound 1369) Step 1 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phenyl)a mino)ethyl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (15 mg, 32 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO 2 / MeOH + 0.1% NH 3 •H 2 O = 60/40; 80 mL/min) to afford (R)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one (2.3 mg, first peak) and (S)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phen yl)amino)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (2.68 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.87 (s, 1H), 7.61 - 7.56 (m, 1H), 7.55 - 7.50 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.11 - 7.08 (m, 1H), 6.68 - 6.64 (m, 1H), 6.45 - 6.41 (m, 1H), 6.45 - 6.41 (m, 2H), 5.99 (d, J = 7.2 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). MS: m/z 471.2 (M+H + ). Second peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.86 (s, 1H), 7.58 - 7.56 (m, 1H), 7.54 - 7.50 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.11 - 7.07(m, 1H), 6.67 - 6.63 (m, 1H), 6.44 - 6.39 (m, 2H), 5.98 (d, J = 6.8 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 471.2 (M+H + ). Example 50: (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)o xy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(3,7-dimethyl-4-oxo-2- ((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compounds 1370 and Compound 1371) Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4- yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9-yl)ethyl)amino)benzoate (500 mg, 1.22 mmol), tetrahydropyran-4-ol (187 mg, 1.83 mmol), PPh 3 (480 mg, 1.83 mmol) in THF (10 mL) was added DEAD (319 mg, 1.83 mmol) at 0 °C under N 2 atmosphere. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (300 mg, 50%) as yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (s, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.25 - 7.16 (m, 1H), 6.58 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.28 – 5.15 (m, 1H), 3.91 - 3.78 (m, 2H), 3.61 - 3.47 (m, 2H), 2.32 (s, 3H), 2.06 - 2.02 (m, 5H), 1.75 - 1.72 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H), 1.56 (s, 9H). MS: m/z 494.3 (M+H + ). Step 2 – Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (300 mg, 608 μmol) in DCM (6 mL) was added TFA (0.5 mL, 6.73 mmol). The reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 52% - 82% / 0.225% formic acid in water) to give the title compound (225 mg, 84%) as a white solid. MS: m/z 438.2 (M+H + ). Step 3 – Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4- yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(3,7-dimethyl- 4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2-a]pyri midin-9- yl)ethyl)amino)benzoic acid 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)- 4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (150 mg, 304 μmol) was separated using chiral SFC (DAICEL CHIRALPAK AD 250mm*30mm,10um); Supercritical CO 2 / MeOH = 60/40; 80 mL/min) to afford (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)o xy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (36 mg, first peak) and (S)-2-((1-(3,7- dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1 ,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (34 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.69 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.71 (s, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 5.27 - 5.18 (m, 1H), 3.87 - 3.83 (m, 2H), 3.61 - 3.48 (m, 2H), 2.31 (s, 3H), 2.05 - 2.03 (m, 5H), 1.79 - 1.66 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 438.1 (M+H + ). Second peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 8.69 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.71 (s, 1H), 7.25 - 7.15 (m, 1H), 6.59 - 6.49 (m, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.28 - 5.18(m, 1H), 3.91 - 3.80 (m, 2H), 3.60 - 3.47 (m, 2H), 2.31 (s, 3H), 2.05 - 2.03 (m, 5H), 1.80 - 1.67 (m, 2H), 1.59 (d, J = 6.8 Hz, 3H). MS: m/z 438.1 (M+H + ). Example 51: (R)-2-(3-fluorophenyl)-9-(1-((3-hydroxybenzo[d]isoxazol-4- yl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1374) Step 1 - Synthesis of 9-chloro-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (8 g, 22.4 mmol, prepared according to Example 72, Step 2), (3- fluorophenyl)boronic acid (3.77 mg, 26.9 mmol), Pd(PPh 3 ) 4 (1.29 g, 1.1 mmol) and K 2 CO 3 (6.30 g, 67.3 mmol) in dioxane (80 mL) and H 2 O (8 mL). The mixture was heated to 80 °C for 10 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), diluted with EtOAc (140 mL). The mixture was stirred at room temperature for 10 minutes, then the suspension was filtered and the filter cake was dried in vacuo to give the title compound (2.2 g, 32%) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.49 - 7.41 (m, 3H), 7.19 - 7.13 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H). MS: m/z 303.0 (M+H + ). Step 2 - Synthesis of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimi din-4-one (3.3 g, 10.90 mmol), CsF (3.3 g, 21.80 mmol) and Sphos Pd G3 (850 mg, 1.09 mmol) in toluene (40 mL) was degassed and purged with N 2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (8.3 g, 22.89 mmol) was added, the final mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, HCl (8 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 80 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (2.34 g, 85%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.39 - 7.34 (m, 1H), 7.20 - 7.14 (m, 1H), 2.88 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H). MS: m/z 311.0 (M+H + ). Step 3 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimi din-4-one (2.34 g, 7.5 mmol), NH 4 OAc (8.72 g, 113.1 mmol) and AcOH (452.83 mg, 7.5 mmol, 432 μL) in MeOH (40 mL) was added NaBH 3 CN (1.42 g, 22.6 mmol). The reaction was heated to 60 °C for 3 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL). The mixture was washed with saturated NaHCO 3 solution (30 mL x 3), brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% MeOH in EtOAc (contain 0.1% NH 3 ·H 2 O)) to give the title compound (700 mg, 30%) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.37 (m, 1H), 7.34 - 7.28 (m, 1H), 7.20 - 7.06 (m, 1H), 4.83 - 4.78 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). MS: m/z 312.1 (M+H + ). Step 4 - Synthesis of 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benz o[d]isoxazol-3(2H)-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin- 4-one (221 mg, 710 μmol), 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one (200 mg, 507 μmol) (prepared according to the procedure in Eur. J. Med. Chem.2018, 150, 930), Pd(OAc) 2 (5.7 mg, 25 μmol), BINAP (19.0 mg, 30 μmol), Cs 2 CO 3 (1.49 g, 4.57 mmol) in dioxane (2 mL) was stirred at 110 °C for 5 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (130 mg, 41%) as yellow oil. MS: m/z 625.1 (M+H + ). Step 5 - Synthesis of (R)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxy benzyl)benzo[d]isoxazol- 3(2H)-one & (S)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1 ,2-a]pyrimidin-9- yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3 (2H)-one 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a ]pyrimidin-9- yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3 (2H)-one (70 mg, 112 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ-H (250mm*30mm,10um); Supercritical CO 2 / EtOH + 0.1% NH 3 ·H 2 O = 50/50; 80 mL/min) to afford (R)-4-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)-2-(2,4,6- trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (22 mg, first peak) and (S)-4-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)-2-(2,4,6- trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (23 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 625.1 (M+H + ). Step 6 - Synthesis of (R)-2-(3-fluorophenyl)-9-(1-((3-hydroxybenzo[d]isoxazol-4- yl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of (R)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1 ,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benz o[d]isoxazol-3(2H)-one (22 mg, 35 μmol) in DCM (1 mL) was added TFA (0.5 mL) and triisopropylsilane (6.3 mg, 39 μmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 53% - 83% / 0.225% formic acid in water) to give the title compound (4.7 mg, 28%) as a white solid. NMR (400MHz, DMSO-d 6 ) δ 12.62 (s, 1H), 8.71 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.61 - 7.53 (m, 3H), 7.37 - 7.32 (m, 1H), 7.22 - 7.12 (m, 1H), 6.55 (m, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.42 - 5.34 (m, 1H), 2.35 (s, 3H), 2.23 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 445.1 (M+H + ). Example 52: 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one (Compound 1389) Step 1 – Synthesis of 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1 ,2- a]pyrimidin-4-one (3.3 g, 10.6 mmol), 1,2-diiodobenzene (6.99 g, 21.2 mmol), Xantphos (613 mg, 1.1 mmol), Pd 2 (dba) 3 (971 mg, 1.1 mmol) and Cs 2 CO 3 (10.4 g, 31.8 mmol) in dioxane (80 mL) was heated to 100 °C and stirred for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc in petroleum ether) to give the title compound (0.8 g, 15%) as a yellow solid. MS: m/z 514.0 (M+H + ). Step 2 – Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidi n-4-one To a solution of 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7-dime thyl-4H- pyrido[1,2-a]pyrimidin-4-one (0.14 g, 0.27 mmol) and oxetan-3-one (37 mg, 0.51 mmol) in THF (4 mL) was added n-BuLi (0.11 ml, 0.27 mmol, 2.5 M in n-hexane ) at -78 °C under N 2 atmosphere. The mixture was stirred at room temperature for 3 h under N 2 atmosphere. The mixture was quenched with NH 4 Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 68 - 98% / 0.225% formic acid in water) to give the title compound (2.6 mg, 2%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.65 (s, 1H), 7.61 - 7.55 (m, 3H), 7.39 - 7.31 (m, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.66 - 6.57 (m, 2H), 6.27 (d, J = 8.0 Hz, 1H), 5.50 (d, J = 6.8 Hz, 1H), 5.33 - 5.25 (m, 1H), 5.04 - 4.94 (m, 2H), 4.86 - 4.77 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 460.1 (M + H + ). Example 53: (S)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan -3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (Compound 1393) Step 1 – Synthesis of 2-(3-fluorophenyl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyr imidin-4- one (1 g, 3.22 mmol) in MeOH (20 mL) was added NaBH 4 (180 mg, 4.76 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h under N 2 atmosphere. The mixture was quenched with NH 4 Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (0.68 g, 68%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (s, 1H), 7.50 - 7.43 (m, 2H), 7.40 - 7.36 (m, 1H), 7.34 - 7.28 (m, 1H), 7.20 - 7.14 (m, 1H), 5.33 - 5.18 (m, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 313.0 (M+H + ). Step 2 - Synthesis of 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4 H- pyrido[1,2-a]pyrimidin-4-one To a solution of 2-(3-fluorophenyl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H-pyrido [1,2- a]pyrimidin-4-one (680 mg, 2.18 mmol) and 2-iodophenol (718 mg, 3.27 mmol) in THF (10 mL) was added PPh 3 (857 mg, 3.27 mmol) and DIAD (660 mg, 3.27 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h under N 2 atmosphere. The solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (0.6 g, 54%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 7.83 - 7.76 (m, 2H), 7.62 - 7.47 (m, 3H), 7.36 - 7.32 (m, 1H), 7.25 - 7.19 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.73 - 6.69 (m, 1H), 6.23 - 6.17 (m, 1H), 2.40 (s, 3H), 2.22 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H). MS: m/z 515.0 (M+H + ). Step 3 – Synthesis of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxythietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne To a solution of 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4 H- pyrido[1,2-a]pyrimidin-4-one (0.6 g, 1.17 mmol) and thietan-3-one (204 mg, 2.31 mmol) in THF (20 mL) was added n-BuLi (0.47 ml, 1.17 mmol, 2.5 M in n-hexane ) at -78 °C under N 2 atmosphere. The mixture was stirred at room temperature for 3 h under N 2 atmosphere. The mixture was quenched with NH 4 Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (120 mg, 22%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.42 - 7.31 (m, 2H), 6.99 - 6.93 (m, 1H), 6.79 (s, 1H), 6.63 - 6.58 (m, 1H), 6.25 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 5.6 Hz, 1H), 5.54 - 5.25 (m, 1H), 3.74 - 3.61 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H). MS: m/z 476.1 (M+H + ). Step 4 – Synthesis of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne To a solution of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxythietan-3-yl)phenoxy)et hyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 209 umol) in EtOH (4 mL) and H 2 O (1 mL) was added oxone (516 mg, 838 umol) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with NaHCO 3 (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 60 - 90% / 0.225% formic acid in water) to give the title compound (30 mg, 28%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.63 - 7.43 (m, 4H), 7.38 - 7.29 (m, 1H), 7.17 -7.11 (m, 1H), 6.95 - 6.89 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 6.24 - 6.16 (m, 1H), 5.09 - 4.94 (m, 2H), 4.26 - 4.12 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na + ). Step 5 – Synthesis of (R)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan -3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne & (S)-2-(3-fluorophenyl)- 9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3-yl)phenoxy)ethyl)-3, 7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3-y l)phenoxy)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (30 mg, 59 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AS (250 mm*30 mm,5 um); Supercritical CO 2 / EtOH + 0.1% NH 3 •H 2 O = 25/75; 60 mL/min) to afford (R)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1- dioxidothietan-3-yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1, 2-a]pyrimidin-4-one (5.4 mg, first peak) and (S)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan -3-yl)phenoxy)ethyl)- 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one(15 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.61 - 7.45 (m, 4H), 7.38 - 7.28 (m, 1H), 7.19 - 7.11 (m, 1H), 6.95 - 6.88 (m, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.24 - 6.16 (m, 1H), 5.11 - 4.91 (m, 2H), 4.23 - 4.10 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na + ). Second peak: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.63 - 7.44 (m, 4H), 7.39 - 7.30 (m, 1H), 7.18 -7.11 (m, 1H), 6.95 - 6.89 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.24 - 6.17 (m, 1H), 5.12 - 4.90 (m, 2H), 4.25 - 4.12 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na + ). Compounds of Formula (I) in Table A can be prepared analogously to Examples 1-53. Compounds of Formula (I) in Table B below were prepared analogously to Examples 1- 53. Table B
ASSAY PI3Ka cellular assay experimental procedure: SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25k cells/well into 96-well cell culture format. Cells are incubated overnight at 37℃ in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed 1X with room temperature PBS prior to serum-free media application. Cells are returned to 37℃ 5% CO2 incubator and incubated a further 16hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000nM and 3x multiple dose reductions for a minimum dose of 0.5nM diluted in DMSO. Cell/compound incubation continues for 1hr in a 37°C, 5% CO2 incubator prior to 10 minute PIK3CA stimulation with 20ng/ml EGF. Cells treated with 0.1% DMSO and 20ng/mL EGF are employed as negative control, cells treated with 10uM Alpelisib and 20ng/mL EGF are employed as a positive control. After 10 mins, plates are removed from incubator and cells are lysed with buffer and shaking 45 minutes.20uL of lysate is transferred to an opti-384 plate and 2.5 μl of Phospho-AKT d2 antibody with 2.5 μl of Phospho-AKT Eu Cryptate solution in the detection buffer are added to each well. 384 well plate is left overnight at room temperature before reading HTRF on an Envision plate reader. The biological activity of certain compounds using the assays described above is shown in Table A. The ranges are as follows: for T47D pAKT IC 50 (nM): A denotes < 100 nM; B denotes 100 nM ≤ IC 50 < 500 nM; C denotes 500 nM ≤ IC 50 < 2,000 nM; and D denotes ≥ 2,000 nM. ND denotes value not determined with that assay for the specified compound; for T47D (H1047R) selectivity over SKBR3 (WT): A denotes > 20-fold; B denotes 20- fold ≥ value > 5-fold; C denotes ≤ 5-fold. ND denotes value not determined with that assay for the specified compound; and for T47D pAKT lipophilic efficiency (LiPE): A denotes > 4; B denotes 4 ≥ value > 2; C denotes ≤ 2. ND denotes value not determined with that assay for the specified compound . Table 1
Next Patent: METHODS OF ASSESSING METABOLIC FLUX