STOCK NICHOLAS SIMON (US)
NAGLE ADVAIT (US)
FEINBERG EVAN NATHANIEL (US)
INDARTE MARTIN (US)
| WHAT IS CLAIMED IS: 1. A compound of Formula (I), Formula (II), or Formula (III): (I) or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is NR1A or CR1; Z is NRZ1 or CRZ2, wherein one or both of Q and Z is N; Z1 is S, -S(O2)-, or O; each represents a single bond or a double bond; 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; R1A is absent, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; RZ1 is absent, hydrogen, cyano, C1-C6 alkyl, or C1-C6 alkyl; RZ2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2 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, or C1-C6 alkoxy optionally substituted with –C(=O)NRARC; 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) -SO F 2R, (xi) -NHSO F 2R, (xii) -SO F G 2NRR , (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, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, (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; each RA and RB is 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, 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; R7 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, -C(=O)C1-C6 alkyl, -NH(CN), 5-6 membered heteroaryl, -NR7AR7B, -NR7AC(=O)R7B, -C(=NR7A)NR7AR7B, or -C(=O)NR7AR7B, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, - C(=O)NR7AR7B, or -NHC(=O)C1-C6 alkyl optionally substituted with –NR7AR7B, or when each adjacent to CR7 is a single bond, R7 can be oxo; each R7A and R7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; X is a bond, CH2, CH(CH3), C(CH3)2, or ; W 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, –CO A 2R , -SO F G F F G A B 2NRR , -NHSO2R, –S(=O)(=NR)R , –SO2(C1-C6 alkyl), -C(=O)NR R, 5-6 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 the compound is a compound of Formula (II). 3. The compound of Claim 1, wherein the compound is a compound of Formula (III). 4. The compound of Claim 1 or 3, wherein Z1 is S. 5. The compound of Claim 1 or 3, wherein Z1 is O. 6. The compound of Claim 1 or 3, wherein Z1 is -S(O2)-. 7. The compound of Claim 1, wherein the compound is a compound of Formula (I). 8. The compound of Claim 1 or 7, wherein Q is CR1. 9. The compound of any one of Claims 1-8, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A. 10. The compound of any one of Claims 1-8, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A. 11. The compound of any one of Claims 1-8, wherein R2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A. 12. The compound of any one of Claims 1-8, wherein R2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A. 13. The compound of any one of Claims 1-8, wherein R2 is C1-C6 alkoxy optionally substituted with –C(=O)NRARC. 14. The compound of any one of Claims 1-8, R2 is C1-C6 alkoxyalkyl 15. The compound of any one of Claims 1-14, wherein X is a bond. 16. The compound of any one of Claims 1-14, wherein X is CH2. 17. The compound of any one of Claims 1-14, wherein X is CH(CH3). 18. The compound of any one of Claims 1-14, wherein X is C(CH3)2. 19. The compound of any one of Claims 1-14, wherein X is . 20. The compound of any one of Claims 1-19, wherein W is O. 21. The compound of any one of Claims 1-19, wherein W is NR3B. 22. The compound of any one of Claims 1-21, wherein Y is phenyl optionally substituted with 1-3 independently selected RY. 23. The compound of any one of Claims 1-21, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY. 24. The compound of any one of Claims 1-21, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. 25. The compound of any one of Claims 1-24, wherein RY is halogen. 26. The compound of any one of Claims 1-24, wherein RY is hydroxyl. 27. The compound of any one of Claims 1-24, wherein RY is cyano. 28. The compound of any one of Claims 1-24, wherein RY is C1-C6 haloalkyl. 29. The compound of any one of Claims 1-24, wherein RY is C1-C6 alkoxy. 30. The compound of any one of Claims 1-24, wherein RY is C1-C6 haloalkoxy. 31. The compound of any one of Claims 1-24, wherein RY is C1-C6 hydroxyalkyl. 32. The compound of any one of Claims 1-24, wherein RY is -NHC(=O)RC. 33. The compound of any one of Claims 1-24, wherein RY is -C(=O)NHRY1. 34. The compound of any one of Claims 1-24, wherein RY is –CO2RA. 35. The compound of any one of Claims 1-24, wherein RY is -SO2NRFRG. 36. The compound of any one of Claims 1-24, wherein RY is -NHSO F 2R. 37. The compound of any one of Claims 1-24, wherein RY is –S(=O)(=NRF)RG. 38. The compound of any one of Claims 1-24, wherein RY is –SO2(C1-C6 alkyl). 39. The compound of any one of Claims 1-24, wherein RY is -C(=O)NRARB. 40. The compound of any one of Claims 1-24, wherein RY is 4-6 membered heteroaryl. 41. The compound of any one of Claims 1-24, wherein RY is heteroaralkyl. 42. The compound of any one of Claims 1-24, wherein RY is 4-6 membered heterocyclyl. 43. The compound of any one of Claims 1-24, wherein RY is C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. 44. The compound of any one of Claims 1-24, wherein RY is C1-C6 alkyl substituted with –CO A Y1 2R or 5-6 membered heteroaryl optionally substituted with R . 45. The compound of any one of Claims 1-24, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl substituted with RY1. 46. The compound of any one of Claims 1-24, wherein RY is C1-C6 alkyl substituted with –CO A 2R or 5-6 membered heteroaryl. 47. The compound of any one of Claims 43-45, wherein RY1 is –SO2(C1-C6 alkyl). 48. The compound of any one of Claims 43-45, wherein RY1 is C1-C6 alkyl optionally substituted with oxo. 49. The compound of any one of Claims 43-45, wherein RY1 is hydroxyl. 50. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt of any of the foregoing. 51. A compound selected from the group consisting of the compounds in Table B, or a pharmaceutically acceptable salt of any of the foregoing. 52. A compound selected from the group consisting of the compounds in Table C, or a pharmaceutically acceptable salt of any of the foregoing. 53. A pharmaceutical composition comprising a compound of any one of Claims 1-52, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. 54. 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 1-52, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Claim 53. 55. 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 1-52, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Claim 53. 56. 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 1-52 or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Claim 53. 57. 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 1-52, or a pharmaceutically acceptable salt of any of the foregoing. |
(I-H 2 ) 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 3 ): (I-H 3 ) 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 4 ): (I-H 4 ) 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-H5):
(I-H5) 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-H6): (I-H6) 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-I1): (I-I1) 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-I2):
(I-I2) 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-I3): (I-I3) 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-I4): (I-I4) 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-I5):
(I-I5) 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-I6): (I-I6) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-A1): (II-A1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-B): (II-B) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-C): (II-C) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-A1): (III-A1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-B): (III-B) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-C): (III-C) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-D): (III-D) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-E): (III-E) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof , is a compound of Formula (III-F): (III-F) or a pharmaceutically acceptable salt thereof. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of Compounds 1-147, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt of any of the foregoing. Table A C N 3 3 3 3 3 3 8 8 8 8 8 8 9 9 9 1 1 1 1 1 1 1 1 1 In some embodiments, the compound is selected from the group consisting of Compounds 148-139, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table B, or a pharmaceutically acceptable salt of any of the foregoing. Table B Example No. 148 149 150 151 152 153 154 155 156 In some embodiments, the compound is selected from the group consisting of the Compounds 140-226, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C, or a pharmaceutically acceptable salt of any of the foregoing. Table C Example No. S 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. Methods of Treatment A “PI3Kα inhibitor” as used herein (e.g., compounds of Formula (I), Formula (II), Formula (III), and pharmaceutically acceptable salts of any of the foregoing) 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 EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can selectively target PI3Kα. For example, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can selectively target PI3Kα over another kinase or non- kinase target. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or pharmaceutically acceptable salts of any of the foregoing, 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), Formula (II), or Formula (III), or pharmaceutically acceptable salts of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing. 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. salt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalts of any of the foregoingsalts of any of the foregoingsalt of any of the foregoingsalt of any of the foregoing In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof. 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 Ami A id N Li ii N Li ii E l PI3K A i d C () A Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 20122; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal.6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016/j.ejca.2005.04.022. PMID: 15994075. 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing. 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, 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), Formula (II), or Formula (III), including pharmaceutically acceptable salts of any of the foregoing, can be administered in the form of pharmaceutical compositions as described hereinsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalts of any of the foregoing. EMBODIMENTS 1. A compound of Formula (I), Formula (II), or Formula (III): ( or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is NR 1A or CR 1 ; Z is NR Z1 or CR Z2 , wherein one or both of Q and Z is N; Z 1 is S, -S(O 2 )-, or O; each represents a single bond or a double bond; 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 1A is absent, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R Z1 is absent, hydrogen, cyano, C1-C6 alkyl, or C1-C6 alkyl; R Z2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R 2 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 , or C1-C6 alkoxy optionally substituted with –C(=O)NR A R C ; 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 F 2R, (xi) -NHSO F 2R, (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 , 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 , (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; each R A and R B is 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, 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; R 7 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, -C(=O)C1-C6 alkyl, -NH(CN), 5-6 membered heteroaryl, -NR 7A R 7B , -NR 7A C(=O)R 7B , -C(=NR 7A )NR 7A R 7B , or -C(=O)NR 7A R 7B , 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, - C(=O)NR 7A R 7B , or -NHC(=O)C1-C6 alkyl optionally substituted with –NR 7A R 7B , or when each adjacent to CR 7 is a single bond, R 7 can be oxo; each R 7A and R 7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; X is a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or ; W 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 A 2R , -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 , 5-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R Y1 , and C1-C6 alkyl optionally substituted with –CO A 2R 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 the compound is a compound of Formula (II). 3. The compound of Embodiment 1, wherein the compound is a compound of Formula (III). 4. The compound of Embodiment 1 or 3, wherein Z 1 is S. 5. The compound of Embodiment 1 or 3, wherein Z 1 is O. 6. The compound of Embodiment 1 or 3, wherein Z 1 is -S(O 2 )-. 7. The compound of Embodiment 1, wherein the compound is a compound of Formula (I). 8. The compound of Embodiment 1 or 7, wherein Q is CR 1 . 9. The compound of any one of Embodiments 1-8 wherein R 1 is hydrogen. 10. The compound of any one of Embodiments 1-8, wherein R 1 cyano. 11. The compound of any one of Embodiments 1-8, wherein R 1 is C3-C6 cycloalkyl. 12. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. 13. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. 14. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkyl substituted with phenyl substituted with halogen. 15. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkyl substituted with phenyl. 16. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkyl. 17. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 thioalkyl. 18. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 haloalkyl. 19. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkoxy. 20. The compound of any one of Embodiments 1-8, wherein R 1 is C1-C6 alkoxyalkyl. 21. The compound of any one of Embodiments 1-7, wherein Q is NR 1A . 22. The compound of Embodiment 21, wherein R 1A is absent. 23. The compound of Embodiment 21, wherein R 1A is hydrogen. 24. The compound of Embodiment 21, wherein R 1A is C1-C6 alkyl. 25. The compound of Embodiment 24, wherein R 1A is C1-C3 alkyl. 26. The compound of Embodiment 25, wherein R 1A is methyl. 27. The compound of Embodiment 21, wherein R 1A is C1-C6 haloalkyl. 28. The compound of Embodiment 27, wherein R 1A is trifluoromethyl. 29. The compound of Embodiment 21, wherein R 1A is C1-C6 thioalkyl. 30. The compound of Embodiment 21, wherein R 1A is C1-C6 alkoxy. 31. The compound of Embodiment 21, wherein R 1A is C1-C6 alkoxyalkyl. 32. The compound of any one of Embodiments 1 or 7-31, wherein Z is NR Z1 . 33. The compound of Embodiment 32, wherein R Z1 is absent. 34. The compound of Embodiment 32, wherein R Z1 is hydrogen. 35. The compound of Embodiment 32, wherein R Z1 is C1-C6 alkyl. 36. The compound of Embodiment 32, wherein R Z1 is C1-C3 alkyl. 37. The compound of Embodiment 36, wherein R Z1 is methyl. 38. The compound of Embodiment 32, wherein R Z1 is C1-C6 haloalkyl. 39. The compound of Embodiment 38, wherein R Z1 is trifluoromethyl. 40. The compound of Embodiment 32, wherein R Z1 is cyano. 41. The compound of any one of Embodiments 1 or 7-31, wherein Z is CR Z2 . 42. The compound of Embodiment 41, wherein R Z2 is hydrogen. 43. The compound of Embodiment 41, wherein R Z2 is C1-C6 alkyl. 44. The compound of Embodiment 43, wherein R Z2 is C1-C3 alkyl. 45. The compound of Embodiment 44, wherein R Z2 is methyl. 46. The compound of Embodiment 41, wherein R Z2 is C1-C6 haloalkyl. 47. The compound of Embodiment 46, wherein R Z2 is trifluoromethyl. 48. The compound of any one of Embodiments 1-47, wherein R 2 is phenyl optionally substituted with 1-3 independently selected R 2A . 49. The compound of any one of Embodiments 1-47, wherein R 2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R 2A . 50. The compound of any one of Embodiments 1-47, wherein R 2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R 2A . 51. The compound of any one of Embodiments 1-47, wherein R 2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R 2A . 52. The compound of any one of Embodiments 1-51, wherein 1, 2, or 3 of R 2A are independently halogen. 53. The compound of any one of Embodiments 1-52, wherein 1, 2, or 3 of R 2A are independently cyano. 54. The compound of any one of Embodiments 1-53, wherein 1, 2, or 3 of R 2A are independently hydroxyl. 55. The compound of any one of Embodiments 1-54, wherein 1, 2, or 3 of R 2A are independently -NR A R B . 56. The compound of any one of Embodiments 1-55, wherein 1, 2, or 3 of R 2A are independently -C(=O)NR A R B . 57. The compound of any one of Embodiments 1-56, wherein 1, 2, or 3 of R 2A are independently . 58. The compound of any one of Embodiments 1-57, wherein 1, 2, or 3 of R 2A are independently -NHC(=O)R C . 59. The compound of any one of Embodiments 1-58, wherein 1, 2, or 3 of R 2A are independently -C(=O)NR D R E . 60. The compound of any one of Embodiments 1-59, wherein 1, 2, or 3 of R 2A are independently -C(=O)OR F . 61. The compound of any one of Embodiments 1-60, wherein 1, 2, or 3 of R 2A are independently -SO 2 R F . 62. The compound of any one of Embodiments 1-61, wherein 1, 2, or 3 of R 2A are independently -NHSO 2 R F . 63. The compound of any one of Embodiments 1-62, wherein 1, 2, or 3 of R 2A are independently -SO F G 2NRR . 64. The compound of any one of Embodiments 1-63, wherein 1, 2, or 3 of R 2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NR A R B . 65. The compound of any one of Embodiments 1-64, wherein 1, 2, or 3 of R 2A are independently -NHC(=O)C1-C6 alkyl substituted with NR A R B . 66. The compound of any one of Embodiments 1-65, wherein 1, 2, or 3 of R 2A are independently C1-C6 haloalkyl. 67. The compound of any one of Embodiments 1-66, wherein 1, 2, or 3 of R 2A are independently C1-C6 hydroxyalkyl. 68. The compound of any one of Embodiments 1-67, wherein 1, 2, or 3 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 . 69. The compound of any one of Embodiments 1-68, wherein 1, 2, or 3 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 . 70. The compound of any one of Embodiments 1-69, wherein 1, 2, or 3 of R 2A are independently 5-10 membered heteroaryl. 71. The compound of any one of Embodiments 1-70, wherein 1, 2, or 3 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 F G A B 2NRR , C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NR R, or -NHC(=O)C1-C6 alkyl optionally substituted with -NR A R B . 72. The compound of any one of Embodiments 1-71, wherein 1, 2, or 3 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 F G 2(C1-C6 alkyl), -SO 2 NRR , 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 . 73. The compound of any one of Embodiments 1-72, wherein 1, 2, or 3 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 . 74. The compound of any one of Embodiments 1-73, wherein 1, 2, or 3 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, -C(=O)NR A R B , or -NHC(=O)C1-C6 alkyl. 75. The compound of any one of Embodiments 1-70, wherein 1, 2, or 3 of R 2A are independently 4-10 membered heterocyclyl. 76. The compound of any one of Embodiments 1-75, wherein 1, 2, or 3 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. 77. The compound of any one of Embodiments 1-76, wherein 1, 2, or 3 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 optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B , or – C(=O)C3-C6 cycloalkyl. 78. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 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. 79. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 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. 80. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkyl. 81. The compound of any one of Embodiments 1-80, wherein 1, 2, or 3 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. 82. The compound of any one of Embodiments 1-81, wherein 1, 2, or 3 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. 83. The compound of any one of Embodiments 1-82, wherein 1, 2, or 3 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. 84. The compound of any one of Embodiments 1-82, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl. 85. The compound of any one of Embodiments 1-81, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkoxy. 86. The compound of any one of Embodiments 1-85, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 87. The compound of any one of Embodiments 1-86, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 88. The compound of any one of Embodiments 1-87, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. 89. The compound of any one of Embodiments 1-87, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl. 90. The compound of any one of Embodiments 1-86, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl. 91. The compound of any one of Embodiments 1-47, wherein R 2 is C1-C6 alkoxy optionally substituted with –C(=O)NR A R C . 92. The compound of any one of Embodiments 1-47 or 91, wherein R 2 is C1-C6 alkoxy substituted with –C(=O)NR A R C . 93. The compound of any one of Embodiments 1-47 or 91, wherein R 2 is C1-C6 alkoxy. 94. The compound of any one of Embodiments 1-47, R 2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NR A R C . 95. The compound of any one of Embodiments 1-47, R 2 is C1-C6 alkoxyalkyl 96. The compound of any one of Embodiments 1-95, wherein X is a bond. 97. The compound of any one of Embodiments 1-95, wherein X is CH 2 . 98. The compound of any one of Embodiments 1-95, wherein X is CH(CH 3 ). 99. The compound of any one of Embodiments 1-95, wherein X is C(CH 3 ) 2 . 100. The compound of any one of Embodiments 1-95, wherein X is . 101. The compound of any one of Embodiments 1-72, wherein W is O. 102. The compound of any one of Embodiments 1-72, wherein R 3A is hydrogen. 103. The compound of any one of Embodiments 1-72, wherein R 3A is C1-C6 alkyl. 104. The compound of any one of Embodiments 1-73, wherein R 3A is methyl. 105. The compound of any one of Embodiments 1-72, wherein R 3A is C1-C6 alkoxy. 106. The compound of any one of Embodiments 1-72, R 3A is C1-C6 haloalkyl. 107. The compound of any one of Embodiments 1-72, wherein W is NR 3B . 108. The compound of Embodiment 107, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkyl. 109. The compound of Embodiment 107-108, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is methyl. 110. The compound of Embodiment 107, wherein each of R 3A and R 3B is hydrogen. 111. The compound of Embodiment 107, wherein each of R 3A and R 3B is an independently selected C1-C6 alkyl. 112. The compound of Embodiment 107 or 111, wherein each of R 3A and R 3B is methyl. 113. The compound of Embodiment 107, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkoxy. 114. The compound of Embodiment 107, 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. 115. The compound of Embodiment 107, wherein each of R 3A and R 3B is C1-C6 alkoxy. 116. The compound of Embodiment 107, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 haloalkyl. 117. The compound of Embodiment 107, 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. 118. The compound of Embodiment 107, wherein each of R 3A and R 3B is C1-C6 haloalkyl. 119. The compound of Embodiment 107, 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. 120. The compound of any one of Embodiments 1-119, wherein Y is phenyl optionally substituted with 1-3 independently selected R Y . 121. The compound of any one of Embodiments 1-119, wherein Y is naphthyl optionally substituted with 1-3 independently selected R Y . 122. The compound of any one of Embodiments 1-119, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y . 123. The compound of any one of Embodiments 1-122, wherein 1, 2, or 3 of R Y is independently halogen. 124. The compound of any one of Embodiments 1-123, wherein 1, 2, or 3 of R Y is hydroxyl. 125. The compound of any one of Embodiments 1-124, wherein 1, 2, or 3 of R Y is cyano. 126. The compound of any one of Embodiments 1-125, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkyl. 127. The compound of any one of Embodiments 1-126, wherein 1, 2, or 3 of R Y is independently C1-C6 alkoxy. 128. The compound of any one of Embodiments 1-127, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkoxy. 129. The compound of any one of Embodiments 1-128, wherein 1, 2, or 3 of R Y is independently C1-C6 hydroxyalkyl. 130. The compound of any one of Embodiments 1-129, wherein 1, 2, or 3 of R Y is independently -NHC(=O)R C . 131. The compound of any one of Embodiments 1-130, wherein 1, 2, or 3 of R Y is independently -C(=O)NHR Y1 . 132. The compound of any one of Embodiments 1-131, wherein 1, 2, or 3 of R Y is independently –CO 2 R A . 133. The compound of any one of Embodiments 1-132, wherein 1, 2, or 3 of R Y is independently -SO 2 NR F R G . 134. The compound of any one of Embodiments 1-133, wherein 1, 2, or 3 of R Y is independently -NHSO F 2R. 135. The compound of any one of Embodiments 1-134, wherein 1, 2, or 3 of R Y is independently –S(=O)(=NR F )R G . 136. The compound of any one of Embodiments 1-135, wherein 1, 2, or 3 of R Y is independently –SO 2 (C1-C6 alkyl). 137. The compound of any one of Embodiments 1-136, wherein 1, 2, or 3 of R Y is independently -C(=O)NR A R B . 138. The compound of any one of Embodiments 1-137, wherein 1, 2, or 3 of R Y is independently 4-6 membered heteroaryl. 139. The compound of any one of Embodiments 1-138, wherein 1, 2, or 3 of R Y is independently heteroaralkyl. 140. The compound of any one of Embodiments 1-139, wherein 1, 2, or 3 of R Y is independently 4-6 membered heterocyclyl. 141. The compound of any one of Embodiments 1-140, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl optionally substituted with –CO A 2R or 5-6 membered heteroaryl optionally substituted with R Y1 . 142. The compound of any one of Embodiments 1-141, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO A 2R or 5-6 membered heteroaryl optionally substituted with R Y1 . 143. The compound of any one of Embodiments 1-142, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO A 2R or 5-6 membered heteroaryl substituted with R Y1 . 144. The compound of any one of Embodiments 1-143, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO A 2R or 5-6 membered heteroaryl. 145. The compound of any one of Embodiments 1-144, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl. 146. The compound of any one of Embodiments 1-122 or 141-143, wherein R Y1 is – SO 2 (C1-C6 alkyl). 147. The compound of any one of Embodiments 1-122 or 141-143, wherein R Y1 is C1- C6 alkyl optionally substituted with oxo. 148. The compound of any one of Embodiments 1-145, wherein 1, 2, or 3 of R Y1 is hydroxyl. 149. The compound of any one of Embodiments 1-148, wherein R 4 is hydrogen. 150. The compound of any one of Embodiments 1-148, wherein R 4 is C1-C6 alkyl. 151. The compound of any one of Embodiments 1-148, wherein R 4 is acrylamido. 152. The compound of any one of Embodiments 1-151, wherein R 5 is hydrogen. 153. The compound of any one of Embodiments 1-151, wherein R 5 is C1-C6 alkyl. 154. The compound of any one of Embodiments 1-151, wherein R 5 is cyano. 155. The compound of any one of Embodiments 1-151, wherein R 5 is -NR 5A R 5B . 156. The compound of any one of Embodiments 1-151, wherein R 5 is -C(=O)NR 5A R 5B . 157. The compound of any one of Embodiments 1-151, wherein R 5 is -NR 5A C(=O)R 5B . 158. The compound of any one of Embodiments 1-151 or 145-157, 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. 159. The compound of any one of Embodiments 1-151 or 155-157, 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. 160. The compound of any one of Embodiments 1-151 or 155-157, wherein each of R 5A and R 5B is hydrogen. 161. The compound of any one of Embodiments 1-151 or 155-157, wherein each of R 5A and R 5B is an independently selected C1-C6 alkyl. 162. The compound of any one of Embodiments 1-161, wherein R 6 is hydrogen. 163. The compound of any one of Embodiments 1-161, wherein R 6 is halogen. 164. The compound of any one of Embodiments 1-161, wherein R 6 is C1-C6 alkyl. 165. The compound of any one of Embodiments 1-164, wherein R 7 is hydrogen. 166. The compound of any one of Embodiments 1-164, wherein R 7 is halogen. 167. The compound of any one of Embodiments 1-164, wherein R 7 is hydroxyl. 168. The compound of any one of Embodiments 1-164, wherein R 7 is cyano. 169. The compound of any one of Embodiment 1-164, wherein R 7 is C1-C6 alkyl. 170. The compound of any one of Embodiment 1-164, wherein R 7 is C1-C6 alkoxyalkyl. 171. The compound of any one of Embodiment 1-164, wherein R 7 C1-C6 hydroxyalkyl. 172. The compound of any one of Embodiment 1-164, wherein R 7 is C1-C6 cyanoalkyl. 173. The compound of any one of Embodiment 1-164, wherein R 7 is -C(=O)C1-C6 alkyl. 174. The compound of any one of Embodiment 1-164, wherein R 7 is -NH(CN). 175. The compound of any one of Embodiment 1-164, wherein R 7 is 5-6 membered heteroaryl. 176. The compound of any one of Embodiments 1-164, wherein R 7 is -NR 7A R 7B . 177. The compound of any one of Embodiments 1-164, wherein R 7 is -NR 7A C(=O)R 7B . 178. The compound of any one of Embodiment 1-164, wherein R 7 is - C(=NR 7A )NR 7A R 7B . 179. The compound of any one of Embodiment 1-164, wherein R 7 is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, - C(=O)NR 7A R 7B , or -NHC(=O)C1-C6 alkyl optionally substituted with –NR 7A R 7B . 180. The compound of any one of Embodiment 1-164, wherein each adjacent to CR 7 is a single bond, R 7 is oxo. 181. The compound of any one of Embodiments 1-164, wherein R 7 is -C(=O)NR 7A R 7B . 182. The compound of any one of Embodiments 1-164 or 176-179, wherein one of R 7A and R 7B is hydrogen and the other of R 5A and R 5B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo. 183. The compound of any one of Embodiments 1-164 or 176-179, wherein one of R 7A and R 7B is C1-C6 alkyl and the other of R 7A and R 7B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo. 184. The compound of any one of Embodiments 1-164 or 176-179, wherein each of R 7A and R 7B is hydrogen. 185. The compound of any one of Embodiments 1-164 or 176-179, wherein each of R 7A and R 7B is an independently selected C1-C6 alkyl. 186. The compound of any one of Embodiments 1-185, 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. 187. The compound of any one of Embodiments 1-186, 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. 188. The compound of any one of Embodiments 1-187, 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. 189. The compound of any one of Embodiments 1-188, 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. 190. The compound of any one of Embodiments 1-185, 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. 191. The compound of any one of Embodiments 1-185 or 190, 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. 192. The compound of any one of Embodiments 1-185 or 190, wherein R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. 193. The compound of any one of Embodiments 1-176, 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. 194. The compound of any one of Embodiments 1-193, 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. 195. The compound of any one of Embodiments 1-193, 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. 196. The compound of any one of Embodiments 1-192, wherein each R C is independently C3-C6 cycloalkyl, -C(=O)NHR Y1 , or a C1-C6 alkyl. 197. The compound of any one of Embodiments 1-196, 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. 198. The compound of any one of Embodiments 1-196, wherein each of R D and R E is hydrogen. 199. The compound of any one of Embodiments 1-196, wherein each of R D and R E is an independently selected C1-C6 alkyl. 200. The compound of any one of Embodiments 1-196, 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 . 201. The compound of any one of Embodiments 1-196, 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 . 202. The compound of any one of Embodiments 1-196, 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. 203. The compound of any one of Embodiments 1-196, wherein each of R F and R G is hydrogen. 204. The compound of any one of Embodiments 1-196, wherein each of R F and R G is an independently selected C1-C6 alkyl. 205. A compound selected from the group consisting of the compounds in Table A, Table B, or Table C, or a pharmaceutically acceptable salt of any of the foregoing. 206. A pharmaceutical composition comprising a compound of any one of Embodiments 1-205, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. 207. 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- 205, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206. 208. 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 1-205, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206. 209. 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 1-205 or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206. 210. 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 1-205, or a pharmaceutically acceptable salt of any of the foregoing. salt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoing EXAMPLES Preparation of Compounds 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. The general methods for the preparation of the compounds of Formula (I), Formula (II), or Formula (III), have been described in an illustrative manner and are intended to be descriptive, rather than limiting. 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. Example 1: Synthesis of Compound 9: 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4- yl)quinazolin-8-yl)ethyl)amino)benzoic acid Step 1 - Synthesis of 8-bromo-6-methyl-2-(pyridin-4-yl)quinazolin-4-ol: A mixture of 2-amino-3-bromo-5-methyl-benzamide (1.8 g, 8.7 mmol) (prepared according to the procedure in WO 2 0075668), CuO (1.32 g, 16.6 mmol) and pyridine-4- carbaldehyde (1.12 g, 10.5 mmol) in dimethylacetamide (DMA, 50 mL) was stirred at 135 ° C for 16 hours under O 2 atmosphere. After cooling to room temperature, the reaction was poured into water (100 mL). The suspension was filtered and the filter cake was dried in vacuo to give 8- bromo-6-methyl-2-(pyridin-4-yl)quinazolin-4-ol (360 mg, crude) as a white solid that required no further purification. MS: m/z 318.1 (M+H + ). Step 2 - Synthesis of 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan- 1-one: A mixture of 8-bromo-6-methyl-2-(4-pyridyl)quinazolin-4-ol (190 mg, 601 µmol), tributyl(1-ethoxyvinyl)stannane (543 mg, 1.5 mmol) and Pd(dppf)Cl 2 (44 mg, 60 umol) in dioxane (10 mL) was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (1 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 10 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (20 mL x 3). 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 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan- 1-one (110 mg, 60%) as a white solid. MS: m/z 280.1 (M+H + ). Step 3 - Synthesis of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)et han-1-one: To a solution of 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan- 1-one (110 mg, 508 µmol), K2CO3 (105 mg, 763 µmol) in DMF (10 mL) was added BnBr (83 mg, 483 µmol). The reaction mixture was heated to 65 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was added water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 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 1-(4-(benzyloxy)-6-methyl-2- (pyridin-4-yl)quinazolin-8-yl)ethan-1-one (180 mg, 44%) as a white solid. MS: m/z 370.1 (M+H + ). Step 4 - Synthesis of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)et han-1- amine: To a solution of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)et han-1-one (180 mg, 327 µmmol), NH 4 OAc (252 mg, 3.27 mmol) in MeOH (10 mL) was added NaBH 3 CN (62 mg, 980 umol). The reaction was heated to 40 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL x 3). 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 - 10% MeOH in DCM) to give 1-(4-(benzyloxy)-6-methyl- 2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-amine (62 mg, 52%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (d, J = 6.0 Hz, 2H), 8.41 (d, J = 6.4 Hz, 2H), 7.96 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.38 (d, J = 7.2 Hz, 1H), 5.82 (s, 2H), 5.28 - 5.16 (m, 1H), 2.53 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H). MS: m/z 371.1 (M+H + ). Step 5 - Synthesis of tert-butyl 2-((1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoate:
A mixture of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)et han-1-amine (50 mg, 135 umol), tert-butyl 2-bromobenzoate (103 mg, 2.1 mmol), Cs 2 CO 3 (176 mg, 540 umol), Pd 2 (dba) 3 (13 mg, 14 umol), Xantphos (16 mg, 27 umol) in dioxane (5 mL) was stirred at 100 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction 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 (22 mg, 30%) as a white solid. MS: m/z 547.3 (M+H + ). Step 6 - Synthesis of tert-butyl 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoate: To a solution of tert-butyl 2-((1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoate (54 mg, 99 umol) in MeOH (5 mL) was added wet Pd/C (10 mg, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 0.5 hours 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-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin- 8-yl)ethyl)amino)benzoate (12 mg, 27%) as yellow oil that required no further purification. MS: m/z 457.2 (M+H + ). Step 7 - Synthesis of 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoic acid: To a mixture of tert-butyl 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoate (12 mg, 26 umol) in DCM (1.5 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 and the residue was purified by reverse phase chromatography (acetonitrile 32% - 62% / 0.225% formic acid in water) to give 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8- yl)ethyl)amino)benzoic acid (2.4 mg, 24%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.78 (s, 1H), 8.81 (d, J = 6.0 Hz, 2H), 8.49 (d, J = 6.0 Hz, 1H), 8.22 (d, J = 6.0 Hz, 2H), 7.88 (s, 1H), 7.81 - 7.76 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 - 6.45 (m, 2H), 5.72 - 5.57 (m, 1H), 2.40 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 401.2 (M+H + ). Example 2: Synthesis of Compound 20: 2-((1-(7-methyl-3-morpholinoisoquinolin-5- yl)ethyl)amino)benzoic acid Step 1 - Synthesis of (3-bromo-5-methylphenyl)methanamine: To a solution of 3-bromo-5-methyl-benzonitrile (5 g, 26 mmol) in THF (50 mL) was added borane tetrahydrofuran complex (33 mL, 33 mmol, 1M in THF) at room temperature. The mixture was heated to 70 °C and stirred for 2 hours. After cooling to room temperature, the mixture was quenched with MeOH (20 mL), then the mixture was heated to 70 °C and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give (3- bromo-5-methylphenyl)methanamine (3 g, 58%) as yellow oil. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.33 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 3.65 (s, 2H), 2.27 (s, 3H). MS: m/z 202.0 (M+H + ). Step 2 - Synthesis of N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide: A mixture of (3-bromo-5-methylphenyl)methanamine (3 g, 15 mmol) and methyl 2,2- dimethoxyacetate (2.2 mL, 18 mmol) was heated to 130 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% EtOAc in petroleum ether) to give N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide (4.3 g, 88%) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.92 - 6.81 (m, 1H), 4.76 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.42 (s, 6H), 2.32 (s, 3H). MS: m/z 302.0 (M+H + ). Step 3 - Synthesis of 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3- ol A solution of N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide (4.3 g, 14 mmol) in conc. H 2 SO 4 (12 mL, 230 mmol) was stirred at room temperature for 16 h. The reaction mixture was added to ice water (20 mL) slowly and the mixture was adjusted to pH 7-8 with 1M aqueous NaOH solution, then extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3-ol (3.1 g, crude, mixture of two isomers, inseparable) as yellow solids that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.87 (s, 1H), 8.05 - 7.84 (m, 1H), 7.76 - 7.54 (m, 1H), 6.95 - 6.88 (m, 1H), 2.41 (s, 3H). MS: m/z 239.9 (M+H + ). Step 4 - Synthesis of 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate To a solution of 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3-ol (1 g, 4.2 mmol, mixture of two isomers) in DCM (15 mL) was added pyridine (1 mL, 12.6 mmol) and Tf2O (1.8 g, 6.3 mmol). The mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (30 mL) and extracted with DCM (60 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 - 2% EtOAc in petroleum ether) to give 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate (600 mg, 37%) as a yellow solid, which was further confirmed by NOESY. 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 2.58 (s, 3H). MS: m/z 369.9 (M+H + ). Step 5 - Synthesis of 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine A mixture of 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate (500 mg, 1.4 mmol), Pd 2 (dba) 3 (124 mg, 135 μmol), Xantphos (156 mg, 270 μmol), Cs 2 CO 3 (1.3 g, 4.1 mmol) and morpholine (130 mg, 1.5 mmol) in dioxane (20 mL) was stirred at 80 °C for 3 hours 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 (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 - 25% EtOAc in petroleum ether) to give 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine (170 mg, 37%) as a yellow solid. MS: m/z 309.0 (M+H + ). Step 6 - Synthesis of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one A mixture of 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine (170 mg, 0.6 mmol), tributyl(1-ethoxyvinyl)stannane (354 uL, 1 mmol) and Pd(dppf)Cl 2 (40 mg, 55 μmol) in dioxane (10 mL) was degassed and purged with N 2 atmosphere for 3 times. The reaction mixture was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, HCl (2 mL, 1 M) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added 20 mL 10% KF aqueous solution, stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (30 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 - 10% EtOAc in petroleum ether) to give 1-(7- methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one (120 mg, 50%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 3.90 - 3.88 (m, 4H), 3.62 - 3.60 (m, 4H), 2.72 (s, 3H), 2.52 (s, 3H). MS: m/z 271.1 (M+H + ). Step 7 - Synthesis of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-amine To a solution of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one (110 mg, 407 μmol), NH 4 OAc (470 mg, 6 mmol) and AcOH (47 μL, 814 μmol) in MeOH (5 mL). The mixture was stirred at room temperature for 0.5 hours, then NaBH 3 CN (77 mg, 1 mmol) was added. The reaction was heated to 60 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 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 - 5% MeOH in DCM) to give 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1- amine (50 mg, 36%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 7.00 (s, 1H), 4.66 (q, J = 6.4 Hz, 1H), 3.78 - 3.75 (m, 4H), 3.48 - 3.46 (m, 4H), 2.41 (s, 3H), 1.33 (d, J = 6.4 Hz, 3H). MS: m/z 272.3 (M+H + ). Step 8 - Synthesis of tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5- yl)ethyl)amino)benzoate: A mixture of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-amine (50 mg, 184 μmol), Pd 2 (dba) 3 (17 mg, 18 μmol), Xantphos (21 mg, 37 μmol), Cs 2 CO 3 (180 mg, 553 μmol) and tert-butyl 2-iodobenzoate (112 mg, 369 μmol) in dioxane (5 mL) was stirred at 110 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (15 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 crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino)ben zoate (40 mg, 46%) as yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.76 (dd, J = 8.0, 1.2 Hz, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.19 - 7.15 (m, 1H), 7.11 (s, 1H), 6.54 - 6.50 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.36 - 5.29 (m, 1H), 3.78 - 3.75 (m, 4H), 3.51 - 3.49 (m, 4H), 2.33 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.57 (s, 9H). MS: m/z 448.1 (M+H + ). Step 9 - Synthesis of 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino) benzoic acid: To a mixture of tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5- yl)ethyl)amino)benzoate (40 mg, 89 μmol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction 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 40 - 70% / 0.225% formic acid in water) to give 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino) benzoic acid (16 mg, 44%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (s, 1H), 8.46 (s, 1H), 7.81 - 7.79 (m, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.18 - 7.14 (m, 1H), 7.11 (s, 1H), 6.52 - 6.48 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.35 - 5.29 (m, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.50 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H). MS: m/z 392.1 (M+H + ). Example 3: Synthesis of Compound 26: 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoic acid Step 1 - Synthesis of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4( 3H)-one: To a mixture of methyl 2-amino-3-bromo-5-methylbenzoate (3 g, 12.3 mmol) (prepared according to the procedure in CN111440161) and 4,4-dimethylpiperidine-1-carbonitrile (2.55 g, 18.5 mmol) in THF (40 mL) was added NaH (983 mg, 24.8 mmol, 60% purity). The reaction mixture was heated to 90 °C for 5 hours under N 2 atmosphere. After cooling to room temperature, the reaction was quenched water (50 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 crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-4(3H)-one (1.5 g, 35%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 3.70 - 3.63 (m, 4H), 2.32 (s, 3H), 1.40 - 1.33 (m, 4H), 0.96 (s, 6H). MS: m/z 352.0 (M+H + ). Step 2 - Synthesis of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4 (3H)-one: A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4( 3H)-one (650 mg, 1.87 mmol), tributyl(1-ethoxyvinyl)stannane (1.90 g, 5.26 mmol) and Pd(dppf)Cl 2 (272 mg, 0.4 mmol) in dioxane (6 mL) was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (2 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 20 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (30 mL x 3). 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 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-4(3H)-one (450 mg, 51%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.45 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 3.66 - 3.60 (m, 4H), 2.73 (s, 3H), 2.35 (s, 3H), 1.41 - 1.35 (m, 4H), 0.97 (s, 6H). MS: m/z 314.1 (M+H + ). Step 3 - Synthesis of 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-6-methylqu inazolin- 4(3H)-one: To a solution of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4 (3H)-one (0.6 g, 1.91 mmol) in MeOH (10 mL) was added NaBH 4 (150 mg, 3.96 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours under N 2 atmosphere. The reaction was quenched with saturated aqueous (sat. aq.) NH 4 Cl (3 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 - 10% MeOH in DCM) to give 2-(4,4-dimethylpiperidin-1-yl)-8-(1- hydroxyethyl)-6-methylquinazolin-4(3H)-one (460 mg, 76%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 5.36 - 5.27 (m, 1H), 5.11 (d, J = 4.4 Hz, 1H), 3.62 - 3.55 (m, 4H), 2.34 (s, 3H), 1.41 - 1.31 (m, 7H), 0.97 (s, 6H). MS: m/z 316.2 (M+H + ). Step 4 - Synthesis of 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methylquin azolin- 4(3H)-one: To a solution of 2-(4,4-dimethyl-1-piperidyl)-8-(1-hydroxyethyl)-6-methyl-3H- quinazolin-4-one (460 mg, 1.46 mmol) in DCM (6 mL) was added PBr 3 (592.16 mg, 2.19 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N 2 atmosphere. The mixture was quenched with sat. aq. NaHCO 3 (20 mL), extracted with DCM (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 to give 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methylquin azolin-4(3H)-one (500 mg, crude) as a yellow solid that required no further purification. Step 5 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate: To a solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-6-methyl-3H-qu inazolin- 4-one (0.4 g, 1.06 mmol) in DMF (4 mL) was added tert-butyl 2-aminobenzoate (613 mg, 3.17 mmol). The mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (40 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 residue was purified by reverse phase chromatography (acetonitrile 85% - 100% / 0.225% formic acid in water) to give tert-butyl 2-((1-(2-(4,4- dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)benzoate (30 mg, 7%) as yellow oil. MS: m/z 491.4 (M+H + ). Step 6 - Synthesis of tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoate: To a solution of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (30 mg, 61 μmol) in DMF (1 mL) was added BOP (35 mg, 79 μmol), DBU (14 mg, 92 μmol), NaCN (10 mg, 183 μmol,) and 18-crown-6 (48 mg, 182 μmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was added water (20 mL) and extracted with EtOAc (30 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 - 5% EtOAc in petroleum ether) to give tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoate (18 mg, 59%) as a yellow solid. 1 H NMR (500 MHz, CDCl 3 ) δ 7.88 - 7.85 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.24 - 7.20 (m, 1H), 6.83 - 6.77 (m, 2H), 5.65 - 5.59 (m, 1H), 3.94 - 3.88 (m, 4H), 2.41 (s, 3H), 1.82 (d, J = 5.2 Hz, 3H), 1.60 (s, 9H), 1.48 - 1.43 (m, 4H) 1.05 (s, 6H). MS: m/z 500.1 (M+H + ). Step 7 - Synthesis of 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinaz olin-8- yl)ethyl)amino)benzoic acid:
To a solution of tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoate (18 mg, 36 umol) 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 85% - 100% / 0.225% formic acid in water) to give 2-((1-(4-cyano-2-(4,4- dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino) benzoic acid (2.7 mg, 19%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (s, 1H), 8.48 (s, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.16 (s, 1H), 6.52 - 6.48 (m, 1H), 6.40 (s, 1H), 5.43 (s, 1H), 3.89 (s, 4H), 2.39 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H), 1.46 - 1.40 (m, 4H), 1.01 (s, 6H). MS: m/z 444.2 (M+H + ). Example 4: Synthesis of Compound 32: (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid Step 1 - Synthesis of 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one: A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.3 g, 9.5 mmol) (prepared according to the procedure in Eur. J. Med. Chem., 2021, 225, 113764), 4-fluorobenzaldehyde (2 g, 16.1 mmol) and CuO (1.5 g, 18.9 mmol) in DMA (20 mL) was stirred at 135 °C for 16 hours under O 2 atmosphere. After cooling to room temperature, the reaction was poured into water (50 mL), the suspension was filtered and the filter cake was dried in vacuo to give 8-bromo-2-(4- fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.3 g, crude) as a white solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.99 (s, 1H), 7.95 (s, 1H), 7.79 - 7.74 (m, 2H), 7.44 - 7.35 (m, 2H), 3.35 (s, 3H), 2.45 (s, 3H). MS: m/z 347.0 (M+H + ). Step 2 - Synthesis of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one : A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4( 3H)-one (1.28 g, 3.69 mmol), tributyl(1-ethoxyvinyl)stannane (4 mL, 11.85 mmol) and Pd(dppf)Cl 2 (270 mg, 0.37 mmol) in dioxane (10 mL) was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (5 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 40 mL 10% KF solution, stirred at room temperature over 2 hours. 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 - 30% EtOAc in petroleum ether) to give 8-acetyl-2-(4-fluorophenyl)-3,6- dimethylquinazolin-4(3H)-one (500 mg, 44%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 1.2 Hz, 1H), 7.84 - 7.74 (m, 3H), 7.43 - 7.37 (m, 2H), 3.40 (s, 3H), 2.71 (s, 3H), 2.49 (s, 3H). MS: m/z 311.1 (M+H + ). Step 3 - Synthesis of 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4 (3H)-one: To a solution of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (180 mg, 0.58 mmol), NH 4 OAc (447 mg, 5.8 mmol) in MeOH (10 mL) was added NaBH 3 CN (110 mg, 1.74 mmol). The reaction was heated to 40 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 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 - 10% MeOH in DCM) to give 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6- dimethylquinazolin-4(3H)-one (160 mg, 88%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (s, 1H), 7.81 - 7.77 (m, 3H), 7.43 - 7.37 (m, 2H), 4.88 - 4.82 (m, 1H), 3.38 (s, 3H), 2.47 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). MS: m/z 312.2 (M+H + ). Step 4 - Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate: A mixture of 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4 (3H)-one (160 mg, 514 μmol), tert-butyl 2-iodobenzoate (391 mg, 1.28 mmol), Pd 2 (dba) 3 (47 mg, 51 μmol), Xantphos (60 mg, 103 μmol) and Cs 2 CO 3 (502 mg, 1.54 mmol) in dioxane (5 mL) was stirred at 100 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction 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 tert-butyl 2-((1-(2- (4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (180 mg, 71%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (d, J = 6.8 Hz, 1H), 7.93 - 7.84 (m, 3H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.22 - 7.13 (m, 1H), 6.55 - 6.42 (m, 2H), 5.47 - 5.36 (m, 1H), 3.41 (s, 3H), 2.40 (s, 3H), 1.59 - 1.53 (m, 12H). MS: m/z 488.2 (M+H + ). Step 5 - Synthesis of 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoic acid: To a mixture of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (100 mg, 205 μmol) in DCM (2 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 residue was purified by reverse phase chromatography (acetonitrile 51% - 81% / 0.225% formic acid in water) to give 2-((1-(2-(4-fluorophenyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (65 mg, 73%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.69 (s, 1H), 8.52 - 8.31 (m, 1H), 7.88 - 7.83 (m, 3H), 7.78 (dd, J = 8.0,1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.19 - 7.13 (m, 1H), 6.52 - 6.46 (m, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.50 - 5.43 (m, 1H), 3.41 (s, 3H), 2.39 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H + ). Step 6 - Synthesis of (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(4-fluorophenyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid:
2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8-yl)ethyl)amino) benzoic acid (65 mg, 151 umol) was separated by using chiral SFC (DAICEL CHIRALCEL 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-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)amino)benzoic acid (19 mg, first peak) and (S)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (16 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 - 8.39 (m, 1H), 7.88 - 7.82 (m, 3H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.19 - 7.12 (m, 1H), 6.51 - 6.45 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.49 - 5.43 (m, 1H), 3.41 (s, 3H), 2.38 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H + ). Example 5: Synthesis of Compound 33: (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid Step 1 – Synthesis of 1,3-dimethyl-1H-indazole-5-carbaldehyde: To a stirred solution of 5-bromo-1,3-dimethyl-indazole (2 g, 8.89 mmol) in dry THF (20 mL) was added n-BuLi (4.27 mL, 10.68 mmol, 2.5 M in hexane) at -78 °C under N 2 atmosphere. The resulting reaction mixture was stirred at this temperature for 15 minutes. Then dry DMF (685 uL, 8.89 mmol) was added to the reaction mixture at -78 °C. The mixture was stirred at this temperature for 2 hours. After complete consumption of the starting material, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (50 mL x 2). 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 - 30% EtOAc in petroleum ether) to give 1,3-dimethyl-1H-indazole-5-carbaldehyde (1.5 g, 96%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 4.00 (s, 3H), 2.54 (s, 3H). MS: m/z 175.1 (M+H + ). Step 2 – Synthesis of 8-bromo-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazo lin- 4(3H)-one: A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.17 mmol) (prepared according to the procedure in Eur. J. Med. Chem., 2021, 225, 113764), 1,3-dimethyl-1H-indazole- 5-carbaldehyde (1.29 g, 7.40 mmol) and CuO (982 mg, 12.34 mmol) in DMA (30 mL) was stirred at 135 °C for 16 hours under O 2 atmosphere. After cooling to room temperature, the reaction was poured into water (100 mL), extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 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 - 50% EtOAc in petroleum ether) to give 8-bromo-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6- dimethylquinazolin-4(3H)-one (1.5 g, 61%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 4.03 (s, 3H), 3.40 (s, 3H), 2.53 (s, 3H), 2.47 (s, 3H). MS: m/z 397.1 (M+H + ). Step 3 – Synthesis of 8-acetyl-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinaz olin- 4(3H)-one: A mixture of 8-bromo-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-quinazolin -4-one (400 mg, 1.01 mmol), tributyl(1-ethoxyvinyl)stannane (1.09 g, 3.02 mmol), Pd(dppf)Cl 2 (74 mg, 101 μmol) in dioxane (10 mL) was stirred at 90 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (5 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 50 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (60 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 - 50% EtOAc in petroleum ether) to give 8-acetyl-2-(1,3-dimethyl-1H-indazol-5-yl)- 3,6-dimethylquinazolin-4(3H)-one (200 mg, 51%) as yellow oil. MS: m/z 361.2 (M+H + ). Step 4 – Synthesis of 8-(1-aminoethyl)-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6- dimethylquinazolin-4(3H)-one: To a solution of 8-acetyl-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-quinazoli n-4-one (700 mg, 1.94 mmol), NH 4 OAc (1.50 g, 19.42 mmol) in MeOH (10 mL) was added NaBH 3 CN (336 mg, 5.83 mmol). The reaction was heated to 40 °C for 16 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (30 mL), 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 - 10% MeOH in DCM) to give 8-(1-aminoethyl)-2-(1,3- dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one (250 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.73 - 7.67 (m, 2H), 4.85 - 4.67 (m, 1H), 4.02 (s, 3H), 3.42 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 2.11 (s, 2H), 1.31 (d, J = 6.4 Hz, 3H). MS: m/z 362.3 (M+H + ). Step 5 – Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate: A mixture of 8-(1-aminoethyl)-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-q uinazolin-4- one (250 mg, 692 μmol), tert-butyl 2-iodobenzoate (421 mg, 1.38 mmol), Pd 2 (dba) 3 (63 mg, 69 μmol), Xantphos (80 mg, 138 μmol) and Cs 2 CO 3 (676 mg, 2.08 mmol) in dioxane (10 mL) was stirred at 100 °C for 3 hours under N 2 atmosphere. After cooling to room temperature, the reaction 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 tert-butyl 2-((1- (2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)amino)benzoate (350 mg, 94%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (d, J = 6.8 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.74 - 7.71 (m, 2H), 7.59 (d, J = 1.6 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.54 - 6.40 (m, 2H), 5.51 - 5.43 (m, 1H), 3.47 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H), 1.99 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H). MS: m/z 538.2 (M+H + ). Step 6 – Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid:
To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (350 mg, 651 μmol) in DCM (3 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 51% - 81% / 0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-indazol- 5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)benzoic acid (150 mg, 41%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.78 - 7.75 (m, 1H), 7.74 - 7.71 (m, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.17 (s, 1H), 6.55 - 6.39 (m, 2H), 5.51 - 5.49 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). MS: m/z 482.3 (M+H + ). Step 7 – Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid: 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (150 mg, 312 μmol) 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; 70 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (60 mg, first peak) and (S)-2-((1-(2-(1,3- dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzoic acid (59 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 8.51 - 8.35 (m, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.82 - 7.70 (m, 3H), 7.57 (d, J = 1.8 Hz, 1H), 7.23 - 7.10 (m, 1H), 6.54 - 6.40 (m, 2H), 5.53 - 5.42 (m, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). MS: m/z 482.2 (M+H + ). Example 6: Synthesis of Compound 62: 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoic acid Step 1 - Synthesis of methyl 2-amino-3-bromo-5-methylbenzoate: To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (30 g, 130.4 mmol) in MeOH (100 mL) was slowly added concentrated H 2 SO4 (30 mL, 562.8 mmol) dropwise with stirring at room temperature. After the addition, the reaction was heated to 50 °C and stirred for 16 h. After cooling to room temperature, the reaction solution was slowly poured into ice water (60 mL). The mixture was adjusted to pH 7 with aqueous NaOH (2M), then extracted with EtOAc (200 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 - 30% EtOAc in petroleum ether) to give the title compound (30 g, 94% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.59 (s, 1H), 7.51 (s, 1H), 6.47 (s, 2H), 3.81 (s, 3H), 2.17 (s, 3H). Step 2 - Synthesis of 8-bromo-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one: To a solution of methyl 2-amino-3-bromo-5-methyl-benzoate (15 g, 61.45 mmol) and isoindoline-2-carbonitrile (13.29 g, 92.18 mmol) in THF (30 mL) was added NaH (4.92 g, 122.91 mmol) with stirring at room temperature. The mixture was heated to 70 °C for 3 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with sat. aq. NH 4 Cl (40 mL), then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 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 (11 g, 50%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.43 - 7.40 (m, 2H), 7.34 - 7.31 (m, 2H), 4.90 (s, 4H), 2.34 (s, 3H). Step 3 - Synthesis of 8-acetyl-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one: A mixture of 8-bromo-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (24.0 g, 67.4 mmol), tributyl(1-ethoxyvinyl)stannane (37.8 g, 104.6 mmol), Pd(dppf)Cl 2 (2.46 g, 3.37 mmol) in dioxane (300 mL) was stirred at 90 °C for 16 h under N 2 atmosphere. After cooling to room temperature, the mixture was quenched with 200 mL of 10% KF aqueous solution and stirred for 30 min. The mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a curde product (23 g) as a yellow solid. The crude product was dissolved in dioxane (300 mL), then added aqueous HCl (1M, 40 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered to give the title compound (21 g, crude) as a gray solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (s, 1H), 7.54 - 7.30 (m, 5H), 4.98 (s, 4H), 2.84 (s, 3H), 2.42 (s, 3H). MS: m/z 320.2 (M+H + ). Step 4 - Synthesis of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4( 3H)-one: To a solution of 8-acetyl-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (16.0 g, 50.1 mmol) in MeOH (30 mL) was added NaBH 4 (3.61 g, 95.4 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h under N 2 atmosphere. The mixture was quenched with sat. aq. NH 4 Cl (30 mL) at 0 °C, diluted with water (30 mL). The mixture was stirred at 0°C for 10 min. The suspension solution was filtered, the filter cake was washed with water (30 mL x 2) and dried in vacuo to give the title compound (14 g, crude) as a yellow solid that required no further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.44 - 7.39 (m, 2H), 7.34 - 7.30 (m, 2H), 5.45 - 5.33 (m, 1H), 5.23 (s, 1H), 4.87 (s, 4H), 2.34 (s, 3H), 1.41 (d, J = 6.0 Hz, 3H). MS: m/z 322.2 (M+H + ). Step 5 - Synthesis of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H )-one: To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4( 3H)-one (1.1 g, 3.4 mmol) in DCM (33 mL) was slowly added PBr3 (926 mg, 3.4 mmol) at 0 °C under N 2 atmosphere. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated to give the title compound (1.31 g, crude) that required no further purification. Step 6 - Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate: The solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H )-one (1.31 g, 3.4 mmol) in dioxane (11 mL) was adjusted to pH 8 with DIPEA at 0 °C.The mixture was added tert-butyl 2-aminobenzoate (1.32 g, 6.8 mmol) and heated to 90 °C for 16 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1 g, 40%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.34 - 8.27 (m, 1H), 7.75 - 7.70 (m, 2H), 7.66 - 7.62 (m, 1H), 7.41 - 7.40 (m, 2H), 7.34 - 7.32 (m, 2H), 7.25 - 7.17 (m, 1H), 6.61 - 6.55 (m, 1H), 6.50 - 6.44 (m, 1H), 5.42 - 5.35 (m, 1H), 5.02 - 4.90 (m, 4H), 2.28 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 497.3 (M+H + ). Step 7 - Synthesis of tert-butyl 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8- yl)ethyl)amino)benzoate: To a solution of tert-butyl 2-((1-(4-hydroxy-2-(isoindolin-2-yl)-6-methylquinazolin-8- yl)ethyl)amino)benzoate (30 mg, 60 umol) in DMF (3 mL) was added K 2 CO 3 (25 mg, 0.18 mmol) and iodoethane (10 mg, 66 μmol). The mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction was added water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 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 - 10% EtOAc in petroleum ether) to give the title compound (23 mg, 73%) as yellow oil, which was further confirmed by 2D NMR ( 13 C NMR). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.40 (d, J = 7.6 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.60 (s, 1H), 7.49 - 7.45 (m, 3H), 7.35 - 7.31 (m, 2H), 7.22 - 7.15 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.49 - 6.45 (m, 1H), 5.51 - 5.47 (m, 1H), 5.02 - 4.89 (m, 4H), 4.64 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H), 1.48 (t, J = 7.2 Hz, 3H). MS: m/z 525.3 (M+H + ). Step 8 - Synthesis of 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8- yl)ethyl)amino)benzoic acid: To a mixture of tert-butyl 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8- yl)ethyl)amino)benzoate (70 mg, 80 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 75% - 100% / 0.225% formic acid in water) to give the title compound (7 mg, 19%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.63 (s, 1H), 8.63 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.50 - 7.43 (m, 3H), 7.36 - 7.33 (m, 2H), 7.23 - 7.16 (m, 1H), 6.56 (d, J = 8.8 Hz, 1H), 6.47 (t, J = 7.6 Hz, 1H), 5.54 - 5.50 (m, 1H), 5.11 - 4.87 (m, 4H), 4.63 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.65 (d, J = 6.4 Hz, 3H), 1.48 (t, J = 7.2 Hz, 3H). MS: m/z 469.1 (M+H + ). Example 7: Synthesis of Compound 63: 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)- 6-methylquinazolin-8-yl)ethyl)amino)benzoic acid
Step 1 - Synthesis of tert-butyl 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoate: To a solution of tert-butyl 2-((1-(4-hydroxy-2-(isoindolin-2-yl)-6-methylquinazolin-8- yl)ethyl)amino)benzoate (150 mg, 302 μmol) in acetonitrile (6 mL) was added BOP (200 mg, 453 μmol) and DBU (138 mg, 906 μmol). The mixture was stirred at room temperature for 10 min, azetidin-3-ol (44 mg, 604 μmol,) was added. The final mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (110 mg, 81%) as a white solid. MS: m/z 552.1 (M+H + ). Step 2 - Synthesis of 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoic acid:
To a mixture of tert-butyl 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6- methylquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 80 umol) in DCM (2 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 26% - 56% / 0.225% formic acid in water) to give the title compound (11 mg, 56%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.78 - 7.73 (m, 1H), 7.65 - 7.53 (m, 1H), 7.47 - 7.39 (m, 3H), 7.35 - 7.28 (m, 3H), 7.20 - 7.12 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.47 - 6.43 (m, 1H), 5.81-5.77 (m, 1H), 5.57 - 5.48 (m, 1H), 4.98 - 4.81(m, 4H), 4.72 - 4.65 (m, 2H), 4.23 - 4.13 (m, 2H), 2.29 (s, 3H), 1.61 (d, J = 6.4 Hz, 3H). MS: m/z 496.1 (M+H + ). Example 8: Preparation of (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H- thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 159) and (S)-2-((1-(2-(isoindolin-2- yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 157) Step 1: Synthesis of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-ol To a solution of 3-bromo-2-fluoro-5-methyl-benzaldehyde (3 g, 13.8 mmol) in THF (20 mL) was added MeMgBr (3 M in THF, 9.22 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h under a 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 - 20% EtOAc in petroleum ether) to give the title compound (2.5 g, 78%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.25 - 7.12 (m, 2H), 5.08 (q, J= 6.4 Hz, 1H), 1.97 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H). Step 2: Synthesis of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-one To a solution of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-ol (2.8 g, 12.01 mmol) in DCM (20 mL) was added Dess-Martin (7.6 g, 18 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with sat. aq. Na2S2O3 (20 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 (2.6 g, 93%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.59 - 7.39 (m, 2H), 2.64 (d, J = 5.2 Hz, 3H), 2.34 (s, 3H). Step 3: Synthesis of 8-bromo-2-mercapto-6-methyl-4H-thiochromen-4-one To a solution of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-one (3.1 g, 13.42 mmol) in DMF (12 mL) and PhMe (8 mL) was added NaH (1.07 g, 26.8 mmol, 60% purity) and and CS2 (2.04 g, 26.8 mmol). The mixture was stirred at room temperature for 2 h. The reaction 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 to give the title compound (3 g, 78%) as a yellow solid. MS: m/z 572.8 (2M+H + ). Step 4: Synthesis of 8-bromo-2-(ethylthio)-6-methyl-4H-thiochromen-4-one To a solution of 8-bromo-2-mercapto-6-methyl-4H-thiochromen-4-one (2.5 g, 8.7 mmol) in DCM (20 mL) was added EtI (2.72 g, 17.41 mmol) and Et3N (2.4 mL, 17.41 mmol). The mixture was stirred at room temperature for 2 h. The reaction 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 (2.5 g, 91%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.21 - 8.08 (m, 1H), 8.01 - 7.88 (m, 1H), 6.99 (s, 1H), 3.30 - 3.24 (m, 2H), 2.45 - 2.41 (m, 3H), 1.36 - 1.29 (m, 3H). MS: m/z 315.0 (M+H + ). Step 5: Synthesis of 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-thiochromen-4-one To a solution of 8-bromo-2-(ethylthio)-6-methyl-4H-thiochromen-4-one (2.3 g, 7.20 mmol) in AcOH (15 mL) was added H 2 O 2 (1.80 g, 15.84 mmol). The mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the mixture was filtered. The crude filter was concentrated in vacuo to give title compound (2.4 g, crude) as a yellow soild. MS: m/z 348.9 (M+H + ). Step 6: Synthesis of 8-bromo-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one To a solution of 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-thiochromen-4-one (1.2 g, 3.46 mmol) in t-BuOH (10 mL) was added isoindoline (823 mg, 6.9 mmol). The mixture was stirred at 130 °C for 36 h. 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 give the title compound (1.2 g, 93%) as a black solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.14 (s, 1H), 7.83 (s, 1H), 7.45 - 7.42 (m, 2H), 7.38 - 7.34 (m, 2H), 5.89 (s, 1H), 4.88 (s, 4H), 2.41 (s, 3H). MS: m/z 371.8 (M+H + ). Step 7: Synthesis of 8-acetyl-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one To a solution of 8-bromo-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one (1 g, 2.69 mmol) in dioxane (10 mL) was added Pd(PPh 3 ) 2 Cl 2 (188 mg, 268 μmol) and tributyl(1- ethoxyvinyl)stannane (1.94 g, 5.37 mmol). The mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature. Aq. HCl (1M, 2 mL) was added and the mixture was stirred at 50 °C for additional 3 h. 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 the title compound (800 mg, 88%) as colorless oil. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.43 (s, 1H), 8.29 (s, 1H), 7.45 - 7.42 (m, 2H), 7.37 - 7.34 (m, 2H), 5.76 - 5.75 (m, 1H), 4.83 (s, 4H), 2.72 (s, 3H), 2.47 (s, 3H). MS: m/z 336.1 (M+H + ). Step 8: Synthesis of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochrom en-4- one To a solution of 8-acetyl-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one in MeOH (5 mL) was added NaBH 4 (45 mg, 1.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h under N 2 atmosphere. The reaction was quenched with sat. aq. NH 4 Cl (2 mL), diluted with water (20 mL), extracted with EtOAc (10 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 (0.18 g, 89%) as a yellow solid. 1 H NMR (400 MHz, CD3OD): δ 8.16, (s, 1H), 8.13 (s, 1H), 7.44 - 7.40 (m, 2H), 7.35 - 7.32 (m, 2H), 6.03 (s, 1H), 5.49 (s, 4H), 4.77 - 4.74 (m, 1H), 2.41 (s, 3H), 1.61 - 1.54 (m, 3H). MS: m/z 338.2 (M+H + ). Step 9: Synthesis of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen -4-one To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochrom en-4-one (150 mg, 444 umol) in DCM (3 mL) was added PBr3 (120 mg, 666 umol) at 0 °C. The mixture was stirred at 0 °C for 1 h under N 2 atmosphere. The reaction was concentrated in vacuo to give the title compound (2.25 g, crude) as a yellow solid. MS: m/z 400.1 (M+H+). Step 10: Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H- thiochromen-8-yl)ethyl)amino)benzoate To a solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen -4-one (50 mg, 125 umol) in DMF (2 mL) was added tert-butyl 2-aminobenzoate (48 mg, 250 umol). The mixture was stirred at 100 °C for 2 h. The reaction 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 (25 mg, 39%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.29 (d, J = 5.6 Hz, 1H), 8.05 (m, 1H), 7.78 (d, J = 6.8 Hz,1H), 7.51 (s, 1H), 7.45 - 7.32 (m, 4H), 7.25 - 7.18 (m, 1H), 6.61 - 6.52 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.90 (s, 1H), 5.04 - 4.93 (m, 1H), 4.91 - 4.80 (m, 4H), 2.34 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.60 (s, 9H). MS: m/z 513.1 (M+H + ). Step 11: Synthesis of 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8- yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8- yl)ethyl)amino)benzoate (25 mg, 49 umol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM (1% AcOH)) to give the title compound (20 mg, 89%) as a white soild. 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.85 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.88 - 7.78 (m, 1H), 7.50 - 7.47 (m, 1H), 7.47 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 7.23 - 7.21 (m, 1H), 6.62 - 6.48 (m, 1H), 6.35 - 6.24 (m, 1H), 5.92 (s, 1H), 5.03 - 4.95 (m, 1H), 4.93 - 4.83 (m, 4H), 2.34 (s, 3H), 1.63 (d, J = 6.8 Hz, 1H). MS: m/z 457.1 (M+H + ). Step 12: Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen -8- yl)ethyl)amino)benzoic acid (Compound 159) and (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4- oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 157) 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-y l)ethyl)amino)benzoic acid (20 mg, 43 umol) was separated by using chiral SFC (DAICEL CHIRALCEL J (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)-6-methyl-4-oxo-4H-thiochromen -8-yl)ethyl)amino)benzoic acid (8 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen -8- yl)ethyl)amino)benzoic acid (7 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 159: 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.87 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.83 (d, J = 5.6 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.47 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 7.22 - 7.20 (m, 1H), 6.62 - 6.48 (m, 1H), 6.35 - 6.24 (m, 1H), 5.93 (s, 1H), 5.03 - 4.95 (m, 1H), 4.93 - 4.83 (m, 4H), 2.34 (s, 3H), 1.63 (d, J = 6.8 Hz, 1H). MS: m/z 457.1 (M+H + ). Example 9: Preparation of (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H- pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 158) Step 1: Synthesis of 2,4-dibromo-3-(methoxymethoxy)-6-methylpyridine To a solution of 2,4-dibromo-6-methyl-pyridin-3-ol (3.4 g, 12.7 mmol) in DCM (30 mL) was added DIEA (3.33 mL, 19.1 mmol) and bromo(methoxy)methane (1.25 mL, 15.3 mmol) dropwise at room temperature. After the addition, the reaction was stirred at room temperature for 2 h. The reaction was quenched 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 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% ethyl acetate in petroleum ether) to give the title compound (3.7 g, 93%) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.34 (s, 1H), 5.19 (s, 2H), 3.73 (s, 3H), 2.50 (s, 3H). Step 2: Synthesis of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-o l To a solution of 2,4-dibromo-3-(methoxymethoxy)-6-methylpyridine (3.7 g, 11.9 mmol) in THF (40 mL) was added n-BuLi (2.5 M, 5.71 mL) dropwise at -78 °C under N 2 atmosphere. After the addition, the mixture was stirred at -78 °C for 10 min. Then acetaldehyde (5 M, 7.14 mL) was added to the mixture dropwise. The mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. NH 4 Cl (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% ethyl acetate in petroleum ether) to give the title compound (1.67 g, 51%) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.22 (s, 1H), 5.22 - 5.16 (m, 2H), 5.10 (d, J = 6.4 Hz, 1H), 3.64 (s, 3H), 2.86 (d, J = 3.6 Hz, 1H), 2.52 (s, 3H), 1.51 (d, J = 6.4 Hz, 3H). MS: m/z 276.1 (M+H + ). Step 3: Synthesis of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-o ne To a solution of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-o l (1.67 g, 6.05 mmol) in DCM (30 mL) was added Dess-Martin (3.08 g, 7.26 mmol) in portions at 0 °C. After the addition, the mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. Na 2 S 2 O 3 (20 mL) and washed with sat. aq. NaHCO 3 (100 mL). The mixture was extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 12% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 84%) as colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.13 (s, 1H), 5.09 (s, 2H), 3.51 (s, 3H), 2.61 (s, 3H), 2.55 (s, 3H). MS: m/z 274.1 (M+H + ). Step 4: Synthesis of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one To a solution of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-o ne (1 g, 3.65 mmol) in DCM (5 mL) was added HCl (5 mL, 4M in dioxane). After the addition, the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove the solvent. The residue was dissolved in EtOAc (30 mL), washed with saturated NaHCO 3 (20 mL), brine (20 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 12% EtOAc in petroleum ether) to give the title compound (294 mg, 35%) as a yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 12.03 (s, 1H), 7.34 (s, 1H), 2.69 (s, 3H), 2.55 (s, 3H). MS: m/z 230.0 (M+H + ). Step 5: Synthesis of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)-3-(pyridin-4- yl)propane-1,3-dione To a solution of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one (1 g, 4.35 mmol) in THF (15 mL) was added LiHMDS (1 M, 13.9 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 1 hour. Then the mixture was cooled to -78 °C and to the mixture was added methyl pyridine-4-carboxylate (0.62 mL, 5.22 mmol) dropwise. The mixture was stirred at room temperature for 16 h. The reaction was quenched with aq. HCl (1M, 10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the title compound (1.34 g, crude) as a yellow solid that required no further purification. MS: m/z 337.0 (M+H + ). Step 6: Synthesis of 8-bromo-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4- one To a mixture of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)-3-(pyridin-4-yl)p ropane- 1,3-dione (1.34 g, 4.00 mmol) in AcOH (10 mL) was added H 2 SO4 (0.42 mL, 8.00 mmol). After the addition, the mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature and poured into ice-water (30 mL). The mixture was basified with sat. aq. NaHCO 3 to pH ~ 7, extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. 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 (696 mg, 55%) as a brown solid. 1 H NMR (400MHz, DMSO- d 6 ): δ 8.90 - 8.83 (m, 2H), 8.09 - 8.03 (m, 2H), 7.78 (s, 1H), 7.45 (s, 1H), 2.60 (s, 3H). MS: m/z 317.0 (M+H + ). Step 7: Synthesis of 8-(1-ethoxyvinyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3- c]pyridin-4-one A mixture of tributyl(1-ethoxyvinyl)stannane (1.64 g, 4.54 mmol), 8-bromo-6-methyl-2- (pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one (696 mg, 2.19 mmol), Pd(dppf)Cl 2 (160 mg, 219 umol) in dioxane (10 mL) was degassed with N 2 for 3 times and stirred at 100 °C for 16 h. The mixture was cooled to room temperature. The mixture was poured into 10% KF solution (20 mL) and stirred for 30 min. The mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified with silica gel chromatography (solvent gradient: 0 - 60% EtOAc in petroleum ether) to give the title compound (545 mg, 80%) as a brown solid. 1 H NMR (400MHz, CDCl 3 ): δ 8.87 - 8.84 (m, 2H), 8.87 - 8.84 (m, 1H), 7.88 - 7.83 (m, 3H), 6.99 (s, 1H), 4.91 (d, J = 2.8 Hz, 1H), 4.74 (d, J = 2.8 Hz, 1H), 4.17 - 4.11 (m, 2H), 2.72 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). MS: m/z 309.1 (M+H + ). Step 8: Synthesis of 8-acetyl-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4 -one To a solution of 8-(1-ethoxyvinyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c] pyridin-4- one in THF (10 mL) was added aq. HCl (1M, 3 mL). After the addition, the reaction mixture was stirred at room temperature for 3 h. The mixture was basified with sat. aq. NaHCO 3 to pH 7. Then the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated to give the title compound (495 mg, 99%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.88 - 8.85 (m, 2H), 8.15 - 8.12 (m, 2H), 8.04 (s, 1H), 7.47 (s, 1H), 2.74 (s, 3H), 2.68 (s, 3H). MS: m/z 281.1 (M+H + ). Step 9: Synthesis of 8-(1-aminoethyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3- c]pyridin-4-one A mixture of 8-acetyl-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4 -one (100 mg, 356 umol) and NH 4 OAc (275 mg, 3.57 mmol) in MeOH (4 mL) was stirred at room temperature for 1h. Then to the mixture was added NaBH 3 CN (67.3 mg, 1.07 mmol). The resulting mixture was stirred at 60 °C for 4 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (62 mg, 62%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.90 - 8.82 (m, 2H), 8.27 (s, 2H), 8.12 - 8.06 (m, 2H), 7.84 (s, 1H), 7.44 (s, 1H), 5.30 - 5.22 (m, 1H), 2.68 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). MS: m/z 282.1 (M+H + ). Step 10: Synthesis of tert-butyl 2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3- c]pyridin-8-yl)ethyl)amino)benzoate A mixture of 8-(1-aminoethyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]p yridin-4-one (80 mg, 284 umol), tert-butyl 2-iodobenzoate (173 mg, 569 umol), Pd 2 (dba) 3 (26 mg, 28.4 umol), Xantphos (33 mg, 56.9 umol) and Cs 2 CO 3 (278 mg, 853 umol) in dioxane (2 mL) was degassed with N 2 for 3 times. Then the reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, quenched with water (20 mL). The mixture was extracted with EtOAc (20 mLx 2). The combined organic layers were washed with brine (20 mLx 2), dried over anhyrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 60% EtOAc in petroleum ether) to give the tilte compound (114 mg, 88%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ): δ 8.88 - 8.82 (m, 2H), 8.63 (d, J = 7.6 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.76 - 7.72 (m, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.58 – 6.54 (m, 1H), 5.56 - 5.44 (m, 1H), 2.62 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H), 1.51 (s, 9H). MS: m/z 458.0 (M+H + ). Step 11: Synthesis of tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H- pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate and tert-butyl (S)-2-((1-(6-methyl-4-oxo-2- (pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benz oate. Tert-butyl 2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyrid in-8-yl)ethyl)am ino)benzoate (80 mg, 174.86 umol) was separated by prep.SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um), Supercritical CO 2 / EtOH + 0.1% NH 4 OH = 40/60, 80 mL/min) to giv e tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]p yridin-8-yl)ethyl)amin o)benzoate (27 mg, 34%) and tert-butyl (S)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2, 3-c]pyridin-8-yl)ethyl)amino)benzoate (27 mg, 34%) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 402.0 (M+H + ). Step 12: Synthesis of (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3- c]pyridin-8-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 158) To a solution of tert-butyl tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3- c]pyridin-8-yl)ethyl)amino)benzoate (27 mg, 59.01 umol) in DCM (1 mL) was added TFA (1 mL). After the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated to remove the solvent. The residue was triturated in MeOH (3 mL). The mixture was basified with 1M LiOH to pH 8 and acidified with formic acid to pH 5. To the mixture was added water (2 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhyrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (14 mg, 59%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ): δ 9.00 (s, 1H), 8.84 (d, J = 5.2 Hz, 2H), 8.15 - 8.05 (m, 2H), 7.83 - 7.76 (m, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.35 - 7.28 (m, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.57 - 6.53 (m, 1H), 5.55 - 5.44 (m, 1H), 2.62 (s, 3H), 1.65 (d, J = 6.4 Hz, 3H). MS: m/z 402.0 (M+H + ). Compounds of Formula (III) in Table C can be prepared analogously to Example 8 and 9. Compounds of Formula (I) in Table A can be prepared analogously to Examples 1-7 Compounds of Formula (I) in Table D below were prepared analogously to Examples 1-7. Table D C 136 LCMS (MH) f d 4551 1 1 1 1 1 1 1 1 1 Biochemical Assays 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% CO 2 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% CO 2 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% CO 2 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 2. The ranges are as follows: for T47D pAKT IC 50 (nM): A denotes < 750 nM; B denotes 750 nM ≤ IC 50 < 2,000 nM; C 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; for PI3K H1047R ADP-Glo (PI/PS) IC 50 (nM): A denotes < 1,000 nM; B denotes 1,000 nM ≤ IC 50 < 10,000 nM; C denotes ≥ 10,000 nM. ND denotes value not determined with that assay for the specified compound; and for PI3K H1047R ADP-Glo (PI/PS) IC 50 : H1047R Selectivity: 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. Table 2. Biological Activity of Selected Compounds Cmpd. T47D pAKT S473 T47D pAKT S473 HTRF PI3K H1047R PI3K H1047R No. HTRF IC50 IC (H1047R) T47D ADPGl ADPGl (PI/PS) A 1 C 2 C 3 C 4 C 5 B 6 C 7 C 8 A 9 A 10 A 11 B 12 C 17 A 18 C 19 B 21 C 23 C 24 A 26 C C C C 30 B B ND ND 32 A A A A 33 A A A B 34 35 36 37 38 39 40 41 46 51 57 58 59 60 61 63 65 69 71 73 74 75 76 77 78 79 80 81 82 83 84 A A A A 85 C B B C 86 A A ND ND 87 A A ND ND 88 A 89 A 128 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 B 140 A 141 A 142 A 143 A 144 B 145 A 146 A 147 C
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