PI3k-alpha binding compounds and uses thereof

Abstract

Provided herein are small molecule [compounds of formula (I)] covalent inhibitors of the PI3Kα-KRAS G12C interaction which are useful as cancer therapeutics. The compounds disclosed herein disrupt, and in certain embodiments, impede or inhibit PI3Kα-KRA SG12C interaction, but cause minimal interference with the active site of P13Ka. The inhibitors as disclosed disrupt P13Ka-KRA sG12C interaction and disrupt the PI3Kα / Akt pathway without causing hyperglycemia or other undesirable off-target effects.

Description

Atorney Docket No.: 130238.00003FM0040WQPI3K-ALPHA BINDING COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS[1] This application claims priority to Provisional Patent No. 63 / 679,564 filed August 5, 2024, the entirety of which is incorporated by reference for all purposes.BACKGROUND OF THE INVENTION[2] Phosphoinositide-3 kinases (PI3Ks) are a family of lipid kinases that regulate diverse cellular signaling pathways and glucose homeostasis. Among them is the PIK3CA gene that encodes for the pl 10a subunit protein. Genetic alterations in PIK3CA are frequently associated with cancer. Another family of proteins frequently mutated in cancer is the RAS proteins, a family of GTPases. The GTP -bound state of RAS is known to engage in a protein-protein- interaction with the pl 10a subunit of PI3Ka. This association controls the signaling of both RAS and PI3Ka through downstream pathways and steers the complex to distinct subcellular compartments, such as the plasma membrane. Furthermore, PI3Ka is regulated by post- translational modifications that control its stability and half-life in cells. These post-translational modifications, subcellular localization, and protein-protein interactions collectively regulate signaling by PI3Ka. PI3Ka signaling is altered in the contexts of oncogenesis and cancer. Importantly, genetic disruption of the PI3Ka-RAS protein-protein interaction disrupts downstream signaling, leading to inhibition of tumor cell proliferation and survival.[3] Current therapies targeting PI3Ka, whether approved or in clinical trials, have challenges that impact their broad utility. Active site inhibitors, such as Alpelisib, carry a limited therapeutic index owing to on-target alterations in insulin signaling, glucose homeostasis, and other cellular functions. Allosteric site inhibitors commonly target a limited array of PIK3CA mutations, restricting efficacy to a limited subset of cancers and are subject to rapid resistance due to an inability to suppress signaling by the wild type PIK3CA allele. An allosteric PI3Ka binder that disrupts RAS interaction with both WT and mutant forms of the protein alike, would carry expanded benefit for cancer patients while sparing on-target toxicities associated with insulin or other normal cell signaling pathways. Similarly, patients with cancers harboring activating RAS mutations or activation of upstream receptor tyrosine kinases (e.g. EGFR, HER2, etc.) may also11105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ realize therapeutic benefit through disruption of the PI3Ka-RAS interaction either as a monotherapy or in combination.[4] The pl 10a subunit of PI3Ka contains a variety of cysteines unique to this isoform versus other members of the PI3K family. Thus, targeting one of these cysteines with a covalent inhibitor could impart isoform selectivity while modulating the activities or stability of the protein once bound. It is known that pl 10a may engage a variety of protein partners or subcellular compartments. Without wishing to be bound by any theory, disruption, and in some embodiments, inhibition, of the RAS-PI3Ka interaction, such as by a small molecule inhibitor, could attenuate oncogenic signaling while sparing the insulin signaling pathway, thus retaining normal glucose homeostasis in healthy cells. There is thus a need for compounds that can disrupt, and in certain embodiments, inhibit the RAS-PI3Ka interaction without interfering with the insulin signaling pathway.SUMMARY OF THE INVENTION[5] Disclosed herein are compounds of Formula (I):wherein:R1is N, C(R6), or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or Ci-C4alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which21105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ they are attached formor two R6present on the same atom taken together with the atom to which they are attached form; when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which they are attached form;R7in each instance is independently: Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci- Ce hydroxyalkyl; C2-C6 haloalkenyl; C3-C7 cycloalkyl; 4-12 membered heterocyclyl substituted with 0, 1, or 2 instances of -NRaRf; 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; oxo; halo; -ORd; -NRaRd; =N(Ra); -CN;-COOH; -C(O)O-Ci-C6alkyl; -C(O)-Ci-C6alkyl; -C(O)N(Ra)(R11); -S(O)2N(Ra)(Re); -S(O)2-Ci- C6alkyl; -S(O)(=NRa)-Ci-C6alkyl; -S(O)(=NRa)NHRb; or -P(=O)(Ra)(Rb);R8in each instance is independently Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, halo, or deutro-Ci-Ce alkyl;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl),-C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -Ci- C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-Ce alkyl;31105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Cg haloalkyl; Ci-Cg heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Cg alkoxy; Ci- Cg haloalkoxy; Ci-Cg hydroxyalkyl; C2-C6 alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Cg heteroalkyl, hydroxy, Ci-Cg hydroxyalkyl, -Ci-Cg heteroalkyl-hydroxy, or -NHC(O)-Ci-Cg alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(0)N(Rb)(Rc); -S(O)2N(Rb)(Rc); - S(O)2(Ra); -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, or C3-C4 cycloalkyl;Rein each instance is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -Ci-C3alkylene- (6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); andRfin each instance is independently H, C1-C4 alkyl, or -C(O)-Ci-C4 alkyl; or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or a isotopologue thereof.[6] In some aspects of Formula (I) or (P-I), R1is N or CH. In some aspects of Formula (I) or (P-I), R1is C(R6).[7] In some aspects of Formula (I) or (P-I), including any of the foregoing, R2is a bond or - N(Ra)-. In some aspects of Formula (I) or (P-I), including any of the foregoing, R2is a bond. In some aspects of Formula (I) or (P-I), including any of the foregoing, R2is -N(Ra)-.41105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ[8] In some aspects of Formula (I) or (P-I), including any of the foregoing, R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-, and R9is H or C1-C4 alkyl.[9] In some aspects of Formula (I) or (P-I), including any of the foregoing, R3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl.

[0010] In some aspects of Formula (I) or (P-I), including any of the foregoing, R4and R5are independently H or C1-C4 alkyl. In some aspects of Formula (I) or (P-I), including any of the foregoing, R4and R5together form oxo.

[0011] In some aspects of Formula (I) or (P-I), including any of the foregoing, when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached form present on the same atom taken together with the atom to which they are attac e orm

[0012] In other aspects of Formula (I) or (P-1), including any of the foregoing, when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same,0, atom taken together with the atom to which they are attached form

[0013] In some aspects of Formula (I) or (P-I), including any of the foregoing, R7in each instance is independently: Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, 4- 12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, -NRaRd, =N(Ra), -CN, - COOH, -C(O)O-Ci-C6alkyl, -C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), -S(O)2N(Ra)(Re), -S(O)2-Ci- Ce alkyl, -S(O)(=NH)-Ci-Ce alkyl, or -S(O)(=NRa)NHRb. In some aspects of Formula (I), including any of the foregoing, R7in each instance is independently: Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci-Ce hydroxyalkyl; C2-Ce haloalkenyl; C3-C7 cycloalkyl; 4-1251105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ membered heterocyclyl substituted with 0, 1, or 2 instances of -NRaRf; 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; oxo; halo; -ORd; -NRaRd; =N(Ra); -CN; -COOH; -C(O)O-Ci-C6alkyl; -C(O)-Ci-C6alkyl; -C(O)N(Ra)(Rn); -S(O)2N(Ra)(Re); -S(O)2-Ci-C6alkyl; -S(O)(=NRa)-Ci-C6alkyl;-S(O)(=NRa)NHRb; or -P(=O)(Ra)(Rb); wherein Rfin each instance is independently H, C1-C4 alkyl, or -C(O)-Ci-C4alkyl.

[0014] In some aspects of Formula (I) or (P-I), including any of the foregoing, R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, C3-C7 cycloalkyl, or halo. In some aspects of Formula (I), including any of the foregoing, R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, halo, or deutro-Ci-Ce alkyl.

[0015] In some aspects of Formula (I) or (P-I), including any of the foregoing, R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), -C1-C3 alkylene- (5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl). In some aspects of Formula (I) or (P-I), including any of the foregoing, R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl). In some aspects of Formula (I) or (P-I), including any of the foregoing, R10is 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl). In some aspects of Formula (I) or (P-I), including any of the foregoing, R10is 6 membered aryl.

[0016] In some aspects of Formula (I) or (P-I), including any of the foregoing, R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C -C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene- 6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxy alky lene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy,61105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQCi-Ce haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl,5-6 membered heteroaryl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), - C(O)N(Rb)(Rc), -S(O)2N(Rb)(Re), -S(O)2(Ra), -S(O)(=NRa)CH3, -S(O)(=NRa)NHRb, or - P(O)(CH3)2. In some aspects of Formula (I), including any of the foregoing, R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cs cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-Ce alkyl; wherein the C3-Cs cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Cs haloalkyl; Ci-Ce heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-Ce alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Ce heteroalkyl, hydroxy, Ci-Ce hydroxyalkyl, -Ci-Ce heteroalkyl-hydroxy, or -NHC(O)-CI-C6 alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(O)N(Rb)(Rc); -S(O)2N(Rb)(Re); - S(O)2(Ra), -S(O)(=NRa)CH3; -S(0)(=NRa)NHRb; or -P(O)(CH3)2.

[0017] In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring A is a 4-11 membered carbocyclyl or heterocyclyl, 6-11 membered aryl, or a 5-11 membered heteroaryl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring A is a 4-11 membered carbocyclyl or heterocyclyl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring A is a 6-11 membered aryl or a 5-11 membered heteroaryl.

[0018] In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring B is a 6 membered aryl, or 5-6 membered heteroaryl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring B is a 6 membered aryl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Ring B is a 5-6 membered heteroaryl.71105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0019] In some aspects of Formula (I) or (P-I), including any of the foregoing, x is 0. In some aspects of Formula (I) or (P-I), including any of the foregoing, x is 1, 2, or 3. In some aspects of Formula (I) or (P-I), including any of the foregoing, x is 1. In some aspects of Formula (I) or (P- I), including any of the foregoing, x is 2. In some aspects of Formula (I) or (P-I), including any of the foregoing, x is 3.

[0020] In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 0, 1, 2, 3, or 4. In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 0. In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 1. In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 2. In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 3. In some aspects of Formula (I) or (P-I), including any of the foregoing, y is 4.

[0021] In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 0, 1, 2, 3, or 4. In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 0. In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 1. In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 2. In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 3. In some aspects of Formula (I) or (P-I), including any of the foregoing, z is 4.

[0022] In some aspects of Formula (I) or (P-I), including any of the foregoing, Rais H or Rais C1-C4 alkyl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Rais H. In some aspects of Formula (I) or (P-I), including any of the foregoing, Rais C1-C4 alkyl.

[0023] In some aspects of Formula (I) or (P-I), including any of the foregoing, Raand Rbare both H. In some aspects of Formula (I) or (P-I), including any of the foregoing, Raand Rbare both C1-C4 alkyl.

[0024] In some aspects of Formula (I) or (P-I), including any of the foregoing, Rband Rcare both H. In some aspects of Formula (I) or (P-I), including any of the foregoing, Rband Rcare both C1-C4 alkyl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Rbis H and Rcis C1-C4 alkyl.

[0025] In some aspects of Formula (I) or (P-I), including any of the foregoing, Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl. In some aspects of Formula (I) or (P-I), including any of the foregoing, Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl and Rais H. In some aspects of Formula (I) or81105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-I), including any of the foregoing, Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl and Rais C1-C4 alkyl.

[0026] In some aspects of Formula (I), including any of the foregoing, Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl). In some aspects of Formula (I), including any of the foregoing, Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl) and Rais H.

[0027] In another aspect, provided is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, as a medicament. In another aspect is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, for treating or suppressing cancer. In another aspect is the use of a compound as described herein, including but not limited to any of the foregoing embodiments, in the manufacture of a medicament for use in treating or suppressing cancer.

[0028] It is to be understood that the description of compounds, compositions, formulations, and methods of treatment described herein include “comprising” and “consisting of’ embodiments. In some embodiments, for all compositions described herein, and all methods using a composition described herein, the compositions can comprise the listed components or steps. In some embodiments, for all compositions described herein, and all methods using a composition described herein, the compositions can consist of, or consist essentially of, the listed components or steps.

[0029] Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and through practice of the present disclosure.BRIEF DESCRIPTION OF DRAWINGS

[0030] FIG. 1 provides Table 1 showing the protein-protein interaction inhibition activity or protein-protein interaction enhancement activity of certain Example compounds disclosed in this application.91105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0031] FIG. 2 provides Table 2 showing the structures of the Example compounds disclosed in this application.

[0032] FIG. 3 provides Table 3 showing the activity of certain Example compounds on the viability of NCI-N87 HER2 amplified tumor cells as evaluated by the Promega CellTiter-Glo assay.DETAILED DESCRIPTION OF THE INVENTION

[0033] Disclosed herein are covalent protein-protein-interaction disruptors, in some embodiments inhibitors, of the PI3Ka-KRASG12Cinteraction for use as cancer therapeutics, which advantageously do not inhibit the insulin IRS 1 -signaling arm of PI3Ka. Existing therapies directed against the active site of PI3Ka have shown anti-cancer efficacy, but also cause undesirable effects such as hyperglycemia. Without wishing to be bound by theory, the compounds disclosed herein impede PI3Ka-KRASG12Cinteraction with minimal interference with the active site of PI3Ka. These compounds allow disruption, in some embodiments inhibition, of the PI3Ko / Akt pathway without hyperglycemia or other undesirable off-target effects, which are common with inhibitors of the PI3Ka active site. Accordingly, small-molecule induced disruption, in some embodiments inhibition, of the PI3Ka-KRASG12Cinteraction with the compounds disclosed herein reduces pAkt473 signaling while sparing the associated insulin IRS1 signaling pathway.Definitions

[0034] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.

[0035] It is to be understood that descriptions of compound structures, including possible substitutions, are limited to those which are chemically possible.

[0036] The terms “a” and “an,” as used in herein mean one or more, unless context clearly dictates otherwise.

[0037] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is101105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent.

[0038] “Administration,” “administer,” and the like, as they apply to, for example, a patient, cell, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt and / or isotopologue thereof, a pharmaceutical composition comprising same, or a diagnostic agent with the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent with the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[0039] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0040] “In need of treatment” as used herein means the patient is being treated by a physician or other caregiver after diagnoses of the disease, or a determination that the patient is at risk for developing the disease.

[0041] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0042] A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier or excipient” includes both one and more than one such excipient.

[0043] The terms “subject,” “individual,” and “patient” mean an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human. Examples of patients include111105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses.

[0044] As used herein, “substantially” means almost entirely or completely with respect to a given value, amount, dimension, shape, element, material, or another aspect it modifies. For example, in some embodiments, when used in connection with an amount, “substantially” refers to, e.g., at least 90%, 91%, 92%>, 93%, 94%, 95%, 96%, 97%>, 98%, 99%, or more of the amount.

[0045] “Suppression” of a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disorder, or to suppress the manifestation of adverse symptoms of the disorder. The distinction between treatment and suppression is that treatment occurs after adverse symptoms of the disorder are manifest in a subject, while suppression occurs before adverse symptoms of the disorder are manifest in a subject. Suppression may be partial, substantially total, or total. In some embodiments, genetic screening can be used to identify patients at risk of the disorder. The compounds and methods disclosed herein can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disorder, in order to suppress the appearance of any adverse symptoms.

[0046] “Therapeutic use” of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disorder, as defined herein. A “therapeutically effective amount” of a compound is an amount of the compound, which, when administered to a subject, is sufficient to reduce or eliminate either the disorder or one or more symptoms of the disorder, or to retard the progression of the disorder or of one or more symptoms of the disorder, or to reduce the severity of the disorder or of one or more symptoms of the disorder, or to suppress the clinical manifestation of a disorder, or to suppress the manifestation of adverse symptoms of a disorder. A therapeutically effective amount can be given in one or more administrations.

[0047] “Treating” a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disorder or one or more symptoms of the disorder, or to retard the progression of the disorder or of one or more symptoms of the disorder, or to reduce the severity of the disorder or of one or more symptoms of the disorder.121105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0048] The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule or a tablet having a fixed ratio of active ingredients or in multiple, separate capsules or tablets for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.Chemical definitions

[0049] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “Ci-Ce alkyl” is intended to encompass, among others, Ci, C2, C3,C4, C5, C6, C1-C4, and Ci-C2alkyl.

[0050] Unless otherwise specified, “alkyl” means a linear or branched saturated monovalent hydrocarbon radical having the defined number of carbons. For example, C1-C4 alkyl refers to an alkyl group having 1 to 4 carbons, e.g., methyl (Ci), ethyl (C2), propyl (C3), 2-propyl (C3), n- butyl (C4), isobutyl (C4), sec-butyl (C4), t-butyl (C4), and the like.

[0051] Unless otherwise specified, “alkylene,” by itself or as part of another substituent, means a linear or branched saturated divalent hydrocarbon radical derived from an alkyl. For example, C1-C4 alkylene refers to an alkyl group having 1 to 4 carbons, e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH2CH(CH2)CH2-, -CH2CH2CH2CH2-, and the like. For example, Ci-C2alkylene includes a -CH2-, -CH2CH2-, and the like.

[0052] “Hydroxy alkylene” refers to an alkylene which has a hydroxy group at any position along, A^OH the alkyl chain. Examples include ,, ,

[0053] “Alkenyl” means a linear or branched monovalent hydrocarbon radical having one or more carbon-carbon double bonds and no triple bonds, and having the defined number of carbons. For example, C2-C4 alkenyl refers to an alkenyl group having 2 to 4 carbons, e.g, ethenyl (C2), propenyl (C3), 2-propenyl (C3), butenyl (C4), and the like. The one or more carbon-131105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0054] “Alkynyl” means a linear or branched monovalent hydrocarbon radical having one or more carbon-carbon triple bonds and no double bonds, and having the defined number of carbons. For example, C2-C4 alkynyl refers to an alkynyl group having 2 to 4 carbons, e.g., ethynyl (C2), propynyl (C3), 2-propynyl (C3), butynyl (C4), and the like.

[0055] “Alkoxy” means an -OR radical where R is alkyl as defined above. For example, C1-C4 alkoxy indicates e.g., methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, tert-butoxy, and the like.

[0056] Halo” means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro or chloro.

[0057] “Haloalkyl” means an alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3,-CF2CF3, -CF(CH3)2, -CCI2F, and the like, for example, -CH(CH3)CH2CF3. When the alkyl is substituted with only fluoro, it can be referred to as fluoroalkyl. A haloalkyl group may be described as, e.g., a C1-C4 haloalkyl, wherein the term “C1-C4” refers to the number of carbon atoms within the moiety being 1 to 4.

[0058] “Haloalkenyl” means an alkenyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CF=CH2. When the alkenyl is substituted with only fluoro, it can be referred to as fluoroalkenyl. A haloalkenyl group may be described as, e.g., a C2-C6 haloalkenyl, wherein the term “C2-C6” refers to the number of carbon atoms within the moiety being 2 to 6.

[0059] “Haloalkoxy” means an -ORaradical where Rais haloalkyl as defined above. An haloalkoxy group may be described as, e.g., a C1-C4 haloalkoxy, wherein the term “C1-C4” refers to the number of carbon atoms within the moiety being 1 to 4. When all of the halo atom(s) in the haloalkoxy group are fluoro, it can be referred to as fluoroalkoxy.

[0060] “Hydroxyalkyl” means an alkyl radical as defined above, which is substituted with one or more hydroxyl (-OH) groups, e.g., one to three hydroxyl groups, e.g., -CH2OH, -CH2CH2OH, - C(OH)(CH3)2, -CH(OH)CH3and the like, and for example, -CH2CH(CH3)OH,141105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ-CH(CH2CH3)CH2OH, -CH2CH(OH)CH2CH3, -CH2CH2CH2OH, -CH2C(CH3)2OH, and - CH(CH3)C(CH3)2OH

[0061] “Heteroalkyl” means, unless otherwise stated, a straight or branched chain including at least one carbon atom and at least one heteroatom independently selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. A heteroatom can be either at the attachment point at which the heteroalkyl group is attached to the remainder of the molecule, or can be at any interior position of the heteroalkyl group. For example, a heteroalkyl group may include, but is not limited to -O-CH3, -OCH2CH3, -CH2OCH3, -CH2-CH2-O-CH3, -CH2-CH2- NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -S(O)2-CH3, -CH2-CH2-S(O)2- CH3, -CH=CH-O-CH3, and -CH=CH-N(CH3)-CH3. In some embodiments, the heteroatom(s) is O. In some embodiments, the heteroatom(s) is N. In some embodiments, the heteroatom(s) is S. In some embodiments, the heteroalkyl is selected from Ci-Ce alkoxy, -Ci-6alkylene-O-Ci-3alkyl, -Ci-3alkyl-O-Ci-6alkyl-O-Ci-3alkyl, -O-Ci-6alkyl-O-Ci-3alkyl, -S(O)2-Ci-C6alkyl, -S(O)-Ci-C6alkyl, -NRaRdwherein at least one of Raand Rdis alkyl, and -N(Rb)(Rc) wherein at least one of Rband Rcis alkyl, and the other of Ra, Rb, Rc, and Rdare as provided in any aspect or embodiment herein.

[0062] “Heteroalkyl -hydroxy” means a heteroalkyl as defined above further substituted with one or more hydroxy groups wherein the hydroxy group can be on a terminal or internal carbon, e.g., -OCH2CH2OH or -CH(OH)CH2CH2OCH3.

[0063] “Carbocyclyl” means a monovalent radical of a non-aromatic cyclic hydrocarbon group having the defined number of carbon atoms. The carbocyclyl group may be optionally fused to an aryl or heteroaryl ring, where the heteroaryl ring has 1-4 heteroatoms in the ring system. The heteroatoms are independently selected from the group consisting of nitrogen, oxygen, and sulfur, the remaining ring atoms being C. The sulfur atom may be oxidized, e.g., as -S(O)- or - S(O)2-. The point of attachment of the carbocyclyl group is on the non-aromatic cyclic hydrocarbon group. Examples of carbocyclyl groups include, but are not limited to,some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or151105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ contains a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic carbocyclyl”), and can be saturated or partially unsaturated. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 11 ring atoms (“C3-C11 carbocyclyl”), including C3 carbocyclyl, C4 carbocyclyl, C5 carbocyclyl, Ce carbocyclyl, C7 carbocyclyl, C 8 carbocyclyl, C9 carbocyclyl, C 10 carbocyclyl, and C11 carbocyclyl. In some embodiments, “carbocyclyl” is a saturated carbocyclyl group.

[0064] “Cycloalkyl” means a monovalent radical of a non-aromatic cyclic hydrocarbon group having the defined number of carbon atoms and zero heteroatoms in the ring system. For example, a C3-C6 cycloalkyl refers to a cycloalkyl group having 3 to 6 ring carbon atoms, e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (Ce), and the like. In some embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic cycloalkyl”), and can be saturated or partially unsaturated. “Cycloalkyl” also includes ring systems wherein the non- aromatic cyclic hydrocarbon group, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the non-aromatic cyclic hydrocarbon portion, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system as a whole. In some embodiments, “cycloalkyl” is a monocyclic, saturated cycloalkyl group having from 3 to 11 ring carbon atoms (“C3-C11 cycloalkyl”), including C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, Ce cycloalkyl, C7 cycloalkyl, Cs cycloalkyl, C9 cycloalkyl, C10 cycloalkyl, and Cn cycloalkyl. In some embodiments, “cycloalkyl” is a saturated cycloalkyl group.

[0065] A “heterocyclic group” or “heterocyclyl,” unless otherwise specified, means a radical of a saturated or partially unsaturated cyclic group containing the number of ring atoms specified, such as 3-12 ring atoms, in which 1-6 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, the remaining ring atoms being C (for example, “3-12 membered heterocyclyl”). The sulfur atom may be oxidized, e.g., as -S(O)- or - S(O)2-. The nitrogen atom may be oxidized, e g. as -N(O)-. Unless otherwise specified, the heterocyclic group includes single (“monocyclic heterocyclyl”) as well as multiple ring systems including fused, bridged, and spiro ring systems such as bicyclic systems (“bicyclic heterocyclyl”). In some embodiments, the heterocyclic group is a monocyclic heterocyclyl. In some embodiments, the heterocyclic group comprises two fused rings. In some embodiments, the161105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ heterocyclic group comprises two spiro rings. In some embodiments, the heterocyclic group comprises a bridged ring system. In multiring systems, one or more rings, to which the saturated or partially unsaturated heteroatom-containing cyclic group is directly or indirectly fused, may be aromatic or heteroaromatic, provided that the attachment point to the remainder of the molecule is on the saturated or partially unsaturated heteroatom-containing cyclic portion. “Heterocyclyl” also includes ring systems wherein the saturated or partially unsaturated heteroatom -containing cyclic group, as defined above, is fused or spiro-fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, and includes ring systems wherein the saturated or partially unsaturated heteroatomcontaining cyclic group, as defined above, is fused or spiro-fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the saturated or partially unsaturated heteroatom-containing cyclic group, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system as a whole. A heterocyclyl group may be described as, e.g., a 3-12-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, e.g.., carbon, nitrogen, oxygen, or sulfur, within the moiety. Representative examples include, but are not limited to, azepanyl, pyrrolidinyl, piperidinyl, morpholinyl, and the like. In various embodiments, the heterocyclic group comprises 3 to 11 ring atoms (“3-11 membered heterocyclic”), 4 to 11 ring atoms (“4-11 membered heterocyclic”), 3 to 7 ring atoms (“3-7 membered heterocyclic”), 4 to 7 ring atoms (“4-7 membered heterocyclic”), 3 to 6 ring atoms (“3-6 membered heterocyclic”), or 5 to 6 ring atoms (“5-6 membered heterocyclic”).

[0066] “Aryl” means a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having the number of atoms specified, for example, 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system (“Ce-Cu aryl”). In certain embodiments, an aryl group has 6 to 11 ring carbon atoms (“Ce-Cn aryl”). An aryl group may be described as, e.g., a Ce-Cio-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Unless otherwise specified, the aryl group includes single as well as multiple ring systems including fused, bridged, and spiro ring systems. In multiring systems, one or more rings may be heterocyclic or carbocyclic, provided that the attachment point to the remainder of the molecule is on an aromatic ring which does not contain heteroatoms. Representative examples include, but171105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydroisoquinolinyl, and the like. In various embodiments, the aryl group comprises 6 to 10 ring atoms (“6-10 membered aryl”), or 6 ring atoms (“6 membered aryl”).

[0067] “Heteroaryl,” unless otherwise stated, means a monovalent radical of a monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electrons shared in a cyclic array) having the number of ring atoms specified, for example, 5 to 11 ring atoms, having ring carbon atoms and one or more (in some embodiments, one, two, three, or four, in some embodiments, one, two, three, four, five, or six) heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon (for example, “5-11 membered heteroaryl”). In multiring systems, one or more rings may independently contain one or more heteroatoms. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and ring systems wherein the heteroaiyl ring, as defined above, is fused or spiro-fused with one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. In various embodiments, the heteroaryl group comprises 5 to 11 ring atoms (“5-11 membered heteroaryl”); 5-, 6-, 9-, or 10-membered heteroaryl; or 5 to 6 ring atoms (“5-6 membered heteroaryl”).

[0068] The term “spiro” refers to two rings connected to each other through a shared atom, and the two rings are not linked by a bridge. For example, a cyclohexyl group that is substituted with a spiro cyclopropyl group may be represented by:

[0069] As used herein, “trans,” when used in connection with a provided compound, indicates that substituents are on opposite sides of a ring or opposite sides of a double bond. For example,181105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ if a compound has substituents R1and R2, they are trans to each other in the following ring:are trans to each other in the following alkene compound: R .

[0070] As used herein, “cis,” when used in connection with a provided compound, indicates that substituents are on the same side of a ring or the same side of a double bond. For example, if aR1A^R2compound has substituents R1and R2, they are cis to each other in the following ring:R1R2, and are cis to each other in the following alkene compound: \= /

[0071] “Cyano” refers to the radical -CN.

[0072] “Hydroxy” refers to the radical -OH.

[0073] While the compounds described herein can occur and can be used as the neutral (nonsalt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In some embodiments, the salts of the compounds comprise pharmaceutically acceptable salts.

[0074] A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable to humans and / or animals, and which, upon administration, retains at least some of the desired pharmacological activity of the parent compound. Such salts include: (a) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, aspartic acid, carbonic acid,191105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ decanoic acid, ethylenediaminetetraacetic acid, hydroiodic acid, isethionic acid, lactobionic acid, octanoic acid, oleic acid, pamoic acid, pantothenic acid, polygalacturonic acid, and the like; or (b) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0075] Included herein, when chemically relevant, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted, including mixtures of stereoisomers (such as racemic or scalemic mixtures), stereochemically pure compounds, and compounds with undefined / unknown stereochemistry. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated, mixtures of stereoisomers (such as racemic or scalemic mixtures) for the portion or portions where stereochemistry is not explicitly indicated, compounds which are stereochemically pure for the portion or portions where stereochemistry is not explicitly indicated, and compounds with undefined / unknown stereochemistry for the portion or portions where stereochemistry is not explicitly indicated.

[0076] “Isotopologue” refers herein to a compound which differs in its isotopic composition from its “natural” isotopic composition. “Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition. The description of compounds herein also includes all isotopologues, in some201105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ embodiments, partially deuterated or perdeuterated analogs, of all compounds herein. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0077] “Dysregulation of PI3K-alpha” is intended to include any abnormal activity of PI3K- alpha, whether caused by a genetic mutation(s) of PI3K-alpha, expression of PI3K-alpha, level of PI3K-alpha, activation of PI3K-alpha, activation of an RTK, and / or localization of PI3K-alpha, etc., and includes but is not limited to abnormal genetic alteration, epigenetic alteration, transcription, translation, post-translation modification, and / or alteration of subcellular localization of PI3K-alpha.

[0078] “Dysregulation of a RAS protein” is intended to include any abnormal activity of a RAS protein, whether caused by a genetic mutation(s) of the RAS protein, expression of the RAS protein, level of the RAS protein, activation of the RAS protein, activation of an RTK, and / or localization of the RAS protein, etc., and includes but is not limited to abnormal genetic alteration, epigenetic alteration, transcription, translation, post-translation modification, and / or alteration of subcellular localization of the RAS protein.

[0079] Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio including racemic mixtures, salts and solvates of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.211105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQCompounds

[0080] Disclosed herein are compounds of Formula (I):wherein:R1is N, C(R6), or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or C1-C4 alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached formor two R6present on the same atom taken together with the atom to which they are attached formwhen R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R6present on the same atom taken together with the atom to which they are attached formR7in each instance is independently: Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci-Ce hydroxyalkyl; C2-Ce haloalkenyl; C3-C7 cycloalkyl; 4-12 membered heterocyclyl substituted221105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ with 0, 1, or 2 instances of -NRaRf; 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; oxo; halo; -ORd; -NRaRd; =N(Ra); -CN;-COOH; -C(O)O-Ci-C6alkyl; -C(O)-Ci-C6alkyl; -C(O)N(Ra)(Rn); -S(O)2N(Ra)(Re); -S(O)2-Ci- C6alkyl; -S(O)(=NRa)-Ci-C6alkyl; -S(O)(=NRa)NHRb; or -P(=O)(Ra)(Rb);R8in each instance is independently Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, halo, or deutro-Ci-Ce alkyl;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), -C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -Ci- C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Cg alkylene-6-10 membered aryl, -Ci-Cg alkylene-5-10 membered heteroaryl, -Ci-Cg hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Cg alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Cg hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Cg alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Cg alkyl; Ci-Cg haloalkyl; Ci-Cg heteroalkyl; -Ci-Cg heteroalkyl-hydroxy; Ci-Cg alkoxy; Ci- Ce haloalkoxy; Ci-Cg hydroxyalkyl; C2-Ce alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Cg heteroalkyl, hydroxy, Ci-Cg hydroxyalkyl, -Ci-Cg heteroalkyl-hydroxy, or -NHC(O)-Ci-Ce alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(0)N(Rb)(Rc); -S(O)2N(Rb)(Re); - S(O)2(Ra); -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl;231105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl;Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene- (6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); andRfin each instance is independently H, C1-C4 alkyl, or -C(O)-Ci-C4 alkyl; or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or a isotopologue thereof.

[0081] In one embodiment, the compound of Formula (I) is a compound of Formula (P-I):wherein:R1is N or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or C1-C4 alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, - CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which241105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ they are attached formor two R present on the same atom taken together with the atom to which they are attached form, ■ when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which they are attached form\R7in each instance is independently: Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3- C7 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, - NRaRd, =N(Ra), -CN, -COOH, -C(O)O-Ci-C6alkyl, -C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), - S(O)2N(Ra)(Re), -S(O)2-Ci-C6alkyl, -S(O)(=NH)-CI-C6alkyl, or -S(O)(=NRa)NHRb;R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, C3-C7 cycloalkyl, or halo;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually251105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ substituted with 0, 1 , 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), -C(O)N(Rb)(Rc), -S(O)2N(Rb)(Rc), -S(O)2(Ra), -S(O)(=NRa)CH3, - S(O)(=NRa)NHRb, or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl; and Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene- (6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof.

[0082] In some aspects of Formula (I) or (P-I), R1is N or CH.

[0083] In some aspects of Formula (I) or (P-I), R2is a bond or -N(Ra)-.

[0084] In some aspects of Formula (I) or (P-I), R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-, and R9is H or C1-C4 alkyl.

[0085] In some aspects of Formula (I) or (P-I), R3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl.

[0086] In some aspects of Formula (I) or (P-I), R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo.

[0087] In some aspects of Formula (I) or (P-I), when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, - OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom261105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ taken together with the atom to which they are attached formor two R6present on,0, the same atom taken together with the atom to which they are attached form

[0088] In other aspects of Formula (I) or (P-I), when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form;ortwo R present on the same atom taken together with the atom to which they are attached form

[0089] In some aspects of Formula (I) or (P-1), R7in each instance is independently: Ci-Ce alkyl, Ci-C6haloalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, -NRaRd, =N(Ra), -CN, -COOH, -C(O)O-Ci-Ce alkyl, - C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), -S(O)2N(Ra)(Re), -S(O)2-Ci-C6alkyl, -S(O)(=NH)-CI-C6alkyl, or -S(O)(=NRa)NHRb.

[0090] In some aspects of Formula (I) or (P-I), R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, or halo.

[0091] In some aspects of Formula (I) or (P-I), R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), -C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl).

[0092] In some aspects of Formula (I) or (P-I), R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6- 10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce271105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ alkyl substituted with R10and -N(Ra)-C(0)-Ci-C6 alkyl, wherein the C3-Cg cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), - C(O)N(Rb)(Rc), -S(O)2N(Rb)(Rc), -S(O)2(Ra), -S(O)(=NRa)CH3, -S(O)(=NRa)NHRb, or - P(O)(CH3)2.

[0093] In some aspects of Formula (I) or (P-I), Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl.

[0094] In some aspects of Formula (I) or (P-I), Ring B is a 6 membered aryl or 5-6 membered heteroaryl.

[0095] In some aspects of Formula (I) or (P-I), x is 0, 1, 2, or 3.

[0096] In some aspects of Formula (I) or (P-I), y is 0, 1, 2, 3, or 4.

[0097] In some aspects of Formula (I) or (P-I), z is 0, 1, 2, 3, or 4.

[0098] In some aspects of Formula (I) or (P-I), Ra, Rb, and Rcin each instance are independentlyH or Ci -C4alkyl.

[0099] In some aspects of Formula (I) or (P-I), Rdin each instance is independently H, Ci-Ce alkyl, Ci-C6haloalkyl, or C3-C4cycloalkyl.

[0100] In some aspects of Formula (I) or (P-I), Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected Ci-C4alkyl, 6 membered aryl, 5-6 membered heteroaryl, or -Ci-C3alkylene-(6 membered aryl), or -Ci-C3alkylene-(5-6 membered heteroaryl).

[0101] In some aspects, including any of the foregoing, disclosed herein is a stereoisomer of the compound of Formula (I) or (P-I), and / or or a salt of Formula (I) or (P-I), and / or an isotopologue thereof of Formula (I) or (P-I). In some aspects, including any of the foregoing, disclosed herein is a stereoisomer of the compound of Formula (I) or (P-I), or a salt of Formula (I) or (P-I).

[0102] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue281105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinR7R / kY^R7Ring A is: J W

[0103] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue

[0104] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereofor a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted phenyl group.

[0105] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted 3 -methylphenyl group.

[0106] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue291105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ301105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQIn a further embodiment, R7is -C(O)N(Ra)(Rn).

[0107] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted pyridyl group.

[0108] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted 5-methylpyridin-3-yl group.

[0109] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue311105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0110] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue

[0111] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted phenyl group.

[0112] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted pyridyl group.

[0113] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is selected from the group consisting of:

[0114] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is selected from the group consisting of:321105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0115] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is selected from the group consisting

[0116] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 3 -fluoro-4-m ethylphenyl group.331105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0117] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 3 -trifluoromethylphenyl group.

[0118] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 4-cy cl opropyl-3 -fluorophenyl group.

[0119] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 4-cyclopropylphenyl group.

[0120] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 5-cyclopropylpyridin-2-yl group.

[0121] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a 3-cyclopropylpyridin-2-yl group.

[0122] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is -CH3 or -CH2CH3.

[0123] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is Ci-Ce haloalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is -CF3 or -CHF2.

[0124] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is Ci-Ce alkoxy. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is Ci-Ce haloalkoxy.341105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0125] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is C3-C7 cycloalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is cyclopropyl.

[0126] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is halo. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is -F or -Cl.

[0127] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is deutro-Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R8is -CD3.

[0128] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is -CH2-.

[0129] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is O.

[0130] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is N(Ra).

[0131] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is H.

[0132] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is Me.351105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0133] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is -S-, -S(O)-, or -SO2-.

[0134] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R9is H.

[0135] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R9is C1-C4 alkyl.

[0136] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond.

[0137] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is N(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is NH.

[0138] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R4and R5are H. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R4and R5are C1-C4 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R4is H and R5is C1-C4 alkyl.

[0139] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is C(R6).361105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0140] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH and R6is in each instance independently C1-C4 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH and R6is in each instance independently methyl.

[0141] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N and R6is in each instance independently C1-C4 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N and R6is in each instance independently methyl.

[0142] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R6is methyl and x is 1.

[0143] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein x is 2 and both R6groups are Me.

[0144] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -CH3 or -CH(CH3)2.

[0145] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is Ci-Ce haloalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -CHF2 or -CF3.

[0146] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue371105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ thereof, wherein at least one R7is Ci-Ce heteroalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -Ci- ealkylene-O-Ci-salkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -CH2OCH3 or -CH2CH2OCH3. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)-Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)2-CH2CH3 or -S(O)2-CH(CH3)2. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S-Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S-CH3.

[0147] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is C3-C7 cycloalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is cyclopropyl.

[0148] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is 4-12 membered heterocyclyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is oxetanyl or tetrahydrofuranyl .

[0149] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is 5-12 membered heteroaryl. In some aspects, including any of381105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is

[0150] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is oxo. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -CN. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -COOH.

[0151] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is halo. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -F or -Cl.

[0152] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -ORd. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -NRaRd. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -NH2. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is =N(Ra).

[0153] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -C(O)O-Ci-C6 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -C(O)-Ci-C6 alkyl.391105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0154] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(0)2N(Ra)(Re). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)2NH2 or -S(O)2NH(CH3).

[0155] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)2-Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)2-CH3.

[0156] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)(=NRa)-Ci-C6 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)(=NH)-CH3,

[0157] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)(=NRa)NHRb. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -S(O)(=NH)NH2.

[0158] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is Ci-Ce hydroxyalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -CH2OH.

[0159] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is C2-C6 haloalkenyl. In some aspects, including any of the foregoing,401105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -C(F)=CH2,

[0160] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is 4-12 membered heterocyclyl substituted with 0, 1, or 2 instances of -NRaRf. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is oxetanyl substituted with 1 instance of -NRaRf. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one

[0161] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is a 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl.

[0162] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -P(=O)(Ra)(Rb). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein at least one R7is -P(=O)(CH.3)2.

[0163] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -C(O)N(Ra)(Rn).

[0164] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is -C(O)N(Ra)(Rn) and y is 1. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein and y is 2 and both R7are - C(O)N(Ra)(Ru).411105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0165] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, one R7group is -C(O)N(Ra)(Rn), and the other R7group is Me. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, one R7group is -C(O)N(Ra)(Rn), and the other R7group is halo. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, one R7group is - C(O)N(Ra)(Ru), and the other R7group is Ci-Cs haloalkyl.

[0166] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 3 and at least one R7group is -C(O)N(Ra)(Rn). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 3, at least one R7group is Me, and at least one R7group is -C(O)N(Ra)(Rn). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 3, one R7group is Me, and the other R7groups are -C(O)N(Ra)(Rn). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 3, one R7group is Me, one R7group is -C(O)N(Ra)(Rn), and one R7group is a 4-12 membered heterocyclyl substituted with 1 instance of -NRaR'.

[0167] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is H. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -CH3, -CH(CH3)2, or -CH(CH3)CH2CH3.421105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0168] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce haloalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -CH2CF3, or -CH(CH3)CH2CF3. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce hydroxyalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -CH2CH(CH3)OH, CH(CH2CH3)CH2OH, -CH2CH(OH)CH2CH3, -CH2CH2CH2OH, -CH2C(CH3)2OH, or -CH(CH3)C(CH3)2OH.

[0169] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce heteroalkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -Ci-6alkylene-O-Ci-3alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -CH2CH2OCH3, -CH2CH2CH2OCH3, or -CH(CH3)CH2OCH3.

[0170] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6- 10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), or -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11are individually substituted with 0, 1, 2, or3 instances of independently selected Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce hydroxyalkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra);431105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ-C(O)N(Rb)(Rc); -S(O)2N(Rb)(Rc); -S(O)2(Ra); -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; or -P(O)(CH3)2.

[0171] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -C1-C6 alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), or -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), wherein the C3-Cs cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-Ce alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Ce heteroalkyl, hydroxy, Ci-Ce hydroxyalkyl, -Ci-Ce heteroalkyl-hydroxy, or -NHC(O)-CI-C6 alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(0)N(Rb)(Rc); -S(O)2N(Rb)(Re);-S(O)2(Ra), -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; or -P(O)(CH3)2.

[0172] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, or bicyclo[ 1.1.1 ]pentanyl individually substituted with 0 or 1 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, halo, or -S(O)2(Ra).

[0173] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ph (phenyl) substituted with 0, 1, 2, or 3 instances of independently selected Ci- Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci-Ce alkoxy; halo; cyano; or 3-6 membered carbocyclyl.441105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0174] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof,substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl;Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-C6 alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, Ci- C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Cg heteroalkyl, hydroxy, Ci-Ce hydroxyalkyl, -Ci-Ce heteroalkyl-hydroxy, or -NHC(O)-CI-C6 alkyl; hydroxy; oxo; halo; cyano; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(0)N(Rb)(Rc); -S(O)2N(Rb)(Rc); or -S(O)2(Ra).

[0175] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinwherein the phenyl group is substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce heteroalkyl; Ci-Ce hydroxyalkyl; halo; 3-6 membered carbocyclyl; or Ci-Ce alkoxy.

[0176] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue451105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQeach instance is individually substituted with 0, 1, 2, or 3 instances of independently selected Ci- alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; Ci-Ce alkoxy; halo; or 6 membered aryl.

[0177] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinwherein the phenyl or pyridinyl group is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce heteroalkyl; Ci-Ce alkoxy; halo; or 3-6 membered carbocyclyl.

[0178] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue461105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce hydroxyalkyl, hydroxy, halo, or oxo.

[0179] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinwherein the carbocyclyl group is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected cyano, hydroxy, Ci-Ce hydroxyalkyl, or N(Rb)(Rc).

[0180] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -S(O)2(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is SO2CH3.

[0181] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6 alkyl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc) or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-Ce alkyl and R10is a 6 membered aryl. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0182] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is hydroxy. In some aspects, including any of the foregoing, disclosed471105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is oxo. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is cyano.

[0183] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is halo.

[0184] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -N(Rb)(Re).

[0185] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -C(O)O(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -C(O)N(Rb)(Rc).

[0186] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -S(0)2N(Rb)(Rc). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -S(O)2(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -S(0)(=NRa)CH3. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -S(O)(=NRa)NHRb.

[0187] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is -P(O)(CH )2.

[0188] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is independently selected from -H, Me, iPr, sec-butyl, Ph, -CF^Ph, -CFhCFfcPh,481105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ-CH2CH2OCH3, -CH2CH2CH2OCH3, -CH(CH3)CH2OCH3, -CH2CH(CH3)OH,491105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ501105079198\1\AMERICASAttorney Docket No.: 130238.00003FM0040WQ511105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0189] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue

[0190] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer,521105079198\1\AMERICASAttorney Docket No.: 130238.00003FM0040WQ and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (1) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is

[0191] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinR is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or531105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ isotopologue thereof, wherein R11isIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11issome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0192] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue541105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound551105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11isIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11issome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or(P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11isIn some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is561105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is

[0193] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is independently selected from methyl,571105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0194] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais hydrogen. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais methyl.

[0195] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0196] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0197] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0198] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is581105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0199] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is

[0200] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0201] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0202] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is methyl.

[0203] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein591105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0204] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0205] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein

[0206] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -S(O)2NH2. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1 and R7is -S(O)2NH2.

[0207] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, whereinRing A is:some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt,601105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0208] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue

[0209] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -C(O)NHMe.

[0210] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue^Ny'0’(R7,!'1thereof, wherein Ring A is: O -~w , and yl is 0, 1, 2, or 3.

[0211] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (1) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue611105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ thereof, wherein Ring A is:is 0, 1, 2, or 3.

[0212] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or621105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ isotopologue thereof, wherein Ring A is:some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0213] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0214] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R3is NH, R4and R3are H, and R9is H.

[0215] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Ia)631105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0216] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ia) or (la) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H.

[0217] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ia) or (la), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is methyl.

[0218] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ia) or (la), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H and R11is methyl.

[0219] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ia) or (la), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H and R13is methyl.

[0220] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is -C(O)NRaR11.

[0221] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is -C(O)NRaRn, both Ragroups are H, and R11is independently selected from a 5-10 membered heteroaryl, a 3-12 membered heterocyclyl, and Ci-Ce alkyl wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclyl is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce haloalkyl;641105079198\1\AMERICASAttomey Docket No.: 130238.00003FM0040WQCi-Ce heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Ce alkoxy; Ci-Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-C6 alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Ce heteroalkyl, hydroxy, Ci-Ce hydroxyalkyl, -Ci-Ce heteroalkyl-hydroxy, or -NHC(O)-Ci-Ce alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(0)N(Rb)(Rc); -S(O)2N(Rb)(Rc); -S(O)2(Ra), - S(O)(=NRa)CH3; -S(0)(=NRa)NHRb; or -P(O)(CH3)2.

[0222] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Ib):, wherein R12is CH or N, and R1is H or Ci-C4 alkyl.

[0223] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ib) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein both Raand Reare H.

[0224] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ib) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H.

[0225] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Ib) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ra, Re, and R13are H.

[0226] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Ic):651105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-lc) wherein R12is CH or N, and R13is H or Ci-C4 alkyl.

[0227] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Id):

[0228] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (P-Id) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ringsome aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-Id) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring

[0229] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue661105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Ie):(P-le) wherein yl is 0, 1, 2, or 3.

[0230] In some aspects, including any of the foregoing, disclosed herein is a compound ofFormula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-If):

[0231] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond, R4and R5are both H, and R3is -O-. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond, R4and R5are both H, and R3is N(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond, R4and R5are both H, and R3is NH.

[0232] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R4and R5are both H, and R3is -O-. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R4and R5are both H, and R3is N(Ra). In some aspects, including any of the foregoing,671105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Tb), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R4and R5are both H, and R3is NH.

[0233] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (la), (lb), (Ic), or (le), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH, R2is a bond, R4and R5are both H, and R3is -O-. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (la), (lb), (Ic), or (le), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH, R2is a bond, R4and R5are both H, and R3is N(Ra). In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P- I), (la), (lb), (Ic), or (le), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH, R2is a bond, R4and R3are both H, and R3is NH.

[0234] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R3is NH, R4and R5are H, and R9is H. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH, R2is a bond, R3is NH, R4and R5are H, and R9is H. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R3is O, R4and R5are H, and R9is H. In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P- Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH, R2is a bond, R3is O, R4and R5are H, and R9is H.

[0235] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I), (P-I), (P-Ia), (la), (P-Ib), (P-Ic), (P-Id), (P-Ie), or (P-If), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R6is methyl and x is 1.

[0236] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue681105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-Ig):

[0237] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-II), wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0238] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-II) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1.

[0239] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-II) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, and the remaining R7group is methyl.

[0240] In some aspects, including any of the foregoing, disclosed herein is a compound of Formula (P-II) or (II), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein z is 2, one R8is methyl, and the other R8is fluoro.

[0241] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the691105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIal) or (Illal ):, wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0242] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIa2) or (IIIa2):, wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0243] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the701105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIa3) or (IIIa3):, wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0244] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIa4) or (IIIa4):, wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0245] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIa5) or (IIIa5):711105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ, wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0246] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIbl):(P-lllb1) ,wherejnR12isCHorN, and R13is H or C1-C4 alkyl.

[0247] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIb2):alkyl.

[0248] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIb3):721105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQalkyl.

[0249] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIb4):alkyl.

[0250] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIb5):(P-lllb5) ,wherejnR12jsCH or N, and R13is H or C1-C4 alkyl.

[0251] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIcl):(P'l l lc1 ), wherein R12is CH or N, and R13is H or C1-C4 alkyl.731105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0252] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIc2):(P-lllc2) ,wherein R12isCH or N, and R13is H or C1-C4 alkyl.

[0253] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIc3):alkyl.

[0254] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIc4):alkyl.

[0255] In some aspects, disclosed herein is a compound of Formula (I) or (P-I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) or (P-I) comprises a compound of Formula (P-IIIc5):741105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-l Ilc5) , wherein R12JSQJJOr N, and R13is H or C1-C4 alkyl.

[0256] In some aspects, disclosed herein is a compound of Formula (P-Ia)-(P-Ic), (P-II), (II), (P- IIIal)-(IIIa5), (P-IIIbl)-(P-IIIb5), or (P-IIIcl)-(P-IIIc5) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R12is CH. In some aspects, disclosed herein is a compound of Formula (P-Ia)-(P-Ic), (P-II), (II), (P-IIIal)-(IIIa5), (P-IIIb l)-(P-IIIb5), or (P- IIIcl)-(P-IIIc5) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R12is N. In some aspects, disclosed herein is a compound of Formula (P-Ia)-(P-Ic), (P- II), (II), (P-IIIal)-(IIIa5), (P-IIIbl)-(P-IIIb5), or (P-IIIcl)-(P-IIIc5) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R13is H. In some aspects, disclosed herein is a compound of Formula (P-Ia)-(P-Ic), (P-II), (II), (P-IIIal)-(IIIa5), (P-IIIbl)- (P-IIIb5), or (P-IIIcl)-(P-IIIc5) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R13is C1-C4 alkyl. In some aspects, disclosed herein is a compound of Formula (P-Ia)-(P-Ic), (P-II), (II), (P-IIIal)-(IIIa5), (P-IIIbl)-(P-IIIb5), or (P- IIIcl)-(P-IIIc5) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R13is methyl.

[0257] In some aspects, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound is selected from the group consisting of: 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)- V-(5-cyano-3-methylpyridin-2-yl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-(6-methoxypyridazin-3- yl)benzamide, 4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(5-cyclopropylpyridin-2- yl)ethoxy)-7V-m ethylbenzamide, 4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-7V-(6-methylpyridin-3-yl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- V1,6-dimethylisophthalamide, N- (3 / / -2X2-benzo[d]isoxazol-6-yl)-4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)benzamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV1, / V3,6-trimethylisophthalamide, 4-(2-((J?)-4-acryloyl-3-methylpiperazin-751105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1 -yl)-l -(3-fluoro-4-methylphenyl)ethoxy)-y-(5-hydroxypyrimidin-4-yl)benzamide, 4-(2-((7?)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)benzenesulfonamide, 4-(2- ((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV-(3-oxo-3,4- dihydropyrazin-2-yl)benzamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-methylbenzamide, 4-(2-((J?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3- fluoro-4-methylphenyl)ethoxy)-jV-((7?)-2-(4-chlorophenyl)-2-hydroxyethyl)-2-methylbenzamide, 5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 - methylpicolinamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3 -fluoro-4-methylphenyl)- 2-oxoethoxy)benzenesulfonamide, 5-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-3-methylpyridine-2-sulfonamide, 4-((2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)-2-oxoethyl)amino)benzenesulfonamide, 4- (2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(4-cyclopropylphenyl)ethoxy)-7V- methylbenzamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)-2- oxoethoxy)-jV-((l-phenyl-5-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide, 4-(2-((7?)- 4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV-((l-phenyl-2X2- pyrazolidin-4-yl)methyl)benzamide, 4-(2-((l?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3 -fluoro-4- methylphenyl)ethoxy)-Ar-((l-phenyl-5-(trifluorom ethyl )-2X2-pyrazolidin-4-yl)methyl)benzamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)-l -(3 -fluoro-4-methylphenyl)ethoxy)-JV-((l-methyl- 2X2-pyrazolidin-4-yl)methyl)benzamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1-yl)- 1 -(3- fluoro-4-methylphenyl)ethoxy)-A,-((l-methyl-3-(trifluoromethyl)-2X2-pyrazolidin-4- yl)methyl)benzamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)-l -(4- cyclopropylphenyl)ethoxy)benzenesulfonamide, 5-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l- (3-fluoro-4-methylphenyl)ethoxy)pyridine-2-sulfonamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV,2-dimethylbenzamide, 4-(2-((7?)-4- acryloyl-3 -methylpiperazin-l-yl)-l -(3 -fluoro-4-methylphenyl)ethoxy)-2-m ethylbenzamide, 5-(2- ((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-3-methyl-7V-(3- methyl-5-(methylsulfonyl)pyri din-2 -yl)picolinamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l- yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-7V-(4-(hydroxymethyl)tetrahydro-2 / / -pyran-4- yl)benzamide, 4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-((5)-2-amino-2-oxo-l-phenylethyl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV-((7?)-2-(4-fluorophenyl)-2-761105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ hydroxyethyl)benzamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l -yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-JV-(2 -hydroxy cy cl ohexyl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-metliylphenyl)ethoxy)-rV-(2- hydroxycyclopentyl)benzamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-rV-(2-methylcyclopentyl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((7?)-2-hydroxy-2-(pyridin-3- yl)ethyl)benzamide, 4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)- / V-((7?)-2-hydroxy- l -phenyl ethyl)benzamide, 5-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-7V-((7?)-2-hydroxy-2-(pyridin-3- yl)ethyl)-3-methylpicolinamide, l-((27?)-4-(2-((2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)oxy)- 2-(3-fluoro-4-methylphenyl)ethyl)-2-methylpiperazin-l-yl)prop-2-en-l-one, methyl 6-(2-((7?)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-3,4-dihydroisoquinoline- 2(777)-carboxylate, 5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3-fluoro-4- methylphenyl)ethoxy)-3-methyl-JV-(3-methyl-5-(methylcarbamoyl)pyridin-2-yl)picolinamide, 5- (2-((7?)-4-acryloyl-3-methylpiperazin-l -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-2V-(5- (dimethylcarbamoyl)-3-methylpyridin-2-yl)-3-methylpicolinamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-(trifluoromethyl)phenyl)ethoxy)benzenesulfonamide, 4-(2-((A)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-7V-(((5)-5-oxopyrrolidin- 2-yl)methyl)benzamide, 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3 -fluoro-4- methylphenyl)ethoxy)-7V-(((2?)-5-oxopyrrolidin-2-yl)methyl)benzamide, 4-(2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -(trifluoromethyl)phenyl)ethoxy)-2V-methylbenzamide, 4-(2-((7?)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((ls,45)-4- fluorocyclohexyl)benzamide, 4-((2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethyl)amino)benzenesulfonamide, and 4-(2-((37?,5S)-4-acryloyl-3,5- dimethylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-methylbenzamide.

[0258] In some aspects, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 4-((5')-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-JV-((lS,25)-2-hydroxycyclohexyl)benzamide, 4-((5)-2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3-fluoro-4-methylphenyl)ethoxy)-rV-((15,27?)-2- hydroxycyclohexyl)benzamide, 4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-771105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ methylphenyl)ethoxy)-A-((l / ?,2X)-2-hydroxycyclohexyl (benzamide, 4-((5)-2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-(( lR,2R)-2- hydroxycyclohexyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-7V-((lS,2S)-2-hydroxycyclohexyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV-(( lR,2R)-2- hydroxycyclohexyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-((lS,27?)-2-hydroxycyclohexyl)benzamide, and 4-((7?)-2-((R)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((17?,27?)-2- hydroxycyclohexyl)benzamide.

[0259] In some aspects, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-7V-((lS,2T?)-2-hydroxycyclopentyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV-(( lR,2S)-2- hydroxycyclopentyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-((lS,25)-2-hydroxycyclopentyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-? / -(( 1 R,2R)-2- hydroxycyclopentyl)benzamide, 4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-((15',27?)-2-hydroxycyclopentyl)benzamide, 4-((5)-2-((7?)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV-((17?,25)-2- hydroxy cyclopentyl)benzamide, 4-((S)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-jV-((15,25)-2-hydroxycyclopentyl)benzamide, and 4-((5)-2-((7?)-4- acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-?7-((lJ?,27?)-2- hydroxycyclopentyl)benzamide.

[0260] In some aspects, disclosed herein is a compound of Formula (P-I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (P-I) is selected from the group consisting of: 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-Ar-((15,2 / ?)-2-methylcyclopentyl)benzamide, 4-((A)-2-((K)-4-acryloyl-3- methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV-((17?,25)-2- methylcyclopentyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-7V-((lS,2S)-2-methylcyclopentyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-781105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ methylpiperazin-l -yl)-l -(3-fluoro-4-methylphenyl)ethoxy)-N-((17?,2 / ?)-2- methylcyclopentyl)benzamide, 4-((5)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-A,-((LS',2 / ?)-2-methylcyclopentyl (benzamide, 4-((5)-2-((A)-4-acryloyl-3- methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A-((17?,25’)-2- methylcyclopentyl)benzamide, 4-((5)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)-A-((lS,25)-2-methylcyclopentyl)benzamide, and 4-((5T)-2-((A)-4-acryloyl- 3 -methylpiperazin- 1 -y 1)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-(( lR,2R)-2- methylcyclopentyl)benzamide.

[0261] In some aspects, disclosed herein is a compound selected from Table 2 shown in FIG. 2, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof.

[0262] Also disclosed herein is a pharmaceutical composition comprising a compound of Formula (I) or (P-I) and a pharmaceutically acceptable excipient.

[0263] Also disclosed herein is a method of treating or suppressing cancer comprising administering a therapeutically effective amount of a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) and a pharmaceutically acceptable excipient, to a subject in need thereof.

[0264] In some aspects, the cancer is characterized by dysregulation of PI3K-alpha.

[0265] In some aspects, the dysregulation comprises increased activation or increased expression of PI3K-alpha.

[0266] In some aspects, the dysregulation is caused by increased activation or increased expression of a Receptor Tyrosine Kinase (RTK) family member.

[0267] In some aspects, the RTK is an EGFR, HER2, or HER3.

[0268] In some aspects, the cancer is characterized by mutant PI3K-alpha.

[0269] In some aspects, the mutant PI3K-alpha comprises one of more of the following mutations: N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI HE, KI UN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0270] In some aspects, the cancer is characterized by a dysregulated RAS protein.

[0271] In some aspects, the dysregulation is caused by a mutant RAS protein or increased expression of a RAS protein.791105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0272] In some aspects, the mutant RAS protein is mutant KRAS, NRAS, or HRAS.

[0273] In some aspects, the mutant RAS protein is mutant KRAS.

[0274] In some aspects, the mutant KRAS contains one of more of the following mutations: G12D, G12V, G12C, G12A, G12S, G12R, G13D, G13C, Q61H, or A146T.

[0275] In some aspects, the cancer is characterized by increased expression of the RAS protein.

[0276] In some aspects, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, bladder, breast, and head and neck cancers.

[0277] In some aspects, the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.

[0278] In some aspects, the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

[0279] In some aspects, the subject is treated before the subject is tested for the mutation.801105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0280] Also disclosed herein is a method of identifying a patient population treatable with a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising Formula (I) or (P-I) and a pharmaceutically acceptable excipient comprising testing the population for one or more of certain mutations in the KRAS protein or the PI3K-alpha protein, wherein the certain mutations in the KRAS protein are selected from the group consisting of G12D, G12V, G12C, G12A, G12S, G12R, G13D, GDC, Q61H, and A146T, and wherein the certain mutations in the PI3K- alpha protein are selected from N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0281] In some aspects, the mutation is the G12C or G12D mutation in KRAS.

[0282] In some aspects, the method further comprises treating at least one patient from the patient population with a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising Formula (I) or (P-I) and a pharmaceutically acceptable excipient.

[0283] Also disclosed herein is a method of disrupting interaction between PI3K-alpha and a RAS protein in a cell, comprising contacting the cell with a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)) and a pharmaceutically acceptable excipient, in an amount effective to disrupt the interaction. In some aspects, the cell is in a subject.

[0284] In some aspects, downstream signaling of the PI3K-alpha interaction with the RAS protein is altered.

[0285] Also disclosed herein is a method of modulating the activity of PI3K-alpha in a cell, comprising contacting the cell with a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)) and a pharmaceutically acceptable excipient, in an amount effective to modulate the activity of PI3K-alpha. In some aspects, the cell is in a subject.811105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0286] Also disclosed herein is a method of disrupting interaction between PI3K-alpha and RAS, comprising contacting PI3K-alpha with a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)) and a pharmaceutically acceptable excipient, in an amount effective to disrupt the interaction. In some aspects, the PI3K-alpha is present in a cell. In some aspects, the PI3K-alpha is present in a subject in need of disruption of the interaction between PI3K-alpha and RAS.

[0287] In some aspects, the interaction is inhibited.

[0288] In some aspects, the interaction is reduced by at least 25%.

[0289] In some aspects, the interaction is reduced by at least 50%.

[0290] In some aspects, the interaction is reduced by at least 85%.

[0291] In some aspects, the interaction is measured by an AlphaScreen™ Protein-Protein Interaction Assay Protocol.

[0292] Also disclosed herein is a method of covalently modifying PI3K-alpha comprising contacting PI3K-alpha with a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) (and any embodiments of (I) and (P-I)) and a pharmaceutically acceptable excipient, in an amount effective to covalently modify PI3K-alpha. In some aspects, the PI3K-alpha is present in a cell. In some aspects, the PI3K-alpha is present in a subject.

[0293] Also disclosed herein is a method of covalently modifying PI3K-alpha comprising contacting PI3K-alpha with a compound of Formula (I) or (P-I), or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (P-I) and a pharmaceutically acceptable excipient, in an amount effective to covalently modify PI3K-alpha with the compound of Formula (I or (P-I)). The compound of Formula (I) or (P-I) binds to PI3K-alpha and reacts with PI3K-alpha, thereby covalently modifying PI3K-alpha. In some aspects, the PI3K-alpha is present in a cell. In some aspects, the PI3K-alpha is present in a subject.

[0294] In some aspects, the PI3K-alpha is present in a cell.

[0295] In some aspects, the PI3K-alpha is present in a subject.821105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0296] Non-limiting embodiments of the present disclosure include:

[0297] Embodiment 1: A compound of Formula (P-I):wherein:R1is N or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or Ci-C4alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R6present on the same atom taken together with the atom to which they are attached formwhen R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R6present on the same atom taken together with the atom to which they are attached form831105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQR7in each instance is independently: Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, -NRaRd, =N(Ra), -CN, -COOH, -C(O)O-Ci-C6alkyl, -C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), -S(O)2N(Ra)(Re), -S(O)2-Ci-C6alkyl, -S(O)(=NH)-CI-C6alkyl, or - S(O)(=NRa)NHRb;R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, or halo;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene- (3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and - C(O)N(Rb)(Rc), or Ci-C6alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3- 12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Cs alkoxy, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), -C(0)N(Rb)(Rc), -S(O)2N(Rb)(Re), -S(O)2(Ra), -S(O)(=NRa)CH3, -S(0)(=NRa)NHRb, or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;841105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQRa, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl; andRein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0298] Embodiment 2: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

[0299] Embodiment 3: The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a substituted phenyl group.

[0300] Embodiment 4: The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a substituted 3 -methylphenyl group.

[0301] Embodiment 5: The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a substituted pyridyl group.

[0302] Embodiment 6: The compound of any one of Embodiments 1, 2 or 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a substituted 5- methylpyridin-3-yl group.

[0303] Embodiment 7: The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a substituted phenyl group.

[0304] Embodiment 8: The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a substituted pyridyl group.

[0305] Embodiment 9: The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is selected from the group consisting of:851105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0306] Embodiment 10: The compound of any one of Embodiments 1-6 or 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a 3-fluoro-4- methylphenyl group.

[0307] Embodiment 11 : The compound of any one of Embodiments 1-6 or 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a 3- trifluoromethylphenyl group.

[0308] Embodiment 12: The compound of any one of Embodiments 1-6 or 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a 4-cyclopropyl-3- fluorophenyl group.

[0309] Embodiment 13: The compound of any one of Embodiments 1-6 or 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a 4- cyclopropylphenyl group.

[0310] Embodiment 14: The compound of any one of Embodiments 1-6 or 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring B is a 5- cyclopropylpyridin-2-yl group.

[0311] Embodiment 15: The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is O.

[0312] Embodiment 16: The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is N(Ra).

[0313] Embodiment 17: The compound of any one of Embodiments 1-14 or 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the Raattached to R3is H.

[0314] Embodiment 18: The compound of any one of Embodiments 1-14 or 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the Raattached to R3is Me.

[0315] Embodiment 19: The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R9is H.861105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0316] Embodiment 20: The compound of any one of Embodiments 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is a bond.

[0317] Embodiment 21 : The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R5are H.

[0318] Embodiment 22: The compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is N.

[0319] Embodiment 23 : The compound of any one of Embodiments 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6is methyl and x is 1.

[0320] Embodiment 24: The compound of any one of Embodiments 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein x is 2 and both R6groups are Me.

[0321] Embodiment 25: The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 1, 2, 3, or 4, and at least one R7is - C(O)N(Ra)(Ru).

[0322] Embodiment 26: The compound of any one of Embodiments 1-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7is -C(O)N(Ra)(Rn) and y is 1.

[0323] Embodiment 27: The compound of any one of Embodiments 1-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 2, one R7group is -C(O)N(Ra)(R11), and the other R7group is Me.

[0324] Embodiment 28: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0325] Embodiment 29: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein871105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0326] Embodiment 30: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0327] Embodiment 31 : The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0328] Embodiment 32: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0329] Embodiment 33: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 1is.

[0330] Embodiment 34: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein.

[0331] Embodiment 35: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R11is methyl.

[0332] Embodiment 36: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein881105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0333] Embodiment 37: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0334] Embodiment 38: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0335] Embodiment 39: The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -S(O)2NH2.

[0336] Embodiment 40: The compound of any one of Embodiments 1-24 or 39, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

[0337] Embodiment 41 : The compound of any one of Embodiments 1-26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 1, 2, 3, or 4, and at least one R7is - C(O)NHMe.

[0338] Embodiment 42: The compound of Embodiments 1-26 or 41, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.891105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0339] Embodiment 43: The compound of Embodiments 1-26 or 41, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

[0340] Embodiment 44: The compound of any one of Embodiments 1-26 or 41-42, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and y2 is 0, 1, or 2.

[0341] Embodiment 45: The compound of any one of Embodiments 1-26, 41 or 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is:and y2 is 0, 1, or 2.

[0342] Embodiment 46: The compound of any one of Embodiments 1-14 or 23-45, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is N, R2is a bond, R3is NH, R4and R5are H, and R9is H.

[0343] Embodiment 47: The compound of Embodiment 1 or 7-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-Ia):901105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-Ia) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0344] Embodiment 48: The compound of Embodiment 47, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rais H.

[0345] Embodiment 49: The compound of any one of Embodiments 47-48, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R11is methyl.

[0346] Embodiment 50: The compound of any one of Embodiments 1 or 7-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-Ib):(P-Ib) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0347] Embodiment 51 : The compound of Embodiment 50, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein both Raand Reare H.

[0348] Embodiment 52: The compound of Embodiment 50 or 51, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rais H.

[0349] Embodiment 53: The compound of any one of Embodiments 1 or 7-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P- I) comprises a compound of Formula (P-Ic):911105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-Ic) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0350] Embodiment 54: The compound of any one of Embodiments 1-53, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-Id):(P-Id)

[0351] Embodiment 55: The compound of Embodiment 54, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring

[0352] Embodiment 56: The compound of any one of Embodiments 1 or 7-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-Ie):921105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ wherein y 1 i s 0, 1 , 2, or 3.

[0353] Embodiment 57: The compound of any one of Embodiments 1-53 or 56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P- I) comprises a compound of Formula (P-If):(P-If)

[0354] Embodiment 58: The compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-Ig):

[0355] Embodiment 59: The compound of any one of Embodiments 1 or 7-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P- I) comprises a compound of Formula (P-II):(P-II) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0356] Embodiment 60: The compound of Embodiment 59, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 1.

[0357] Embodiment 61 : The compound of Embodiment 59, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein y is 2, and the remaining R7group is methyl.931105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0358] Embodiment 62: The compound of any one of Embodiment 59-61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein z is 2, one R8is methyl, and the other R8is fluoro.

[0359] Embodiment 63: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound ofFormula (P-IIIal):(P-IIIal) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0360] Embodiment 64: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of(P-IIIa2) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0361] Embodiment 65: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of(P-IIIa3)941105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0362] Embodiment 66: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIa4):(P-IIIa4) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0363] Embodiment 67: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-1) comprises a compound of(P-IIIa5) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0364] Embodiment 68: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of(P-IIIbl) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0365] Embodiment 69: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIb2):951105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-IIIb2) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0366] Embodiment 70: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of(P-IIIb3) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0367] Embodiment 71 : The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound ofFormula (P-IIIb4):(P-IIIb4) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0368] Embodiment 72: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIb5):961105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-IIIb5) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0369] Embodiment 73: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIcl):(P-IIIcl) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0370] Embodiment 74: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIc2):(P-IIIc2) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0371] Embodiment 75: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIc3):971105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-IIIc3) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0372] Embodiment 76: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-I) comprises a compound of Formula (P-IIIc4):(P-IIIc4) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0373] Embodiment 77: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (P-1) comprises a compound of Formula (P-IIIc5):(P-IIIc5) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0374] Embodiment 78: The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of: 4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV-(5-cyano-3 - methylpyri din-2 -yl)benzamide,4-(2-(( ?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(6- methoxypyridazin-3-yl)benzamide,981105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(5-cyclopropylpyridin-2-yl)ethoxy)-Af- methy lb enzami de,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-A -(6- methylpyridin-3-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylpheny l)ethoxy)-JVJ, 6- dimethylisophthal amide,7V-(377-2X2-benzo[d]isoxazol-6-yl)-4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-Arl, N3, 6- trimethy 1 i sophthal ami de,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-(5- hydroxypyrimidin-4-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4- methylphenyl)ethoxy)benzenesulfonamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-(3-oxo-3,4- dihydropyrazin-2-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-A'- methylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-((T?)-2-(4- chlorophenyl)-2-hydroxyethyl)-2-methylbenzamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 - methylpicolinamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)-2- oxoethoxy)benzenesulfonamide,5-(2-((7?)-4-acryloyl -3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-3 - methylpyridine-2-sulfonamide,4-((2-((7?)-4-acryloy 1-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)-2- oxoethyl)amino)benzenesulfonamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- l-yl)-l-(4-cy cl opropy I phenyl )ethoxy)-A'- methy lb enzami de,991105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((7?)-4-acryloyl-3-methylpiperazin-l -yl)-l -(3 -fluoro-4-methylphenyl)-2-oxoethoxy)-Af-((l - phenyl-5-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-7V-(( 1 -phenyl-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(( 1 -phenyl-5-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-(( 1 -methyl-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-rnethylphenyl )ethoxy)-A-(( l -methyl-3-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(4- cyclopropylphenyl)ethoxy)benzenesulfonamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)pyridine-2- sulfonamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V,2- dimethylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-2- methylbenzamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 -methyl-rV-(3-methyl-5-(methylsulfonyl)pyridin-2-yl)picolinamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(4-(hydroxymethyl)tetrahydro-2 / / -pyran-4-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-Ar-((S)-2- amino-2-oxo-l-phenylethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-2V-((7?)-2-(4- fluorophenyl)-2-hydroxyethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(2- hydroxycyclohexyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(2- hydroxycyclopentyl)benzamide,1001105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3 -fluoro-4-methylphenyl)ethoxy)-Ar-(2- methylcyclopentyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-7V-((7?)-2- hydroxy-2-(pyridin-3-yl)ethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-((7?)-2- hydroxy-l-phenylethyl)benzamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-((7?)-2- hydroxy-2-(pyri din-3 -yl)ethyl)-3-methylpicolinamide, l-((27?)-4-(2-((2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-2-(3-fluoro-4- methylphenyl)ethyl)-2-methy Ipiperazin- 1 -yl)prop-2-en- 1 -one, methyl 6-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-3,4- dihydroisoquinoline-2(J / / )-carboxylate,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 -methy I -A-(3-methyl-5-(methylcarbamoyl)pyridin-2-yl)picolinamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-(5-(dimethylcarbamoyl)-3-methylpyridin-2-yl)-3-methylpicolinamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -(trifluoromethyl)phenyl)ethoxy)benzenesulfonamide,4-(2-((A?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-7V-(((S)-5- oxopyrrolidin-2-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(((7?)-5- oxopyrrolidin-2-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -(trifluoromethyl)phenyl)ethoxy)-7V- methy lb enzami de,4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-2V-((ls,45)-4- fluorocyclohexyl)benzamide4-((2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4- methylphenyl)ethyl)amino)benzenesulfonamide, and4-(2-((37?,55)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV- methy lb enzami de .1011105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0375] Embodiment 79: The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of:4-((S)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((lS,2S)-2-hydroxycyclohexyl)benzamide,4-((5)-2-((7?)-4-acryloyl-3-rnethylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-rV-((15,2 / ?)-2-hydroxycyclohexyl)benzamide,4-((1S)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-2V-((17?,2S)-2-hydroxycyclohexyl)benzamide,4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-JV-((17?,27?)-2-hydroxycyclohexyl)benzamide,4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((lS,2S)-2-hydroxycyclohexyl)benzamide,4-((7?)-2-((7?)-4-acry loyl-3 -methy Ipiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylpheny l)ethoxy)-rV-((17?,25)-2-hydroxycyclohexyl)benzamide,4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((lS,27?)-2-hydroxycyclohexyl)benzamide, and4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV- ((17?,27?)-2-hydroxycyclohexyl)benzamide.

[0376] The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (P-I) is selected from the group consisting of:4-((7?)-2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylpheny l)ethoxy)-JV-((15,27?)-2-hydroxycyclopentyl)benzamide,4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-jV-((17?,2S)-2-hydroxycyclopentyl)benzamide,4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-7V-(( 1 S, 2S)-2 -hy droxy cy cl openty l)b enzami de,4-((7?)-2-((7?)-4-acry loyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylpheny l)ethoxy)-jV-((lA,2A)-2-hydroxycyclopentyl)benzamide,4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-jV-((15,27?)-2-hydroxycyclopentyl)benzamide,1021105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l -yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,25)-2-hydroxycyclopentyl)benzamide,4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- V-((15, 25)-2 -hy droxy cy cl openty 1 )b enzami de, and4-((5)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,2A)-2-hydroxycyclopentyl)benzamide.

[0377] Embodiment 80: The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (P-I) is selected from the group consisting of:4-((A)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15,27?)-2-methylcyclopentyl)benzamide,4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,25)-2-methylcyclopentyl)benzamide,4-((R)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15, 25)-2 -m ethyl cy cl op enty 1 )b enzami de, 4-((R)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,2A)-2-methylcyclopentyl)benzamide,4-((5)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15,27?)-2-methylcyclopentyl)benzamide,4-((5)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,25’)-2-methylcyclopentyl)benzamide,4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15, 25)-2 -methyl cy cl op enty 1 )b enzami de, and4-((5)-2-(( ?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,27?)-2-methylcyclopentyl)benzamide.

[0378] Embodiment 82: A compound selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0379] Embodiment 83: A pharmaceutical composition comprising a compound of any one of Embodiments 1-82, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0380] Embodiment 84: A method of treating or suppressing cancer comprising administering a therapeutically effective amount of a compound of any one of Embodiments 1 to 82, or a1031105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 83, to a subject in need thereof.

[0381] Embodiment 85: The method of Embodiment 84, wherein the cancer is characterized by dysregulation of PI3K-alpha.

[0382] Embodiment 86: The method of Embodiment 85, wherein the dysregulation comprises increased activation or increased expression of PI3K-alpha.

[0383] Embodiment 87: The method of Embodiment 85, wherein the dysregulation is caused by increased activation or increased expression of a Receptor Tyrosine Kinase (RTK) family member.

[0384] Embodiment 88: The method of Embodiment 87, wherein the RTK is an EGFR, HER2, or HER3.

[0385] Embodiment 89: The method of Embodiment 84 or 85, wherein the cancer is characterized by mutant PI3K-alpha.

[0386] Embodiment 90: The method of Embodiment 89, wherein the mutant PI3K-alpha comprises one of more of the following mutations: N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0387] Embodiment 91 : The method of Embodiment 84, wherein the cancer is characterized by a dysregulated RAS protein.

[0388] Embodiment 92: The method of Embodiment 91, wherein the dysregulation is caused by a mutant RAS protein or increased expression of a RAS protein.

[0389] Embodiment 93 : The method of Embodiment 92, wherein the mutant RAS protein is mutant KRAS, NRAS, or HR AS

[0390] Embodiment 94: The method of Embodiment 92, wherein the mutant RAS protein is mutant KRAS.

[0391] Embodiment 95: The method of Embodiment 94, wherein the mutant KRAS contains one of more of the following mutations: G12D, G12V, G12C, G12A, G12S, G12R, G13D, G13C, Q61H, or A146T.

[0392] Embodiment 96: The method of Embodiment 92, wherein the cancer is characterized by increased expression of the RAS protein.1041105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0393] Embodiment 97: The method of any one of Embodiments 84-96, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, bladder, breast, and head and neck cancers.

[0394] Embodiment 98: The method of any one of Embodiments 84-96, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.

[0395] Embodiment 99: The method of any one of Embodiments 84-96, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

[0396] Embodiment 100: The method of any one of Embodiments 89-90 or 92-96, wherein the subject is treated before the subject is tested for the mutation.

[0397] Embodiment 101 : A method of identifying a patient population comprising testing the population for one or more of certain mutations in the KRAS protein or the PI3K-alpha protein, wherein the certain mutations in the KRAS protein are selected from the group consisting of G12D, G12V, G12C, G12A, G12S, G12R, G13D, G13C, Q61H, and A146T, and wherein the1051105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ certain mutations in the PI3K-alpha protein are selected from N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0398] Embodiment 102: The method of Embodiment 101, wherein the mutation is the G12C or G12D mutation in KRAS.

[0399] Embodiment 103: The method of Embodiment 101 or 102, wherein at least one patient from the patient population is treated with a compound of any one of claims 1 to 82, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 83.

[0400] Embodiment 104: A method of disrupting interaction between PI3K-alpha and a RAS protein in a cell, comprising contacting the cell with a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 83, in an amount effective to disrupt the interaction.

[0401] Embodiment 105: The method of Embodiment 104, wherein downstream signaling of the PI3K-alpha interaction with the RAS protein is altered.

[0402] Embodiment 106: A method of modulating the activity of PI3K-alpha in a cell, comprising contacting the cell with a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 83, in an amount effective to modulate the activity of PI3K-alpha.

[0403] Embodiment 107: A method of disrupting interaction between PI3K-alpha and RAS, comprising contacting PI3K-alpha with a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 83, in an amount effective to disrupt the interaction

[0404] Embodiment 108: The method of Embodiment 107, wherein the interaction is reduced by at least 25%.

[0405] Embodiment 109: The method of Embodiments 107 or 108, wherein the interaction is reduced by at least 50%.

[0406] Embodiment 110: The method of any one of Embodiments 107-109, wherein the interaction is reduced by at least 85%.

[0407] Embodiment 111 : The method of any one of Embodiments 107-110, wherein the interaction is measured by an AlphaScreen™ Protein-Protein Interaction Assay Protocol.1061105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0408] Embodiment 1 12: A method of covalently modifying PI3K-alpha comprising contacting PI3K-alpha with a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to Embodiment 83, in an amount effective to covalently modify PI3K-alpha.

[0409] Embodiment 113: The method of Embodiments 107 or 112, wherein PI3K-alpha is present in a cell.

[0410] Additional non-limiting embodiments of the present disclosure include:

[0411] Embodiment 1A: A compound of Formula (I):wherein:R1is N, C(R6), or CH;R2is a bond or -N(Ra)-;R3is -O-, -CH2-, -N(Ra)-, -S-, -S(O)-, or -S(O)2-; and R9is H or Ci-C4alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, - CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which they are attached form; when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the1071105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which they are attached form;R7in each instance is independently: -C(O)N(Ra)(Rn); Ci-Ce alkyl; Ci-Ce haloalkyl; Ci- C& heteroalkyl; Ci-Ce hydroxyalkyl; C2-C6 haloalkenyl; C3-C7 cycloalkyl; 4-12 membered heterocyclyl substituted with 0, 1, or 2 instances of -NRaR*; 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; oxo; halo; -ORd; - NRaRd; =N(Ra); -CN; -COOH; -C(O)O-Ci-C6alkyl; -C(O)-Ci-C6alkyl; -S(O)2N(Ra)(Re); - S(O)2-Ci-C6alkyl; -S(O)(=NRa)-Ci-C6alkyl; -S(O)(=NRa)NHRb; or -P(=O)(Ra)(Rb);R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, halo, or deutro-Ci-Ce alkyl;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Ce alkoxy; Ci- Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-C6 alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Ce heteroalkyl,1081105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ hydroxy, Ci-Cg hydroxyalkyl, -Ci-Ce heteroalkyl -hydroxy, or -NHC(O)-Ci-Ce alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(O)N(Rb)(Rc); -S(O)2N(Rb)(Rc); - S(O)2(Ra); -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; and -P(O)(CH3)2;Ring A is a 6-11 membered aryl, a 4-11 membered carbocyclyl or heterocyclyl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl;Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -Ci-C3alkylene- (6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); andR1in each instance is independently H, C1-C4 alkyl, or -C(O)-Ci-C4 alkyl; or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof.

[0412] Embodiment 2A: The compound of Embodiment 1A, wherein the compound of Formula (I) is whereinR1is N or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or C1-C4 alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to1091105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ which they are attached form; or two R present on the same atom taken together with the atom to which they are attached form & ; when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which& they are attached form ;R7in each instance is independently: Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, -NRaRd, =N(Ra), -CN, -COOH, -C(O)O-Ci-C6alkyl, -C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), -S(O)2N(Ra)(Re), -S(O)2-Ci-C6alkyl, -S(O)(=NH)-CI-C6alkyl, or - S(O)(=NRa)NHRb;R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, C3-C7 cycloalkyl, or halo;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene- (3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and - C(O)N(Rb)(Rc), or Ci-C6alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl;1101105079198\1\AMERICASAtorney Docket No.: 130238.00003 FM0040WQ wherein the Ca-Cs cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3- 12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-C6haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), -C(O)N(Rb)(Rc), -S(O)2N(Rb)(Rc), -S(O)2(Ra), -S(O)(=NRa)CH3, -S(O)(=NRa)NHRb, or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl; andRein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof.

[0413] Embodiment 3A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.I l l1105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0414] Embodiment 4A: The compound of any one of Embodiments 1 A-3A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted phenyl group.

[0415] Embodiment 5A: The compound of any one of Embodiments 1A-4A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is

[0416] Embodiment 61 A: The compound of any one of Embodiments 1A-5A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted 3 -methylphenyl group.

[0417] Embodiment 7A: The compound of any one of Embodiments 1A-3A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted pyridyl group.

[0418] Embodiment 8A: The compound of any one of Embodiments 1A-3A and 7A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted 5-methylpyridin-3-yl group.

[0419] Embodiment 9A: The compound of any one of Embodiments 1A-8A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted phenyl group.

[0420] Embodiment 10A: The compound of any one of Embodiments 1A-8A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted pyridyl group.

[0421] Embodiment 11A: The compound of any one of Embodiments 1A-8A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is1121105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0422] Embodiment 12A: The compound of any one of Embodiments 1A-8A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is selected from the group consisting of

[0423] Embodiment 13A: The compound of any one of Embodiments 1A-8A and 11A-12A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 3- fluoro-4-methylphenyl.

[0424] Embodiment 14A: The compound of any one of Embodiments 1A-8A and 11 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 3- fluoro-4-chlorophenyl .

[0425] Embodiment 15A: The compound of any one of Embodiments 1A-8A and 11A-12A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 3- tri fluoromethylphenyl .

[0426] Embodiment 16A: The compound of any one of Embodiments 1A-8A and 12A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 4- cyclopropyl-3 -fluorophenyl .

[0427] Embodiment 17A: The compound of any one of Embodiments 1A-8A and 12A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 4- cyclopropylphenyl.1131105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0428] Embodiment 18A: The compound of any one of Embodiments 1 A-8A and 11 A-12A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 5- cyclopropylpyridin-2-yl.

[0429] Embodiment 19A: The compound of any one of Embodiments 1 A-8A and 11 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 5- cyclopropyl-4-fluoro-pyridin-2-yl.

[0430] Embodiment 20A: The compound of any one of Embodiments 1A-8A and 11 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 5- ethyl-4-fluoro-pyridin-2-yl.

[0431] Embodiment 21 A: The compound of any one of Embodiments 1 A-8A and 11 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 5- methyl-4-fluoro-pyridin-2-yl.

[0432] Embodiment 22A: The compound of any one of Embodiments 1A-8A and 11A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is 5- methyl-pyridin-2-yl.

[0433] Embodiment 23A: The compound of any one of Embodiments 1A-22A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is O.

[0434] Embodiment 24A: The compound of any one of Embodiments 1A-22A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is N(Ra).

[0435] Embodiment 25 A: The compound of any one of Embodiments 1 A-22A and 24, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is H.

[0436] Embodiment 26A: The compound of any one of Embodiments 1 A-22A and 24A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is Me.

[0437] Embodiment 27A: The compound of any one of Embodiments 1A-26A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R9is H.

[0438] Embodiment 28A: The compound of any one of Embodiments 1 A-27A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond.1141105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0439] Embodiment 29A: The compound of any one of Embodiments 1 A-28A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R4and R5are H.

[0440] Embodiment 30A: The compound of any one of Embodiments 1 A-29A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N.

[0441] Embodiment 31 A: The compound of any one of Embodiments 1 A-29A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH.

[0442] Embodiment 32A: The compound of any one of Embodiments 1 A- 31A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R6is methyl and x is 1.

[0443] Embodiment 33A: The compound of any one of Embodiments 1 A-31 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein x is 2 and both R6groups are Me.

[0444] Embodiment 34A: The compound of any one of Embodiments 1A-33A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -C(O)N(Ra)(Rn).

[0445] Embodiment 35A: The compound of any one of Embodiments 1 A-34A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is - C(O)N(Ra)(Ru) and y is 1.

[0446] Embodiment 36A: The compound of any one of Embodiments 1 A-34A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2 and both R7are -C(O)N(Ra)(Rn).

[0447] Embodiment 37A: The compound of any one of Embodiments 1 A-34A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, one R7group is -C(O)N(Ra)(Rn), and the other R7group is Me.

[0448] Embodiment 38 A: The compound of any one of Embodiments 1 A-37 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 3 and at1151105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0449] Embodiment 39A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0450] Embodiment 40A: The compound of any one of Embodiments 1 A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0451] Embodiment 41 A: The compound of any one of Embodiments 1A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0452] Embodiment 42A: The compound of any one of Embodiments 1A-37A and 39 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1161105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0453] Embodiment 43 A: The compound of any one of Embodiments 1 A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one.

[0454] Embodiment 44A: The compound of any one of Embodiments 1A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0455] Embodiment 45A: The compound of any one of Embodiments 1A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0456] Embodiment 46A: The compound of any one of Embodiments 1 A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0457] Embodiment 47A: The compound of any one of Embodiments 1A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one.

[0458] Embodiment 48 A: The compound of any one of Embodiments 1A-37A and 39A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1171105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0459] Embodiment 49A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0460] Embodiment 50A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0461] Embodiment 51 A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1181105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0462] Embodiment 52A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0463] Embodiment 53A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0464] Embodiment 54A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0465] Embodiment 55A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0466] Embodiment 56A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0467] Embodiment 57A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1191105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0468] Embodiment 58A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one R11is methyl.

[0469] Embodiment 59A: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0470] Embodiment 60A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0471] Embodiment 61A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0472] Embodiment 62A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at1201105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0473] Embodiment 63A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0474] Embodiment 64A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0475] Embodiment 65A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1211105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0476] Embodiment 66A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0477] Embodiment 67A: The compound of any one of Embodiments 1A-37A and 62 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0478] Embodiment 68A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0479] Embodiment 69A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0480] Embodiment 70A: The compound of any one of Embodiments 1A-37A and 62 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1221105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0481] Embodiment 71 A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0482] Embodiment 72A: The compound of any one of Embodiments 1A-37A and 62 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is

[0483] Embodiment 73A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0484] Embodiment 74A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0485] Embodiment 75A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0486] Embodiment 76A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one1231105079198\1\AMERICASAtorney Docket No.: 130238.00003 FM0040WQ

[0487] Embodiment 77A: The compound of any one of Embodiments 1 A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0488] Embodiment 78A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at

[0489] Embodiment 79A: The compound of any one of Embodiments 1A-37A and 62A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein one or at least one

[0490] Embodiment 80A: The compound of any one of Embodiments 1 A-33A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -S(O)2NH2.

[0491] Embodiment 81A: The compound of any one of Embodiments 1A-33A and 80A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1 and R7is -S(O)2NH2.

[0492] Embodiment 82A: The compound of any one of Embodiments 1A-33A and 80A-81A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.1241105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0493] Embodiment 83 AA: The compound of any one of Embodiments 1 A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -C(O)NHMe.

[0494] Embodiment 84A: The compound of Embodiment 1A-37A or 83A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

[0495] Embodiment 85A: The compound of Embodiment 1A-37A or 83A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

[0496] Embodiment 86A: The compound of any one of Embodiments 1A-37A or 83A-84A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and y2 is 0, 1, or 2.

[0497] Embodiment 87A: The compound of any one of Embodiments 1A-37A, 83A and 85A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:1251105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ and y2 is 0, 1, or 2.

[0498] Embodiment 88 A: The compound of any one of Embodiments 1A-37A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0499] Embodiment 89A: The compound of any one of Embodiments 1A-37A, 83 A, 84A, 86A, and 88A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0500] Embodiment 90A: The compound of any one of Embodiments 1A-37A, 83A, 84A, 86A, 88A, and 89A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:

[0501] Embodiment 91A: The compound of any one of Embodiments 1A-37A, 83A, and 88A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A

[0502] Embodiment 92A: The compound of any one of Embodiments 1A-2A, 9A-22A, 27A- 34A, and 49A-61A or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue1261105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ thereof, wherein -R3-Ring A is selected from the group consistingthe attachment point of R3to the rest of the compound.

[0503] Embodiment 93A: The compound of any one of Embodiments 1A-2A, 9A-22A, 27A- 34A, 49A-61 A, and 92A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein -R3-Ringwhereinis the attachment point of R3to the rest of the compound.

[0504] Embodiment 94A: The compound of any one of Embodiments 1A-2A, 9A-22A, 27A- 34A, 49A-61A, and 92A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein -R3-Ringwherein •"~ is the attachment point of R3to the rest of the compound.

[0505] Embodiment 95A: The compound of any one of Embodiments 1A-2A, 9A-22A, 27A- 34A, 49A-61A, and 92A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein -R3-Ringwhereinis the attachment point of R3to the rest of the compound.1271105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0506] Embodiment 96A: The compound of any one of Embodiments 1 A-26A and 32A-92A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R3is NH, R4and R5are H, and R9is H.

[0507] Embodiment 97A: The compound of any one of Embodiments 1A-27A, 29A, 30A, and32A-96A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof,

[0508] Embodiment 98A: The compound of any one of Embodiments 1A-2A, 9A-31A, and97A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Ia):(P-la) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0509] Embodiment 99A: The compound of any one of Embodiments 1A-2A, 9A-31A, and 97A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (la):wherein R13is H or C1-C4 alkyl.

[0510] Embodiment 100A: The compound of Embodiment 98 A or 99A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H.1281105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0511] Embodiment 101 A: The compound of any one of Embodiments 98A-100 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R11is methyl.

[0512] Embodiment 102A: The compound of any one of Embodiments 98A-101A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H and R13is methyl.

[0513] Embodiment 103A: The compound of any one of Embodiments 99A-102A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R7is - C(O)NRaRn.

[0514] Embodiment 104A: The compound of any one of Embodiments 1A-2A, 9A-31A, and 97A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Ib):(P-lb)wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0515] Embodiment 105 A: The compound of Embodiment 104A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein both Raand Reare H.

[0516] Embodiment 106 A: The compound of Embodiment 104A or 105 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Rais H.

[0517] Embodiment 107A: The compound of any one of Embodiments 1A-2A, 9A-31A, and 97A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Ic):1291105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0518] Embodiment 108 A: The compound of any one of Embodiments 1A-107A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Id):

[0519] Embodiment 109 A: The compound of Embodiment 108 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring

[0520] Embodiment 110A: The compound of any one of Embodiments 1A-2A, 9A-31A, and 97A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Ie):wherein yl is 0, 1, 2, or 3.

[0521] Embodiment 111A: The compound of any one of Embodiments 1A-107A, and 110A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-If):1301105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0522] Embodiment 112A: The compound of any one of Embodiments 1A-111A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-Ig):

[0523] Embodiment 1 13 A: The compound of any one of Embodiments 1 A-2A and 9A-22A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-II):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0524] Embodiment 114A: The compound of any one of Embodiments 1A-2A and 9A-22A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (II):wherein R13is H or C1-C4 alkyl.

[0525] Embodiment 115A: The compound of Embodiment 113 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1.1311105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0526] Embodiment 1 16A: The compound of Embodiment 113 A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 2, and the remaining R7group is methyl.

[0527] Embodiment 117A: The compound of any one of Embodiments 113A-116A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein z is 2, one R8is methyl, and the other R8is fluoro.

[0528] Embodiment 118A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIal):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0529] Embodiment 119A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (Illal):wherein R13is H or C1-C4 alkyl.

[0530] Embodiment 120A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIa2):wherein R12is CH or N, and R13is H or C1-C4 alkyl.1321105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0531] Embodiment 121 A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (IIIa2):wherein R13is H or C1-C4 alkyl.

[0532] Embodiment 122A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIa3):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0533] Embodiment 123A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (IIIa3):wherein R13is H or C1-C4 alkyl.

[0534] Embodiment 124A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIa4):1331105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQwherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0535] Embodiment 125A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (IIIa4):wherein R13is H or C1-C4 alkyl.

[0536] Embodiment 126A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIa5):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0537] Embodiment 127A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (IIIa5):wherein R13is H or C1-C4 alkyl.1341105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0538] Embodiment 128A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIb 1):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0539] Embodiment 129A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIb2):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0540] Embodiment 130A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIb3):wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0541] Embodiment 131 A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIb4):1351105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ(P-lllb4)2 wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0542] Embodiment 132A: The compound of Embodiment 1A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIb5):(P-lllb5) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0543] Embodiment 133A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIcl):(P-IIIC1) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0544] Embodiment 134A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIc2):(P-lllc2) wherein R12is CH or N, and R13is H or C1-C4 alkyl.1361105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0545] Embodiment 135A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIc3):(P-lllc3) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0546] Embodiment 136A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIc4):(P-lllc4) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0547] Embodiment 137A: The compound of Embodiment 1 A or 2A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound of Formula (I) comprises a compound of Formula (P-IIIc5):(P-IIIC5) wherein R12is CH or N, and R13is H or C1-C4 alkyl.

[0548] Embodiment 138A: The compound of Embodiment 1A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the compound is selected from the group consisting of:4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-A-(5-cyano-3 - methylpyridin-2-yl)benzamide,1371105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3 -fluoro-4-methylphenyl)ethoxy)-Ar-(6- methoxypyridazin-3-yl)benzamide,4-(2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(5-cyclopropylpyridin-2-yl)ethoxy)-7V- methylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(6- methylpyridin-3-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fl iioro-4-methyl phenyl )ethoxy )-Ar|,6- dimethylisophthal amide,7V-(3Z / -2X2-benzo[d]isoxazol-6-yl)-4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-Arl, A'3, 6- trimethyl i sophthal ami de,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(5- hydroxypyrimidin-4-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4- methylphenyl)ethoxy)benzenesulfonamide,4-(2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-Ar-(3-oxo-3,4- dihydropyrazin-2-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-rV- methylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-((7?)-2-(4- chlorophenyl)-2-hydroxyethyl)-2-methylbenzamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 - methylpicolinamide,4-(2-((A)-4-acryloyl -3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )-2- oxoethoxy)benzenesulfonamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 - methylpyridine-2-sulfonamide,4-((2-((R)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)-2- oxoethy l)ami no)b enzene sulfonami de,1381105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-(( / ?)-4-acryloyl-3-methylpiperazin-l -yl)-l -(4-cyclopropylphenyl)ethoxy)-A'f- methy lb enzami de,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )-2-oxoethoxy )-7V-(( 1 - phenyl-5-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(( 1 -phenyl- 2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-(( 1 -phenyl-5-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-Ar-((l -methyl-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-A -(( 1 -methyl-3-(trifluoromethyl)-2X2-pyrazolidin-4-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(4- cyclopropylphenyl)ethoxy)benzenesulfonamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)pyridine-2- sulfonamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-A',2- dimethylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2- methylbenzamide,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 -methyl -A-(3-methyl-5-(methylsulfonyl)pyridin-2-yl)picolinamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-Ar-(4-(hydroxymethyl)tetrahydro-2 / / -pyran-4-yl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-A -(GS')-2- amino-2-oxo-l-phenylethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-A / -((7?)-2-(4- fluorophenyl)-2-hydroxyethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- l-yl)-l -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(2- hydroxycyclohexyl)benzamide,1391105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3 -fluoro-4-methylphenyl)ethoxy)-Ar-(2- hydroxycyclopentyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy )-A -(2- methylcyclopentyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-((7?)-2- hydroxy-2-(pyridin-3-yl)ethyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-2V-((7?)-2- hydroxy-l-phenylethyl)benzamide,5-(2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-Ar-((7?)-2- hydroxy-2-(pyridin-3-yl)ethyl)-3-methylpicolinamide,1 -((2J?)-4-(2 -((2-acetyl- 1,2,3, 4-tetrahy droisoquinolin-6-yl)oxy)-2-(3 -fluoro-4- methylphenyl)ethyl)-2-methylpiperazin- 1 -yl)prop-2-en- 1 -one, methyl 6-(2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-3,4- dihydroisoquinoline-2(7Z / )-carboxylate,5-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-3 -methyl -A- (3-methyl-5-(methylcarbamoyl)pyri din-2 -yl)picolinamide,5 -(2-((7?)-4-acryloyl -3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-m ethylphenyl )ethoxy)-Ar-(5-(dimethylcarbamoyl)-3-methylpyridin-2-yl)-3-methylpicolinamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -(trifluoromethyl)phenyl)ethoxy)benzenesulfonamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-JV-(((5)-5- oxopyrrolidin-2-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-Ar-(((7?)-5- oxopyrrolidin-2-yl)methyl)benzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -(trifluoromethyl)phenyl)ethoxy)-JV- methylbenzamide,4-(2-((7?)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -11 iioro-4-methyl phenyl )ethoxy)-A-(( ls,45)-4- fluorocyclohexyl)benzamide4-((2-((R)-4-acryloyl-3 -methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4- methylphenyl)ethyl)amino)benzenesulfonamide, and1401105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-(2-((37?,55)-4-acryloyl-3,5-dimethylpiperazin-l -yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-? / - methy lb enzami de .

[0549] Embodiment 139A: The compound of Embodiment 1A, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 4-((5)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15,25)-2-hydroxycyclohexyl)benzamide, 4-((5)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15,2A)-2-hydroxycyclohexyl)benzamide, 4-((5)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,25)-2-hydroxycyclohexyl)benzamide, 4-((S)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,27?)-2-hydroxycyclohexyl)benzamide,4-((7?)-2-((7?)-4-acry loyl-3 -methy Ipiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylpheny l)ethoxy)-A- ((15,25)-2-hydroxycyclohexyl)benzamide, 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,25)-2-hydroxycyclohexyl)benzamide, 4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((15,27?)-2-hydroxycyclohexyl)benzamide, and 4-((7?)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,2A)-2-hydroxycyclohexyl)benzamide.

[0550] Embodiment 140A: The compound of Embodiment 1A, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin- 1 -yl)- 1 -(3 -fluoro-4-methylphenyl)ethoxy)-A- ((15,27?)-2-hydroxycyclopentyl)benzamide, 4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,25)-2-hydroxycyclopentyl)benzamide, 4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A-((15, 2S)-2 -hy droxy cy cl openty 1 )b enzami de, 4-((7?)-2-((JR)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((lA,2A)-2-hydroxycyclopentyl)benzamide,1411105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ4-((S)-2-((7?)-4-acryloyl-3-methylpiperazin-l -yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A-((lS,27?)-2-hydroxycyclopentyl)benzamide,4-((S)-2-((S?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((17?,2S)-2-hydroxycyclopentyl)benzamide,4-((S)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((lS,2S)-2-hydroxycyclopentyl)benzamide, and4-((S)-2-(( ?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-A- ((17?,2 ?)-2-hydroxycyclopentyl)benzamide.

[0551] Embodiment 141 A: The compound of Embodiment 1A, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of:4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((lS,27?)-2-methylcyclopentyl)benzamide,4-((7?)-2-((JR)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((17?,2S)-2-methylcyclopentyl)benzamide,4-((7?)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)-7V-((IS, 2S)-2 -methyl cy cl op enty l)b enzami de,4-((A)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((1 ?,2A)-2-methylcyclopentyl)benzamide,4-((S)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-(( 1 S, 27?)-2-methyl cy clopentyl)benzamide,4-((S)-2-((7?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((17?,2S)-2-methylcyclopentyl)benzamide,4-((S)-2-((J?)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- / V-((IS, 2S)-2 -methyl cy cl op enty l)b enzami de, and4-((S)-2-((A)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)ethoxy)- V- ((l ?,27?)-2-methylcyclopentyl)benzamide.

[0552] Embodiment 142A: A compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof.

[0553] Embodiment 143A: A pharmaceutical composition comprising a compound of any one of Embodiments 1A-142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, and a pharmaceutically acceptable excipient.1421105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0554] Embodiment 144A: A method of treating or suppressing cancer comprising administering a therapeutically effective amount of a compound of any one of Embodiments 1A to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, to a subject in need thereof.

[0555] Embodiment 145A: The method of Embodiment 144A, wherein the cancer is characterized by dysregulation of PI3K-alpha.

[0556] Embodiment 146A: The method of Embodiment 145A, wherein the dysregulation comprises increased activation or increased expression of PI3K-alpha.

[0557] Embodiment 147A: The method of Embodiment 145A, wherein the dysregulation is caused by increased activation or increased expression of a Receptor Tyrosine Kinase (RTK) family member.

[0558] Embodiment 148 A: The method of Embodiment 147A, wherein the RTK is an EGFR, HERZ, or HER3

[0559] Embodiment 149A: The method of Embodiment 145A or 146A, wherein the cancer is characterized by mutant PI3K-alpha.

[0560] Embodiment 150A: The method of Embodiment 149A, wherein the mutant PI3K-alpha comprises one of more of the following mutations: N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0561] Embodiment 151A: The method of Embodiment 144A, wherein the cancer is characterized by a dysregulated RAS protein.

[0562] Embodiment 152A: The method of Embodiment 151A, wherein the dysregulation is caused by a mutant RAS protein or increased expression of a RAS protein.

[0563] Embodiment 153A: The method of Embodiment 152A, wherein the mutant RAS protein is mutant KRAS, NRAS, or HRAS.

[0564] Embodiment 154A: The method of Embodiment 152A, wherein the mutant RAS protein is mutant KRAS.

[0565] Embodiment 155A: The method of Embodiment 154A, wherein the mutant KRAS contains one of more of the following mutations: G12D, G12V, G12C, G12A, G12S, G12R, G13D, G13C, Q61H, or A146T.1431105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0566] Embodiment 156 A: The method of Embodiment 152A, wherein the cancer is characterized by increased expression of the RAS protein.

[0567] Embodiment 157A: The method of any one of Embodiments 144A-156A, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, bladder, breast, and head and neck cancers.

[0568] Embodiment 158A: The method of any one of Embodiments 144A-156A, wherein the cancer is selected from the group consisting of: lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, and bladder cancers.

[0569] Embodiment 159A: The method of any one of Embodiments 144A-156A, wherein the cancer is selected from the group consisting of: glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.

[0570] Embodiment 160A: The method of any one of Embodiments 149A-150A or 152A-156A, wherein the subject is treated before the subject is tested for the mutation.

[0571] Embodiment 161 A: A method of identifying a patient population treatable with a compound of any one of Embodiments 1 A to 142A, or a pharmaceutically acceptable salt,1441105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, comprising testing the population for one or more of certain mutations in the KRAS protein or the PI3K-alpha protein, wherein the certain mutations in the KRAS protein are selected from the group consisting of G12D, G12V, G12C, G12A, G12S, G12R, G13D, GI 3C, Q61H, and A146T, and wherein the certain mutations in the PI3K-alpha protein are selected from N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

[0572] Embodiment 162A: The method of Embodiment 161 A, wherein the mutation is the G12C or G12D mutation in KRAS.

[0573] Embodiment 163A: The method of Embodiment 161A or 162A, further comprising wherein at least one patient from the patient population is treated with a compound of any one of Embodiments lA to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A.

[0574] Embodiment 164A: A method of disrupting interaction between PI3K-alpha and a RAS protein in a cell, comprising contacting the cell with a compound of any one of Embodiments 1A to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, in an amount effective to disrupt the interaction.

[0575] Embodiment 165A: The method of Embodiment 164A, wherein downstream signaling of the PI3K-alpha interaction with the RAS protein is altered.

[0576] Embodiment 166A: A method of modulating the activity of PI3K-alpha in a cell, comprising contacting the cell with a compound of any one of Embodiments 1A to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, in an amount effective to modulate the activity of PI3K-alpha.

[0577] Embodiment 167A: A method of disrupting interaction between PI3K-alpha and RAS, comprising contacting PI3K-alpha with a compound of any one of Embodiments 1 A to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, in an amount effective to disrupt the interaction.1451105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0578] Embodiment 168A: The method of Embodiment 167A, wherein the interaction is reduced by at least 25%.

[0579] Embodiment 169A: The method of Embodiments 167A or 168A, wherein the interaction is reduced by at least 50%.

[0580] Embodiment 170A: The method of any one of Embodiments 167A-169A, wherein the interaction is reduced by at least 85%.

[0581] Embodiment 171A: The method of any one of Embodiments 167A-170A, wherein the interaction is measured by an AlphaScreen™ Protein-Protein Interaction Assay Protocol.

[0582] Embodiment 172A: A method of covalently modifying PI3K-alpha comprising contacting PI3K-alpha with a compound of any one of Embodiments 1A to 142A, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to Embodiment 143 A, in an amount effective to covalently modify PI3K- alpha.

[0583] Embodiment 173A: The method of Embodiments 167 A or 17A2, wherein PI3K-alpha is present in a cell.Compound Activity

[0584] The protein-protein interaction inhibition activity or protein-protein interaction enhancement activity of the compounds disclosed herein can be measured by the AlphaScreen™ Protein-Protein Interaction Assay Protocol described in the Example section herein. The AlphaScreen™ is an Amplified Luminescent Proximity Homogeneous Assay, that is, an assay that detects the proximity of two proteins to each other (a “protein proximity assay”). The screen compares the interaction of PI3Ka with KRASG12Cafter contacting PI3Ka with a compound as disclosed herein, versus the interaction of PI3Ka with KRASG12Cin the absence of contacting PI3Ka with a compound as disclosed herein. Interaction of the two tagged proteins binding to donor and acceptor beads brings the donor and acceptor beads in proximity, with subsequent emission of light from the acceptor bead. A decrease in the amount of emitted light after contacting PI3Ka with a compound as disclosed herein, versus in the absence of contacting PI3Ka with a compound as disclosed herein, indicates that protein-protein interaction of PI3Ka with KRASG12Chas been inhibited. An increase in the amount of emitted light after contacting PI3Ka with a compound as disclosed herein, versus in the absence of contacting PI3Ka with a1461105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ compound as disclosed herein, indicates that protein-protein interaction of PI3Ka with KRASG12Chas been enhanced.Methods For Treatment of Cancer

[0585] In one aspect, the present disclosure provides a method of treating or suppressing cancer comprising: administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopologue, or stereoisomer thereof, or a pharmaceutical formulation disclosed herein, to a subject in need thereof. In some embodiments, the method is for treating the cancer. In some embodiments, the method is for suppressing the cancer. The methods of treating or suppressing a cancer as described herein may further comprise administering to a subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0586] The compounds of Formula (I) or (P-I), and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, are useful for the treatment of cancer, which include but are not limited to, various types of cancer including e.g. lung, colorectal, pancreatic, ovarian, bile duct, thyroid, gall bladder, uterine, mesothelioma, cervical, bladder, breast, and head and neck cancers.

[0587] More particularly, cancers that may be treated by the compounds of Formula (I), and pharmaceutically acceptable salts and / or isotopologues thereof, including embodiments thereof disclosed herein, include, but are not limited to cancers such as glioblastoma multiforme, lower grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, esophageal carcinoma, stomach adenocarcinoma, small intestine adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, liver hepatocellular carcinoma, cholangiocarcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, kidney renal clear cell carcinoma, bladder urothelial carcinoma, prostate adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, cervical squamous carcinoma and endocervical adenocarcinoma, skin cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain lower grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, kidney chromophobe, kidney renal1471105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ papillary cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumors, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplastic, breast cancer, thyroid carcinoma, glioma, esophageal / stomach cancer, pediatric Wilms’ tumor, pediatric acute lymphoid leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, non-small cell lung cancer (NSCLC), and melanoma.Pharmaceutical Compositions

[0588] In general, the compounds of Formula (I) or (P-I), and pharmaceutically acceptable salts and / or isotopologues thereof, of this disclosure (also may be referred to herein as “compounds” or “compounds of this disclosure”) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.Therapeutically effective amounts of compounds of this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient. The actual amount of a compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0589] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic, transdermal, intranasal, by suppository, parenteral, intramuscular, intravenous or subcutaneous administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0590] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.1481105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0591] The compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0592] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0593] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0594] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the1491105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0595] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0596] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0597] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e. ., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0598] Certain compounds of the disclosure may be administered topically, that is by non- systemic administration. This includes the application of the compounds externally to the epidermis or the buccal cavity and the instillation of such compounds into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to e.g. oral, intravenous, intraperitoneal and intramuscular administration.

[0599] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation.

[0600] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the1501105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the disclosure may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20thed., 2000).

[0601] The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.Combinations and Combination Therapies

[0602] The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is contemplated. However, the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.

[0603] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of the present disclosure.

[0604] The above combinations include combinations of a compound of this disclosure not only with one other drug, but also with two or more other active drugs. Likewise, a compound of this disclosure may be used in combination with other drugs that are used in the prevention,1511105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of this disclosure is useful. Such other drugs may be administered contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, a therapeutically effective dose of each will be used.

[0605] Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of this disclosure in any combination with one or more other anti-cancer agents.

[0606] The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.EXAMPLES

[0607] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Abbreviations1521105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1531105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1541105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1551105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1561105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ1571105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQChromatography method LC-A

[0608] LCMS [Agilent 1290 Infinity II UHPLC System; Agilent C18 SB-Column; 100 A, 1.8 gm, 2.1 x 50 mm] (5% to 50% MeCN in H2O + 0.1% formic acid over 0.2 min, 0.5 mL / min then 50% to 100% MeCN in H2O + 0.1% formic acid over 2.8 min).1581105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQChromatography method LC-B

[0609] LCMS [Agilent 1290 Infinity II UHPLC System; Agilent C18 SB-Column; 100 A, 1.8 gm, 2.1 x 50 mm] (5% to 100% MeCN in H2O + 0.1% formic acid over 3 min, 0.5 mL / min).Chromatography method LC-C

[0610] LCMS [Agilent 1200 HPLC MSD:6120 single quadrupole MSD; XBridge C18,2.1*50mm, 5pm] (5% MeCN in H2O + lOmM NH4HCO3 hold for 0.4 min, 5% to 95% MeCN in H2O + lOmM NH4HCO3 over 3 min, 95% MeCN in H2O + lOmM NH4HCO3 hold for 0.45 min, 95% to 5% MeCN in H2O + lOmM NH4HCO3 over 0.01 min, 0.8 mL / min).Chromatography method LC-D

[0611] LCMS [Shimadzu LC-20AD MSD: LCMS-2020; Halo Cl 8, 3.0*30mm,5um] (5% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.4 min, 5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 2.6 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 1.00 min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-E

[0612] LCMS [Agilent 1200&6120; Halo C18, 3.0*30mm,5um] (5% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.4 min, 5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 2.6 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 1.00 min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-F

[0613] LCMS [Agilent 1200 HPLC MSD:6130 single quadrupole MSD; XBridge C18,2. l*50mm, 5pm] (5% MeCN in H2O + lOmM NH4HCO3 hold for 0.4 min, 5% to 95% MeCN in H2O + lOmM NH4HCO3 over 3 min, 95% MeCN in H2O + lOmM NH4HCO3 hold for 0.45 min, 95% to 5% MeCN in H2O + lOmM NH4HCO3 over 0.01 min, 0.8 mL / min).Chromatography method LC-G

[0614] LCMS [Agilent 1260 HPLC MSD:6120 single quadrupole MSD; Kinetex C18,2.1*50mm, 5pm] (5% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.4 min, 5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 2.6 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 1.0 min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).1591105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQChromatography method LC-H

[0615] LCMS [Agilent 1200 HPLC MSD:6120 single quadrupole MSD; XBridge C18,2.1*50mm, 5pm] (5% to 95% MeCN in H2O + lOmM NH4HCO3 over 3.4 min, 95% MeCN in H2O + lOmM NH4HCO3 hold for 0.45 min, 95% to 5% MeCN in H2O + lOmM NH4HCO3 over 0.01 min, 0.8 mL / min).Chromatography method LC-I

[0616] LCMS [Agilent 1260 HPLC MSD:6120 single quadrupole MSD; Luna C18,2.0*50mm, 5pm] (5% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.4 min, 5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 2.6 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 1.0 min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-J

[0617] LCMS [Agilent 1260 HPLC MSD:6125B single quadrupole MSD; Xbridge C18,2.1*50mm, 5pm] (5% MeCN in H2O + lOmM NH4HCO3 hold for 0.39 min, 5% to 95% MeCN in H2O + lOmM NH4HCO3 over 3 min, 95% MeCN in H2O + lOmM NH4HCO3 hold for 0.45 min, 95% to 5% MeCN in H2O + lOmM NH4HCO3 over 0.01 min, 0.8 mL / min).Chromatography method LC-K

[0618] LCMS [Agilent 1260 HPLC MSD:6125B single quadrupole MSD; Luna C18,2.0*50mm, 5pm] (5% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.39 min, 5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 2.6 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 1.0 min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-L

[0619] LCMS [Agilent 1260\G6125B; Agilent ChemStation Rev. C. 01.10

[0201] ; ZORBAX SB- 018 2.1x50mm 1.8um 600Bar] (10% to 80% MeCN + 0.02% TFA in H2O + 0.04% TFA over 4.8 min, 0.7mL / min, 80% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.6 min, 80% to 10% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-M

[0620] LCMS [Agilent 1260\G6125B; Agilent ChemStation Rev. C. 01.10

[0201] ; ZORBAX SB- 08 2.1x50mm 1.8um 600Bar] (0% to 60% MeCN + 0.02% TFA in H2O + 0.04% TFA over 4.81601105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ min, 0.7mL / min, 60% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.6 min, 60% to 0% MeCN + 0.02% TFA in H20 + 0.04% TFA over 0.01 min, 1.0 mL / min).Chromatography method LC-N

[0621] LCMS [SHIMADZU LC-20AD; Labsolution Version 5.98; Kinetex C18 LC Column 3.0X50mm, 2.6um] (10% to 80% MeCN + 0.02% TFA in H2O + 0.04% TFA over 5 min, 80% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.7 min, 0.6mL / min, 80% to 10% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.2 mL / min).Chromatography method LC-O

[0622] LCMS [SHIMADZU LCMS-2020; LabSolution Version 5.109; Kinetex® EVO C18 3.0x50mm 2.6um] (5% to 95% MeCN + 0.02% TFA in H2O + 0.04% TFA over 3.4 min, 95% MeCN + 0.02% TFA in H2O + 0.04% TFA hold for 0.3 min, 0.9 mL / min, 95% to 5% MeCN + 0.02% TFA in H2O + 0.04% TFA over 0.01 min, 1.2 mL / min).Chromatography method LC-P

[0623] LCMS [Agilent 1290 Infinity II UHPLC System; Poroshell 120 EC-C18 Column; 120 A, 1.9 pm, 2.1 x 50 mm] (10% to 100% MeCN in H2O + 0.1% formic acid over 2.0 min, then 100% MeCN + 0.1% formic acid over 0.5 min, then 10% MeCN in H2O + 0.1% formic acid over 0.5 min, 0.5 mL / min).Chromatography method LC-Q

[0624] LCMS [Agilent 1290 Infinity II UHPLC System; Poroshell 120 EC-C18 Column; 120 A, 1.9 pm, 2.1 x 50 mm] (10% to 100% MeCN in H2O + 0.1% formic acid over 0.7 min, then 100% MeCN + 0.1% formic acid over 0.2 min, then 10% MeCN in H2O + 0.1% formic acid over 0.1 min, 1.0 mL / min).General method FS

[0625] In a 2-dram scintillation vial, HATU (1.1 eq) and benzoic acid (1.0 eq) were dissolved in DMF (0.05 M with respect to the benzoic acid) and amine (0.9 eq) followed by DIPEA (3.0 eq) were added to the reaction. The reaction was allowed to stir for 15 minutes The reaction mixture was purified by reversed-phase chromatography (water / MeCN with 0.1% trifluoroacetic acid) to deliver the title compound.General method JC1

[0626] In a 2-dram scintillation vial, HATU (1.1 eq) and benzoic acid (1.2 eq) were dissolved in DMF (0.15 M with respect to the benzoic acid) and DIPEA (4.0 eq if amine free base, 5.0 eq if1611105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ amine is HC1 salt, or 6.0 eq if amine bis-HCl salt) followed by amine (1 .0 eq) were added to the reaction. The reaction was allowed to stir for 15 minutes to 3 hours upon which time the reaction was diluted with EtOAc such that it approximately half-filled the 2-dram vial. The reaction was then washed aqueous ammonium chloride followed by aqueous sodium carbonate and sodium chloride. The organic phase was filtered through a pad of sodium sulfate and concentrated on a rotovap. The crude material was then purified by normal-phase chromatography (DCM / MeOH) to deliver the title compound.General method JC2

[0627] Following normal-phase chromatography in general method JC1, the residue was further purified by reversed-phase chromatography (water / MeCN with 0.1% formic acid) to deliver the title compound.General method JC3

[0628] In a 2-dram scintillation vial, HATU (1.2 eq) and benzoic acid (1.0 eq) were dissolved in DMF (0.15 M with respect to the benzoic acid) and DIPEA (3.0 eq if amine free base, 5.0 eq if amine is HC1 or bis-HCl salt) followed by amine (1.5 eq) were added to the reaction. The reaction was allowed to stir for 15 minutes to 3 hours upon which time the reaction was diluted with EtOAc such that it approximately half-filled the 2-dram vial. The reaction was then washed aqueous ammonium chloride followed by aqueous sodium carbonate and sodium chloride. The organic phase was filtered through a pad of sodium sulfate and concentrated on a rotovap. The crude material was then purified by normal-phase chromatography (DCM / MeOH) to deliver the title compound.General method JC4

[0629] Following normal-phase chromatography in general method JC3, the residue was further purified by reversed-phase chromatography (water / MeCN with 0.1% formic acid) to deliver the title compound.General method JC5

[0630] In a 2-dram scintillation vial, HATU (1.2 eq) and benzoic acid (1.0 eq) were dissolved in DMF (0.15 M with respect to the benzoic acid) and DIPEA (3.0 eq if amine free base, 5.0 eq if amine is HC1 or bis-HCl salt) followed by amine (6.0 eq) were added to the reaction. The reaction was allowed to stir at 45 °C to 60 °C for 12 to 20 hours upon which time the reaction was diluted with EtOAc such that it approximately half-filled the 2-dram vial. The reaction was1621105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ then washed aqueous ammonium chloride followed by aqueous sodium carbonate and sodium chloride. The organic phase was filtered through a pad of sodium sulfate and concentrated on a rotovap. The crude material was then purified by normal-phase chromatography (DCM / MeOH) to deliver the title compound.General method JC6

[0631] Following normal-phase chromatography in general method JC5, the residue was further purified by reversed-phase chromatography (water / MeCN with 0.1% formic acid) to deliver the title compound.General method JC7

[0632] In a 2-dram scintillation vial, DMC (2.0 eq) and benzoic acid (1.0 eq) were dissolved in THF (0.15 M with respect to the benzoic acid) and DIPEA (5.0 eq) followed by amine (5.0 eq) were added to the reaction. The reaction was allowed to stir at 45 °C to 60 °C for 12 to 20 hours upon which time the reaction was quenched with IM aqueous sodium carbonate. The reaction was then extracted with DCM, the organic phase was filtered through a pad of sodium sulfate and then concentrated on a rotovap. The crude material was then purified by normal-phase chromatography (DCM / MeOH) to deliver the title compound.General method JC8

[0633] Following normal-phase chromatography in general method JC7, the residue was further purified by reversed-phase chromatography (water / MeCN with 0.1% formic acid) to deliver the title compound.1631105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQMethod 1A: Route for INTERMEDIATE 1 J and INTERMEDIATE IKExperimental DetailsSynthesis of ethyl 2-(3-fluoro-4-methylphenyl)-2-hydroxyacetate

[0634] To a solution of 1A (40.0 g, 190.29 mmol, 1 eq) in THF (600 mL) was added NaBH4 (7.20 g, 190.29 mmol, 1 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was poured into NH4CI (500 mL) under N2, then extracted with EtOAc (500 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to give title compound (40.0 g, crude) as a yellow oil. The intermediate was used in the next step without further purification.

[0635] ‘HNMR (400 MHz, DMSO) 5 7.29 - 7.20 (m, 1H), 7.17 - 7.10 (m, 2H), 6.12 (d, J = 5.5 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.14 - 3.98 (m, 2H), 2.21 (d, J = 1.4 Hz, 3H), 1.16 - 1.08 (m, 3H)1641105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQSynthesis of ethyl 2-chloro-2-(3-fluoro-4-methylphenyl) acetate

[0636] A solution of IB (40.0 g, 188.49 mmol, 1 eq) in SOCI2 (130 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was allowed to room temperature, poured into H2O (500 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to give title compound (43.0 g, crude) was obtained as a yellow oil. The intermediate was used in the next step without further purification.Synthesis of tert-butyl 4-(2-ethoxy-l-(3-fluoro-4-methylphenyl)-2-oxoethoxy)benzoate

[0637] To a solution of 1C (42.75 g, 185.35 mmol, 1.5 eq), 1C (24.0 g, 123.57 mmol, 1 eq) in ACN (500 mL) was added K2CO3 (34.16 g, 247.13 mmol, 2 eq) and KI (4.10 g, 24.71 mmol, 0.2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was poured into H2O (300 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The mixture was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 10 to give title compound (37.0 g, 95.26 mmol, 77.1% yield) was obtained as yellow oil.

[0638] 'H NMR (400 MHz, DMSO) 5 7.84 (d, J = 8.9 Hz, 2H), 7.38 - 7.25 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H), 6.13 (s, 1H), 4.20 - 4.06 (m, 2H), 2.23 (d, J = 0.8 Hz, 3H), 1.51 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H).Synthesis of 2-(4-(tert-butoxycarbonyl)phenoxy)-2-(3-fluoro-4-methylphenyl)acetic acid.

[0639] To a solution of ID (36.0 g, 92.68 mmol, 1 eq) in THF (360 mL) and H2O (360 mL) was added LiOH.H2O (7.78 g, 185.36 mmol, 2 eq). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was added HC1 (IM) to adjust pH = 2 and extracted with EtOAc (300 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and filtrate was concentrated to give title compound (33.0 g, crude) was obtained as a yellow oil. The intermediate was used in the next step without further purification.

[0640] ‘HNMR (400 MHz, DMSO) 8 13.38 (br s, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.38 - 7.25 (m, 3H), 7.05 (d, J = 9.0 Hz, 2H), 5.98 (s, 1H), 2.23 (s, 3H), 1.52 (s, 9H)Synthesis of tert-butyl (2R)-4-(2-(4-(tert-butoxycarbonyl)phenoxy)-2-(3-fluoro-4- methylphenyl)acetyl)-2-methylpiperazine-l-carboxylate.

[0641] To a solution of IE (18.0 g, 49.95 mmol, 1 eq) in DMF (360 mL) was IE' (10.0 g, 49.95 mmol, 1 eq), HATU (28.49 g, 74.92 mmol, 1.5 eq) and DIEA (19.37 g, 149.84 mmol, 26.10 mL,1651105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (500 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were washed with brine (500 mL * 3) and dried over Na2SC>4, fdtered, and concentrated under vacuum to give a residue. The mixture was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 0 to give title compound (15.0 g, 27.64 mmol, 55.34% yield) as a yellow solid.

[0642] 1H NMR (400 MHz, CDCh) 8 8.01 - 7.92 (m, 2H), 7.27 - 6.99 (m, 5H), 6.02 - 5.86 (m, 1H), 4.48 - 3.56 (m, 4H), 3.26 - 2.35 (m, 3H), 2.30 (br d, J = 4.9 Hz, 3H), 1.61 - 1.40 (m, 21H) Synthesis of tert-butyl (2R)-4-(2-(4-(tert-butoxycarbonyl)phenoxy)-2-(3-fluoro-4- methylphenyl)ethyl)-2-methylpiperazine-l-carboxylate.

[0643] A solution of IF (15.0 g, 27.64 mmol, 1 eq) in THF (150 mL) was added BH3.THF (1 M, 138.21 mL, 5 eq) under N2. The mixture was stirred at 70 °C for 2 h under N2. MeOH (50 mL) was added to the mixture under N2, and stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give title compound (15.0 g, crude) as a yellow oil. The intermediate was used in the next step without further purification.Synthesis of 4-(l-(3-fluoro-4-methylphenyl)-2-((R)-3-methylpiperazin-l-yl)ethoxy)benzoic acid.

[0644] A solution of 1G (15.0 g, 28.37 mmol, 1 eq) in HCl / EtOAc (150 mL, 4M) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give title compound (12.0 g, crude, HC1 salt) as a white solid. The intermediate was used in the next step without further purification.Synthesis of 4-(2-((R)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)benzoic acid.

[0645] To a solution of 1H (5.5 g, 13.45 mmol, 1 eq, HC1 salt) in THF (100 mL) and H2O (25.0 mL) was added NaHCCh (5.65 g, 67.25 mmol, 5 eq) and 1H' (2.43 g, 26.90 mmol, 2.19 mL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was removed THF under N2 to give a residue. The residue was purified by prep-HPLC (column: Agela DuraShell C18 250*70mm*10um; mobile phase: [H2O (lOmM NH4HCO3) -ACN]; gradient: 15%-45% B over 17.0 min) to give title compound (5.5 g, 12.55 mmol, 46.7% yield,) as a yellow solid.1661105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQSynthesis of 4-((S)-2-((R)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4- methylphenyl)ethoxy)benzoic acid and 4-((R)-2-((R)-4-acryloyI-3-methylpiperazin-l-yl)-l- (3-fluoro-4-methylphenyl)ethoxy)benzoic acid, Intermediate 1 J, Intermediate IK.

[0646] Compound II (5.5 g, 12.55 mmol, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALCEL OZ 250*50 mm I D. lOum; mobile phase: [CO2-MeOH (0.1%NH3H2O)];B%:55%, isocratic elution mode) to give INTERMEDIATE 1J (1.37 g, 3.12 mmol, 24.2% yield, Peak 1) (Rt = 2.486 min in SFC) as a white solid and INTERMEDIATE IK (1.88 g, 4.22 mmol, 32.7% yield, Peak 2) (Rt = 2.847 min in SFC) as a white solid. These two isomers were assigned arbitrarily.INTERMEDIATE 1J

[0647] ‘HNMR (400 MHz, DMSO) 5 12.57 (s, 1H), 7.79 (d, J= 8.6 Hz, 2H), 7.28 - 7.14 (m, 3H), 7.01 (d, J= 8.8 Hz, 2H), 6.75 (dd, J= 16.7, 10.5 Hz, 1H), 6.07 (dd, J= 16.7, 2.4 Hz, 1H), 5.69 - 5.57 (m, 2H), 4.65 - 3.65 (m, 2H), 3.50 - 2.56 (m, 5H), 2.30 - 2.14 (m, 4H), 2.14 - 2.02 (m, 1H), 1.14 - 0.97 (m, 3H). LCMS m / z = 427.2 [M + H]1, Rt = 2.270 min.INTERMEDIATE IK

[0648] 'H NMR (400 MHz, DMSO) 5 12.46 (s, 1H), 7.84 - 7.73 (m, 2H), 7.29 - 7.13 (m, 3H), 7.05 - 6.96 (m, 2H), 6.83 - 6.68 (m, 1H), 6.11 - 6.02 (m, 1H), 5.68 - 5.58 (m, 2H), 4.73 - 3.67 (m, 2H), 3.50 - 2.63 (m, 5H), 2.30 - 2.14 (m, 4H), 2.14 - 2.00 (m, 1H), 1.20 - 1.03 (m,3H). LCMS m / z = 427.1 [M + H]+, Rt = 2.306 min.Method IB: Route for INTERMEDIATE 2D and Intermediate INTERMEDIATE 2E1671105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQExperimental DetailsSynthesis of ethyl 2-(3-fluoro-4-methylphenyl)-2-(4-(methylcarbamoyl)phenoxy)acetate.

[0649] To a solution of 1C (12.6 g, 54.6 mmol, 1.5 eq) in MeCN (250 mL) was added 2A’, (5.5 g, 36.4 mmol, 1 eq), K2CO3 (10.06 g, 72.77 mmol, 2 eq) and KI (1.21 g, 7.28 mmol, 0.2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-48% Ethyl acetate / Petroleum ethergradient @ 150 mL / min) to give title compound (14.7 g, crude) was obtained as a white solid.

[0650] 'H NMR (400 MHz, DMSO) 3 8.28 (br d, J= 4.5 Hz, 1H), 7.78 (d, J= 8.8 Hz, 2H), 7.39- 7.23 (m, 3H), 7.03 (d, J= 8.9 Hz, 2H), 6.10 (s, 1H), 4.22 - 4.06 (m, 2H), 2.75 (d, J= 4.5 Hz, 3H), 2.23 (d, J= 1.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H).Synthesis of 4-(l-(3-fluoro-4-methylphenyl)-2-hydroxyethoxy)-N-methylbenzamide.

[0651] To a solution of 2A (14.7 g, 42.5 mmol, 1 eq) in THF (150 mL) was added LiBH4 (2 M, 21.3 mL, 1 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into NH4CI (60 mL) and extracted with EtOAc (20 mL * 3), the combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give title compound (14 g, crude) was obtained as a white solid. The intermediate was used in the next step without further purification.

[0652] 'H NMR (400 MHz, CDCI3) 3 8.20 (br d, J= 4.5 Hz, 1H), 7.69 (d, J= 8.9 Hz, 2H), 7.27 - 7.19 (m, 1H), 7.18 - 7.11 (m, 2H), 6.95 (d, .7 = 8.8 Hz, 2H), 5.39 (dd, .7= 3.9, 7.1 Hz, 1H), 5.16 (t, J= 5.8 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.68 - 3.56 (m, 1H), 2.72 (d, J= 4.4 Hz, 3H), 2.17 (s, 3H).Synthesis of 2-(3-fluoro-4-methylphenyl)-2-(4-(methylcarbamoyl)phenoxy)ethyl methanesulfonate.

[0653] To a solution of 2B (21.0 g, 69.2 mmol, 1 eq) in DCM (420 mL) was added TEA (21.0 g, 207 mmol, 28.9 mL, 3 eq) and MsCl (15.9 g, 138 mmol, 10.7 mL, 2 eq) at 0°C. The mixture was stirred at 0°C for 2 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-55% Ethyl1681105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ acetate / Petroleum ethergradient @ 150 mL / min) to give title compound (14.6 g, 36.8 mmol, 53.2% yield) was obtained as a white solid.

[0654] 'H NMR (400 MHz, DMSO) 6 8.23 (q, J = 4.1 Hz, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.26 - 7.20 (m, 1H), 7.02 - 6.96 (m, 2H), 5.80 (dd, J = 3.1, 7.3 Hz, 1H), 4.58 - 4.45 (m, 2H), 3.22 (s, 3H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (d, J = 1.1 Hz, 3H)Synthesis of (R)-2-(3-fluoro-4-methylphenyl)-2-(4-(methylcarbamoyl)phenoxy)ethyl methanesulfonate and (S)-2-(3-fluoro-4-methylphenyl)-2-(4- (methylcarbamoyl)phenoxy)ethyl methanesulfonate.

[0655] Compound 2C (14.6 g, 36.8 mmol, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALCEL OZ 250*50 mm I D. lOum; mobile phase: [CCh-EtOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode) to give INTERMEDIATE 2D (6.30 g, 16.1 mmol, 32.3% yield, Peak 1) (Rt = 2.134 min in SFC) as a white solid and INTERMEDIATE 2E (6.10 g, 15.6 mmol, 31.4% yield, Peak 2) (Rt = 3.021 min in SFC) as a white solid. These two isomers were assigned arbitrarily.INTERMEDIATE 2D

[0656] 'H NMR (400 MHz, DMSO) 5 8.23 (q, J = 4.1 Hz, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.35 - 7.19 (m, 3H), 6.99 (d, J = 8.9 Hz, 2H), 5.80 (dd, J = 3.1, 7.3 Hz, 1H), 4.60 - 4.44 (m, 2H), 3.22 (s, 3H), 2.73 (d, J = 4.5 Hz, 3H), 2.19 (d, J = 1.0 Hz, 3H) LCMS m / z = 382.2 [M + H]+, Rt = 1.914 min.INTERMEDIATE 2E

[0657] XH NMR (400 MHz, DMSO) 5 8.24 (q, J = 4.1 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.35 - 7.19 (m, 3H), 7.00 (d, J = 8.9 Hz, 2H), 5.80 (dd, J = 3.1, 7.3 Hz, 1H), 4.59 - 4.44 (m, 2H), 3.23 (s, 3H), 2.73 (d, J = 4.5 Hz, 3H), 2.19 (d, J = 1.0 Hz, 3H) LCMS m / z = 382.2 [M + H]+, Rt = 1.902 min.1691105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQMethod 1C: Route for Intermediate 4F and Intermediate 4F’Experimental DetailsSynthesis of methyl 2-bromo-2-(3-fluoro-4-methylphenyl)acetate

[0658] To a solution of Compound 4A (8 g, 43.91 mmol, 1 eq) in CCI4 (80 mL) were added NBS (11.72 g, 65.86 mmol, 1.5 eq and HBr (1.08 g, 4.39 mmol, 722.56 pL, 33% purity, 0.1 eq) at 25 °C. The mixture was stirred at 80 °C for 4 h under N2 atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give title compound (8.5 g, crude) as a light-yellow oil. The intermediate was used in the next step without further purification.Synthesis of methyl 2-(3-fluoro-4-methylphenyl)-2-((4-iodophenyl)amino)acetate

[0659] To a solution of Compound 4B (8.5 g, 32.56 mmol, 1 eq) in DMF (80 mL) were added DIPEA (8.42 g, 65.11 mmol, 11.34 mL, 2 eq) and 4-iodoaniline (8.56 g, 39.07 mmol, 1.2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with brine (50 mL * 3), dried over ISfeSCL, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether, gradient @ 85 mL / min) to1701105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ give title compound (2.1 g, 4.57 mmol, 14.0% yield) as a yellow solid. LCMS m / z = 399.8 [M + H]+Synthesis of 2-(3-fluoro-4-methylphenyl)-2-((4-iodophenyl)amino)acetic acid

[0660] To a solution of Compound 4C (2.1 g, 5.26 mmol, 1 eq) in THF (10 mL) was added NaOH (2 M, 10 mL, 3.80 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h under N2 atmosphere. H2O (30 mL) was added, the reaction mixture was acidified with HC1 (1 M) to pH = 2, and extracted with EtOAc (40 mL * 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give title compound (2.03 g, crude) as a yellow solid. The intermediate was used in the next step without further purification. LCMS m / z = 385.7 [M + H]+Synthesis of tert-butyl (2R)-4-(2-(3-fluoro-4-methylphenyl)-2-((4-iodophenyl)amino)acetyl)- 2-methylpiperazine-l-carboxylate

[0661] To a solution of Compound 4D (2 g, 5.19 mmol, 1 eq) in DMF (20 mL) were added DIPEA (1.34 g, 10.38 mmol, 1.81 mL, 2 eq), HATU (2.96 g, 7.79 mmol, 1.5 eq) and tert-butyl (2R)-2 -m ethylpiperazine- 1 -carboxylate (1.25 g, 6.23 mmol, 1.2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether, gradient @ 85 mL / min) to give title compound (1.98 g, 3.34 mmol, 64.3% yield) as a yellow solid. LCMS m / z = 568.2 [M + H]+Synthesis of tert-butyl (R)-4-((R)-2-(3-fluoro-4-methylphenyl)-2-((4- iodophenyl)amino)acetyl)-2-methylpiperazine-l-carboxylate and tert-butyl (R)-4-((S)-2-(3- fluoro-4-methylphenyl)-2-((4-iodophenyl)amino)acetyl)-2-methylpiperazine-l-carboxylate

[0662] Compound 4E (1.75 g, 3.08 mmol, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CO2- MeOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode) to give Compound 4F (722 mg, 1.27 mmol, 41.3% yield, Peak 1) (Rt = 1.830 min in SFC) as a light-yellow solid and Compound 4F’ (693 mg, 1.22 mmol, 39.6% yield, Peak 2) (Rt = 2.055 min in SFC) as a light-yellow solid. These two isomers were assigned arbitrarily.1711105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQMethod 2A: Route for Example 1Experimental DetailsSynthesis of tert-butyl (R)-4-((R)-2-(3-fluoro-4-methylphenyl)-2-((4- (methylcarbamoyl)phenyl)amino)acetyl)-2-methylpiperazine-l-carboxylate

[0663] A mixture of Intermediate 4F (50 mg, 88.12 pmol, 1 eq), MeNH2 (7.14 mg, 105.74 pmol, 1.2 eq), Pd(OAc)2 (395.66 pg, 1.76 pmol, 0.02 eq), Xantphos (1.02 mg, 1.76 pmol, 0.02 eq) and Na2CO3 (23.35 mg, 220.29 pmol, 2.5 eq) in toluene (2 mL) was degassed and purged with CO for 3 times at 25 °C, and then the mixture was stirred at 80 °C for 6 h under CO (50 psi) atmosphere. The mixture was fdtered and the filtrate was concentrated under reduced pressure to give title compound (65 mg, crude) as a brown solid. The intermediate was used in the next step without further purification. LCMS m / z = 499.2 [M + H]+Synthesis of 4-(((R)-l-(3-fluoro-4-methylphenyl)-2-((R)-3-methyIpiperazin-l-yl)-2- oxoethyl)amino)-N-methylbenzamide

[0664] A solution of Compound 4G (50 mg, 100.28 pmol, 1 eq) in HCl / EtOAc (5 mL, 4 M) was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give title compound (50 mg, crude, HC1 salt) as a brown solid. The intermediate was used in the next step without further purification. LCMS m / z = 399.0 [M + H]+Synthesis of 4-(((R)-2-((R)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)- 2-oxoethyl)amino)-N-methylbenzamide, Example 11721105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ

[0665] To a solution of Compound 4H (50 mg, 114.96 pmol, 1 eq, HC1 salt) in THF (3 mL) was added NaHCCL (28.97 mg, 344.88 pmol, 13.42 pL, 3 eq) in H2O (1 mL) at 25 °C, the mixture was stirred at this temperature for 30 min, and then prop-2-enoyl chloride (12.49 mg, 137.95 pmol, 11.21 pL, 1.2 eq) in THF (3 mL) was added dropwise at 0 °C. The mixture was stirred at0 °C for 30 min. The reaction mixture was diluted with H2O (8 mL) and extracted with EtOAc (5 mL * 4). The combined organic layers were washed with brine (10 mL), dried over Na SO4, filtered and concentrated under reduced pressure. The residue was purified by prep - HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [water (FA) - MeCN]; gradient: 20% - 50% B over 10 min) to give Example 1 (7.81 mg, 16.94 pmol, 14.7% yield) as a white amorphous solid. 1H NMR (400 MHz, DMSO ) 8 8.00 - 7.92 (m, 1H), 7.58 - 7.51 (m, 2H), 7.38 - 7.20 (m, 3H), 6.80 - 6.62 (m, 4H), 6.14 - 6.03 (m, 1H), 5.77 - 5.62 (m, 2H), 4.73 - 3.70 (m, 4H), 3.38 - 3.15 (m, 2H), 2.99 - 2.65 (m, 4H), 2.21 - 2.15 (m, 3H), 1.27 - 0.67 (m, 3H).

[0666] LCMS m / z = 453.3 [M + H] ' , Rt = 2.872 min. (Method LC-L)Route for Example 2Synthesis of 4-(((S)-2-((R)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)- 2-oxoethyl)amino)-N-methylbenzamide, Example 2

[0667] The preparation of Example 2 followed method 2A for the synthesis, using Intermediate 4F’. 1H NMR (400 MHz, DMSO-tL) 8 8.00 - 7.93 (m, 1H), 7.60 - 7.50 (m, 2H), 7.35 - 7.20 (m, 3H), 6.82 - 6.68 (m, 3H), 6.67 - 6.61 (m, 1H), 6.10 (d, J= 16.5 Hz, 1H), 5.83 -1731105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ5.55 (tn, 2H), 4.74 - 3.79 (m, 4H), 3.56 - 3.45 (tn, 1H), 2.98 - 2.75 (m, 2H), 2.70 (d, J= 4.4 Hz, 3H), 2.21 - 2.14 (m, 3H), 1.11 - 0.62 (m, 3H). LCMS m / z = 453.3 [M + H]+, Rt = 2.885 min. (Method LC-L)Method 3A: Route for Example 3Experimental DetailsSynthesis of tert-butyl (R)-4-((R)-2-((4-carbamoylphenyl)amino)-2-(3-fluoro-4- methylphenyl)acetyl)-2-methylpiperazine-l-carboxylate

[0668] To a solution of Intermediate 4F (150 mg, 264.35 pmol, 1 eq in toluene (0.5 mL) were added NH3.H2O (49.63 mg, 396.52 pmol, 54.54 pL, 1.5 eq), Na2CO3(42.03 mg, 396.52 pmol, 1.5 eq), Xantphos (3.06 mg, 5.29 pmol, 0.02 eq) and Pd(OAc)2(1.19 mg, 5.29 pmol, 0.02 eq at 25 °C and the mixture was degassed and purged with under Argon for 3 times. Then the mixture was stirred at 80 °C for 12 h under CO (50 Psi). The reaction mixture was fdtered and the filtrate was concentrated under reduced pressure to give title compound (128 mg, crude) as a yellow solid. The intermediate was used in the next step without further purification. LCMS m / z =485.2 [M + H]Synthesis of tert-butyl (R)-4-((R)-2-((4-cyanophenyl)amino)-2-(3-fluoro-4- methylphenyl)acetyl)-2-methylpiperazine-l-carboxylate

[0669] To a mixture of Compound 3A (70 mg, 144.46 pmol, 1 eq) in DCM (2 mL) were added TFAA (45.51 mg, 216.69 pmol, 30.12 pL, 1.5 eq) and Py (17.14 mg, 216.69 pmol, 17.49 pL, 1.5 eq at 25 °C, the mixture was stirred at 25 °C for 0.5 h under N2atmosphere. The reaction mixture was diluted with H2O (2 mL) and extracted with DCM (2 mL * 3). The combined organic layers were washed with brine (3 mL * 2), dried over Na2SO4, filtered and concentrated1741105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ under reduced pressure to give title compound (70 mg, crude) as brown oil. The intermediate was used in the next step without further purification. LCMS m / z = 467.0 [M + H]+Synthesis of 4-(((R)-l-(3-fluoro-4-methylphenyl)-2-((R)-3-methylpiperazin-l-yl)-2- oxoethyl)amino)benzonitrile

[0670] To a solution of Compound 3B (70 mg, 150.04 pmol, 1 eq} in EtOAc (1 mL) was added HCl / EtOAc (2 M, 1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give title compound (85 mg, crude, HC1 salt) as brown solid. The intermediate was used in the next step without further purification. LCMS m / z = 366.9 [M + H]+Synthesis of 4-(((R)-2-((R)-4-acryloyl-3-methylpiperazin-l-yl)-l-(3-fluoro-4-methylphenyl)- 2-oxoethyl)amino)benzonitrile, Example 3

[0671] To a solution of Compound 3C (85 mg, 210.97 pmol, 1 eq, HC1 salt) in THF (0.8 mL) wa...

Claims

1. Atorney Docket No.: 130238.00003FM0040WQCLAIMSWhat is claimed is:

1. A compound of Formula (I):wherein:R1is N, C(R6), or CH;R2is a bond or -N(Ra)-;R3is -O-, -CH2-, -N(Ra)-, -S-, -S(O)-, or -S(O)2-; and R9is H or C1-C4 alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R5are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R6present on the same atom taken together with the atom to which they are attached formwhen R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R6present on the same atom taken together with the atom to which they are attached form9811105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQR7in each instance is independently: -C(O)N(Ra)(Rn); Ci-Ce alkyl; Ci-Ce haloalkyl; Ci- C& heteroalkyl; Ci-Ce hydroxyalkyl; C2-C6 haloalkenyl; C3-C7 cycloalkyl; 4-12 membered heterocyclyl substituted with 0, 1, or 2 instances of -NRaR‘; 5-12 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; oxo; halo; -ORd; - NRaRd; =N(Ra); -CN; -COOH; -C(O)O-Ci-C6alkyl; -C(O)-Ci-C6alkyl; -S(O)2N(Ra)(Re); - S(O)2-Ci-C6alkyl; -S(O)(=NRa)-Ci-C6alkyl; -S(O)(=NRa)NHRb; or -P(=O)(Ra)(Rb);R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C7 cycloalkyl, halo, or deutro-Ci-Ce alkyl;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene-(3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and -C(O)N(Rb)(Rc), or Ci-Ce alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11, alone or part of another group, is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl; Ci-Ce haloalkyl; Ci-Ce heteroalkyl; -Ci-Ce heteroalkyl-hydroxy; Ci-Ce alkoxy; Ci- Ce haloalkoxy; Ci-Ce hydroxyalkyl; C2-Ce alkynyl substituted with 0, 1, or 2 instances of independently selected 3-7 membered heterocyclyl (wherein the 3-7 membered heterocyclyl is optionally substituted with hydroxy, C1-C4 heteroalkyl, or -C(O)-Ci-C4 alkyl), Ci-Ce heteroalkyl, hydroxy, Ci-Ce hydroxyalkyl, -Ci-Ce heteroalkyl-hydroxy, or -NHC(O)-Ci-Ce alkyl; hydroxy; oxo; halo; cyano; -N(Rb)(Rc); 6 membered aryl; 5-6 membered heteroaryl; 3-6 membered carbocyclyl; 3-6 membered heterocyclyl; -C(O)O(Ra); -C(O)N(Rb)(Rc); -S(O)2N(Rb)(Rc); - S(O)2(Ra); -S(O)(=NRa)CH3; -S(O)(=NRa)NHRb; and -P(O)(CH3)2;9821105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQRing A is a 6-11 membered aryl, a 4-1 1 membered carbocyclyl or heterocyclyl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl;Rein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene- (6 membered aryl), or -C1-C3 alkylene-(5-6 membered heteroaryl); andRfin each instance is independently H, C1-C4 alkyl, or -C(O)-Ci-C4 alkyl; or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof.

2. The compound of claim 1, wherein the compound of Formula (I) is whereinR1is N or CH;R2is a bond or -N(Ra)-;R3is -CH2-, -N(Ra)-, -O-, -S-, -S(O)-, or -S(O)2-; and R9is H or C1-C4 alkyl; orR3and R9together with the atom to which they are both attached form a 3-5 membered cycloalkyl;R4and R?are independently H or C1-C4 alkyl; or R4and R5together form oxo; when R1is CH or C(R6), then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C3-C4 cycloalkyl, -F, -OH, -OCH3, -CN, -CH2CN, -CH2OH, -CH2NH2, or -NH2; or two R6present on the same atom taken together with the atom to which they are attached formor two R6present on the same atom taken together with the atom to which they are attached form9831105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ when R1is N, then R6is in each instance independently C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4 heteroalkyl, C3-C4 cycloalkyl, -CN, -CH2CN, CH2OH, or -CH2NH2; or two R6present on the same atom taken together with the atom to which they are attached form; or two R present on the same atom taken together with the atom to which £ they are attached form61;R7in each instance is independently: Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, oxo, halo, -ORd, -NRaRd, =N(Ra), -CN, -COOH, -C(O)O-Ci-C6alkyl, -C(O)-Ci-C6alkyl, -C(O)N(Ra)(Rn), -S(O)2N(Ra)(Re), -S(O)2-Ci-C6alkyl, -S(O)(=NH)-CI-C6alkyl, or - S(O)(=NRa)NHRb;R8in each instance is independently Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Cg haloalkoxy, C3-C7 cycloalkyl, or halo;R10is 6 membered aryl, 5-6 membered heteroaryl, -C1-C3 alkylene-(6 membered aryl), - C1-C3 alkylene-(5-6 membered heteroaryl), 3-9 membered carbocyclyl or heterocyclyl, or -C1-C3 alkylene-(3-9 membered carbocyclyl or heterocyclyl);R11is in each instance independently: H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, -S(O)2(Ra), 6-10 membered aryl, 5-10 membered heteroaryl, -Ci-Ce alkylene-6-10 membered aryl, -Ci-Ce alkylene-5-10 membered heteroaryl, -Ci-Ce hydroxyalkylene-6-10 membered aryl, -Ci-Ce hydroxyalkylene-5-10 membered heteroaryl, 3-12 membered carbocyclyl or heterocyclyl, -Ci-Ce alkylene-(3-12 membered carbocyclyl or heterocyclyl), -Ci-Ce hydroxyalkylene- (3-12 membered carbocyclyl or heterocyclyl), Ci-Ce alkyl substituted with R10and - C(O)N(Rb)(Rc), or Ci-C6alkyl substituted with R10and -N(Ra)-C(O)-Ci-C6alkyl; wherein the C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3- 12 membered carbocyclyl, and 3-12 membered heterocyclyl of R11is in each instance individually substituted with 0, 1, 2, or 3 instances of independently selected Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, hydroxy, oxo, halo, cyano, -N(Rb)(Rc), 6 membered aryl, 5-6 membered heteroaryl, 3-6 membered9841105079198\1\AMERICASAtorney Docket No.: 130238.00003 FM0040WQ carbocyclyl, 3-6 membered heterocyclyl, -C(O)O(Ra), -C(O)N(Rb)(Rc), -S(O)2N(Rb)(Rc), -S(O)2(Ra), -S(O)(=NRa)CH3, -S(O)(=NRa)NHRb, or -P(O)(CH3)2;Ring A is a 4-11 membered carbocyclyl or heterocyclyl, a 6-11 membered aryl, or a 5-11 membered heteroaryl;Ring B is a 6 membered aryl or 5-6 membered heteroaryl; x is 0, 1, 2, or 3; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4;Ra, Rb, and Rcin each instance are independently H or C1-C4 alkyl;Rdin each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C4 cycloalkyl; andRein each instance is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Cg hydroxyalkyl, Ci-Ce heteroalkyl, 3-6 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, 6 membered aryl, 5-6 membered heteroaryl, -Ci-C3alkylene-(6 membered aryl), or -Ci-C3alkylene-(5-6 membered heteroaryl); or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and / or an isotopologue thereof.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted phenyl group.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is a substituted pyridyl group.

6. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted phenyl group.9851105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring B is a substituted pyridyl group.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is O.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R3is N(Ra).

10. The compound of any one of claims 1-7 and 9, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is H.

11. The compound of any one of claims 1-7 and 9, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein the Raattached to R3is Me.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R9is H.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R2is a bond.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R4and R5are H.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is CH.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R6is methyl and x is 1.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein x is 2 and both R6groups are Me.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is - C(O)N(Ra)(Rn).

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -S(O)2NH2.9861105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ21 . The compound of any one of claims 1-18 and 20, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein y is 1, 2, 3, or 4, and at least one R7is -C(O)NHMe23. The compound of claim 1-19 or 22, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

24. The compound of claim 1-19 or 22, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein Ring A is:and yl is 0, 1, 2, or 3.

25. The compound of any one of claims 1-2, 6-7, and 12-19, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein -R3-Ring A is selected from the9871105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ group consisting<img src='' class="img-anchor img-center" img-id="IMGF000989_0001" / >□ is the attachment point of R to the rest of the compound.

26. The compound of any one of claims 1-11 and 17-25, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein R1is N, R2is a bond, R3is NH, R4and R5are H, and R9is H.

27. The compound of any one of claims 1-22, 14-15, and 17-26, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, wherein28. A compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1-28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, and a pharmaceutically acceptable excipient.

30. A method of treating or suppressing cancer comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, to a subject in need thereof.

31. A method of identifying a patient population treatable with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, comprising testing the population for one or more of certain mutations in the KRAS protein or the PI3K-alpha protein, wherein the9881105079198\1\AMERICASAtorney Docket No.: 130238.00003FM0040WQ certain mutations in the KRAS protein are selected from the group consisting of G12D, G12V, G12C, G12A, G12S, G12R, G13D, G13C, Q61H, and A146T, and wherein the certain mutations in the PI3K-alpha protein are selected from N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, KI 1 IE, KI 1 IN, E81K, E545A, E545G, N1044K, El lOdel, Q546P, E542K, E545K, H1047R, and H1047L.

32. A method of disrupting interaction between PI3K-alpha and a RAS protein in a cell, comprising contacting the cell with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, in an amount effective to disrupt the interaction.

33. A method of modulating the activity of PI3K-alpha in a cell, comprising contacting the cell with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, in an amount effective to modulate the activity of PI3K-alpha.

34. A method of disrupting interaction between PI3K-alpha and RAS, comprising contacting PI3K-alpha with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, in an amount effective to disrupt the interaction.

35. A method of covalently modifying PI3K-alpha comprising contacting PI3K-alpha with a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, and / or isotopologue thereof, or a pharmaceutical composition according to claim 29, in an amount effective to covalently modify PI3K-alpha.9891105079198\1\AMERICAS

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