P53 mutant stabilizer and uses thereof

Abstract

The present disclosure relates to compounds and methods to restore wild-type function of p53 mutants and to treat proliferative disorders or cancers associated with p53 mutation.

Description

P53 MUTANT STABILIZER AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 645,777, filed May 10, 2024; U.S. Provisional Patent Application No. 63 / 660,364, filed June 14, 2024; and U.S. Provisional Patent Application No. 63 / 738,437, filed December 23, 2024, the disclosure of each of which is hereby incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure in some aspects relates generally to compounds that bind to a mutant p53 protein and are capable of modulating the conformation thereof. The present disclosure in some aspects relates generally to method of restoring wild-type function of p53 mutants and treating proliferative disorders, such as cancers associated with p53 mutation. BACKGROUND

[0003] The transcription factor p53 functions as a tumor suppressor and is one of the most potent tumor suppressors in the cell, as it regulates a plethora of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. The gene encoding the p53 protein is the most frequently altered gene in human tumors. The loss of transcriptional functions leading to the deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 is the primary outcome of p53 mutations, and is a hallmark of most cancers.

[0004] Y220C is the most common mutation outside the DNA-binding surface and is associated with over 100,000 new cancer cases per year worldwide. The hydrophobic and “druggable” nature of the Y220C pocket offers a fruitful opportunity for targeting using small-molecule stabilizers. However, small molecules with high potency of binding to the Y220C mutation and restoring the wild-type function of p53 remain an unmet need. The present disclosure addresses this and other needs. SUMMARY

[0005] In some embodiments of the method described herein, the compound is of any one of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F),(I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the forgoing Formulae are as defined herein or any variation thereof.

[0006] In some embodiments, provided herein is a pharmaceutical formulation comprising a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, provided herein is a formulation comprising a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a pharmaceutically acceptable salt thereof, wherein the composition is sterile.

[0007] In yet another aspect, provided herein is a composition comprising a mutant p53 protein and a p53 stabilizer having a covalent bond to the mutant p53 protein, wherein the mutant p53 protein comprises a Y220C mutation, and the covalent bond is formed between a vinyl group of the p53 stabilizer and the cysteine at position 220 in the mutant p53 protein. In some embodiments of the foregoing, the mutant p53 protein has greater wild-type function compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments of the foregoing, the mutant p53 protein has a greater wild-type conformation compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments of the foregoing, the p53 stabilizer is a compound of any one of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof. DETAILED DESCRIPTION

[0008] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that the description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.I. Definition

[0009] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

[0010] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0011] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C1-C10alkyl”), having 6 to 10 carbon atoms (a “C6-C10alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0012] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20alkylene”), having 1 to 10 carbon atoms (a “C1-C10alkylene”), having 6 to 10 carbon atoms (a “C6-C10alkylene”), having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4alkylene”) or 1 to 3 carbon atoms (a “C1-C3alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0013] “Haloalkyl”, as used herein refers to the same residues as alkyl, but having at least one (e.g., 1, 2, 3, 4, 5, or 6) hydrogens replaced with halogen, including F, Cl, Br, and I. When more than one hydrogen is replaced by halogen, each halogen is independently selected from F, Cl, Br, and I. For example, an alkyl can be substituted with one F group and one Br group, with two F groups, with one Cl group and one Br group, or with one Br group and one I group. Examples of haloalkyl include trifluoromethyl, difluoromethyl, 2- fluoroethyl, penta-fluoroethyl, and 3-bromo-1-fluoro-butyl.

[0014] “Heteroalkyl”, as used herein, refers to the same residues as alkyl, but having at least one heteroatom at the connection point or at any interior point within the hydrocarbon chain, wherein the heteroatom can be -NH-, -O-, -S-, -NR-, -S(O)-, or -S(O)2-, wherein R can be alkyl. Particular heteroalkyl groups are those having 1 to 20 carbon atoms (a “C1-C20heteroalkyl”) and 1 to 8 (e.g., 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1, 2, 3, or 4) heteroatoms selected from -NR-, -NH-, -O-, -S-, -S(O)-, or -S(O)2-, those having 1 to 10 carbon atoms (a “C1-C10 heteroalkyl”) and 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from -NR-, -NH-, - O-, -S-, -S(O)-, or -S(O)2-, those having 1 to 6 carbon atoms (a “C1-C6heteroalkyl”) and 1 to 3 (e.g., 1, 2, or 3) heteroatoms selected from -NR-, -NH-, -O-, -S-, -S(O)-, or -S(O)2-, or those having 1 to 3 carbon atoms (a “C1-C3 heteroalkyl”) and one heteroatom selected from -NR-, - NH-, -O-, -S-, -S(O)-, or -S(O)2-. For example, -CH2CH2OH is not understood as a heteroalkyl as used herein. In some embodiments, the R is H or C1-C3 alkyl. Examples of heteroalkyl include, but are not limited to, -CH2OCH3, -CH2NHCH3, -CH2SCH3, -CH2S(O)2CH3, -O-CH2CH3, -NH-CH2CH3, - N(CH3)-CH2CH3, -O-CH2CH2(CH3), and the like.

[0015] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “C6-C10 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4alkenyl”). Alkenyl groups also include dienes, including cumulated dienes (i.e., two C=C share a common carbon), conjugated dienes (i.e., two conjugated C=C separated by a single bond), and unconjugated dienes (i.e., two C=C separated by two or more single bonds). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3- dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1,2-propadiene, 2- methyl-1,3-butadiene, and the like.

[0016] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20alkenylene”), having 2 to 10 carbon atoms (a “C2-C10alkenylene”), having 6 to 10 carbonatoms (a “C6-C10alkenylene”), having 2 to 6 carbon atoms (a “C2-C6alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-), and the like.

[0017] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2- C20 alkynyl”), having 6 to 10 carbon atoms (a “C6-C10 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4alkynyl”). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2- ynyl, but-3-ynyl, and the like.

[0018] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “C6-C10alkynylene”), having 2 to 6 carbon atoms (a “C2-C6alkynylene”), 2 to 4 carbon atoms (a “C2-C4alkynylene”) or 2 to 3 carbon atoms (a “C2-C3alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-), and the like.

[0019] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 14 annular carbon atoms, from 3 to 13 annular carbon atoms, or from 3 to 6 annular carbon atoms. A particular cycloalkyl is a cyclic hydrocarbon having from 3 to 14 annular carbon atoms (a “C3-C14cycloalkyl”), 3 to 13 annular carbon atoms (a “C3-C13 cycloalkyl”), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C3-C4cycloalkyl”). Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0020] “Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A particular cycloalkylene is a cyclic hydrocarbon having from 3 to 4 annular carbon atoms (a “C3-C14 cycloalkylene”), from 3 to 13 annular carbon atoms (a “C3-C13cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C3-C4 cycloalkylene”). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropylene or trans-1,2- cyclopropylene), or a mixture thereof.

[0021] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A particular cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms (a “C3-C13 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0022] “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.

[0023] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14aryl”). In some instances, all rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an arylgroup having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0024] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “C6-C14arylene”).

[0025] “Heteroaryl”, as used herein, refers to an aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen or sulfur (e.g., S, S(O), or S(O)2). A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple rings (e.g., fused rings such as indolizinyl, benzothienyl), wherein at least one ring of the multiple rings is aromatic and the remaining rings may each be aromatic or non-aromatic. When a heteroaryl group comprises at least one ring that is aromatic and at least one ring that is non-aromatic, the annular heteroatom(s) may be present in an aromatic ring, in a non-aromatic ring, or in both aromatic and non-aromatic rings. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at an aromatic ring position or a non-aromatic ring position. For example, a heteroaryl may encompass condensed ring systems such,, wherein the wavy line indicates the connection point to the parent structure, and X represents a heteroatom such as nitrogen, oxygen or sulfur (e.g., S, S(O), or S(O)2). Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), 5 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2). In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2). In another variation, particular heteroaryl groupsare polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2).

[0026] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or a partially unsaturated non-aromatic cyclic group having a single ring or multiple rings (e.g., fused rings, bridged rings, spiro rings, or any combination thereof), and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur (e.g., S, S(O), or S(O)2), or oxygen, and the like, wherein none of the rings of the multiple rings are aromatic. A heterocycle group having more than one ring may be connected to the parent structure at any ring position. A heterocyclyl group may be connected to the parent structure via either a heteroatom or a carbon atom. For example, a heterocycle may encompass condensed ring systems such aswherein the wavy line indicates the connection point to the parent structure, and X represents a heteroatom such as nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2). Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), 3 to 12- membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), 3 to 10- membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), 3 to 8- membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2), or 3 to 6- membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2). In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2). In another variation, heterocyclyl includes polycyclic non-aromatic rings having from1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., S, S(O), or S(O)2).

[0027] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3).

[0028] “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 some 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.

[0029] “Oxo” refers to the moiety =O.

[0030] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In some embodiments, an optionally substituted group has more than one substituent, wherein each substituent is independently selected. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. It should be understood that substitution as used herein, unless otherwise specified, encompasses the scenario where the substituent(s) replaces a hydrogen, and may also encompasses the scenario where the substitution(s) does not replace a hydrogen. For example, in some embodiments, substitution encompasses the formation of N-oxide, S-oxide, and quaternized N. For example, heterocycle substituted with oxo group may encompass groups such as. should be understood that substituent(s) can be at any position of the substituted group, as valency permits, including the connection point of the substituted group to the rest of the compound. For example, a cyclopropyl substituted with F encompasses, but is not limited to, groups like, wherein the wavy line indicates the connection point of the group to the rest of the compound.

[0031] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different. Where there are multiple substituents within a moiety or compound, it is to be understood that each substituent may be selected independently of each other substituent.

[0032] Unless clearly indicated otherwise, “an individual” or “a subject” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.

[0033] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of cancer. The methods provided herein contemplate any one or more of these aspects of treatment.

[0034] In certain instances, the terms “prevention”, “prophylaxis” and “preclusion” are used synonymously and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder (e.g., a proliferative disorder), a symptom or a health problem, or a development or advancement of such states and / or the symptoms of such states. In certain instances, prevention means delaying the development of a disease or any symptom thereof. For example, prevention of a proliferative disorder means to delay, defer, hinder, slow, retard, stabilize, and / or postpone development of the disorder or any symptom thereof. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant prevention or delay can, in effect, result in that the individual does not develop the disease. A method that prevents development of a proliferative disorder (e.g., cancer) is a method that reduces probability of disease development in a given time frame and / or reduces the extent of the disorder in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Cancer development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence, and onset. The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.

[0035] The term “effective amount” as used herein, refers to a sufficient amount of at least one agent being administered to achieve a desired result, e.g., to induce apoptosis in at least one abnormally proliferating cell or to relieve to some extent one or more symptoms of a disease or condition being treated. In certain instances, the method is in vitro, and the desired result may comprise certain desired alteration of cells or biological processes. In certain instances, the method is in vivo, and the result may comprise a reduction and / or alleviation of the signs, symptoms, or causes of a disease, such as cancer. In certain instances, the result is a death of or decrease in the growth of at least one abnormally proliferating cell, e.g., a cancer cell. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0036] In certain instances, an “effective amount” is considered in the context of therapeutical uses and may be optionally referred to as “therapeutically effective amount”. A “therapeutically effective amount” refers to an amount of the compound or the composition comprising a compound or salt thereof as set forth herein sufficient to produce a desired therapeutic outcome and / or required to provide a clinically significant decrease in a disease. An appropriate “effective” or “therapeutically effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. In various embodiments, an effective amount or a therapeutically effective amount of the compound may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of a tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and / or delay one or more of symptoms of cancer.

[0037] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated toproduce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0038] As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0039] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have in some embodiments met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0040] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) 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 acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) 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. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.In some embodiments, the pharmaceutically acceptable salt is a TFA, formate, or hydrochloride (HCl) salt. In some embodiments, the compounds described herein are in free form.

[0041] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound provided herein as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0042] Unless otherwise stated, “substantially pure” intends a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5%, 0.1% impurity.

[0043] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

[0044] In the descriptions herein (e.g., compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1) it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. Forexample, every description, variation, embodiment or aspect provided herein with respect to L of Formula (A) may be combined with every description, variation, embodiment or aspect of E of Formula (I-3A) the same as if each and every combination were specifically and individually listed.

[0045] Provided herein are all salts of compounds referred to herein, such as pharmaceutically acceptable salts. Also provided herein are any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.

[0046] In some embodiments, unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and embraced by the disclosure. When a specific stereo configuration is indicated at certain positions of a compound, the compound should be understood as encompassing all possible stereoisomers at any other positions (without specified stereo configuration). In some embodiments, the compound described herein may be described as “trans” or “trans racemic”, and these terms encompass trans isomers with any absolute stereo configurations and any mixture of them. For example, cyclobutyl labeled with “trans racemic” may refer t. Likewise, “cis” or “cis racemic” encompasses any cis isomers with any absolute stereo configurations, and any mixture of them. All forms of the compounds are also provided herein, such as crystalline or non-crystalline forms of the compounds. It is also understood that prodrugs, solvates and metabolites of the compounds are provided herein. Compositions comprising a compound described herein are also provided herein, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds described herein in any ratio are also provided herein, including mixtures of two or more stereochemical forms of a compound in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0047] The disclosure also includes isotopically-labeled and / or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or variations thereof described herein, where one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, such as2H,3H,11C,13C,14C13N,15O,17O,35S,18F,36Cl. Incorporation of heavier isotopes such as deuterium (2H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. As used herein, each instance of enrichment, substitution, or replacement of an atom with corresponding isotope of that atom encompasses isotopic enrichment levels of one of about: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the preceding percentages.

[0048] Isotopically-labeled compounds of the present disclosure can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.

[0049] It should be understood that the chemical structures, formulae, and descriptions set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. The descriptions of compounds are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would not be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. In some embodiments, the substituents for rings (e.g. cycloalkyl, heterocycle aryl, heteroaryl, or cycloalkylene,), unless otherwise specified, may be attached to any of the ring atoms (obeying the rules of chemical valency). When a ring is substituted with multiple substituents, unless otherwise specified, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and eachsubstituent may be independently selected and optionally be different. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the substitution positions on the ring, fused rings, or spirocyclic rings are not specified, the substituents (including, but not limited to, points of attachment to the remainder of the molecule or other substituents) may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with one or more substituent, unless otherwise specified, the substituent can be understood to replace the hydrogen, including the hydrogen on the heteroatom, while obeying the rules of chemical valency. II. Compounds

[0050] In one aspect, provided herein is a compound of Formula (A), (B), (C), (D), (E), (F),wherein:each ring bond represented by a dashed line is independently a single bond or a double bond; Z1is N or CH; Z2is N or CR2; Z3is N or CH; wherein at least one of Z1, Z2when present, and Z3is N; Z4is N, NR4, CR4, CR4H, or C(R4)R4B, wherein when Z4is C(R4)R4Band R4is attached to the rest of the compound through O or N, then R4Bis C1-C2alkyl, or C1-C2haloalkyl, and when Z4is C(R4)R4Band R4is attached to the rest of the compound through C, then R4Bis C1-C2 alkyl, C1-C2 haloalkyl, F, -OH, -OMe, -OCF3, -OCH2F, - OCHF2, -NH2, -NHMe, or NMe2; Z4Ais N, C, or CH; Z5is N, NR5, CR5, or CHR5; Z6is N, NR6, CR6, or CHR6; Z7is N, NH, CH, or CH2; when the compound is of Formula (B) and R8Ais -H and R15is C1-C3 alkyl, then Z1is N; when the compound is of Formula (B), (C), or (D), then: (a) Z5and Z6are N, NH, or CH; and (b) R2and R4are not -H, -F, -NH2, -CH3, or -CF3; when the compound is of Formula (E), then (a) Z4is CR4wherein R4is not -H and / or (b) Z5is CR5wherein R5is not -H; when the compound is of Formula (F), then R2is not -H, -CH3, or -CF3; when the compound is of Formula (G), then: (a) L is -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; (b) R4Ais R4or a bond; (c) one side of L’ is bound to any chemically possible location on R2, and the other side of L’ is bound to any chemically possible location on R4A; and (d) L’ is selected from the group consisting of: -(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-, -C2-C12 alkylene-, -NH-C2-C10 alkylene-, -C2-C10 alkylene-NH-,, , , -O-C2-C10alkylene-, -C2-C10alkylene-O-, -NH-C(O)-C2-C10alkylene-, -C2-C10alkylene-C(O)-NH-, -NH-C(O)-C2-C10alkylene-C(O)-NH-, -C(O)- C2-C10 alkylene-, -C2-C10 alkylene-C(O)-, -C(O)-C2-C10 alkylene-C(O)-, -C(O)-C2- C10 alkylene-C(O)-NH-, and -NH-C(O)-C2-C10 alkylene-C(O)-, wherein any terminal -C(O)- group in L’, when present, is directly attached to a nitrogen atom in R2or R4A, or Z4Awhen R4Ais a bond; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4alkylene-; -C2-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7 cycloalkylene-; -CH=CH-C3-C7 cycloalkylene-; -C2-C4 alkynylene-; -NRa-; -NRa-C1-C5alkylene-; -NRa-C1-C3alkylene-O-; -NRa-C1- C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3 alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7cycloalkylene-, -C3-C7cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7cycloalkylene-(C1-C3alkylene)-, or -C3-C7cycloalkenylene-(C1-C3alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7 cycloalkylene, or C3-C7 cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -O-C3-C6 cycloalkylene-; -O-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; -O- C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; and -C(O)-NRa-C1-C4 alkylene-; E is selected from the group consisting of: H; C1-C4 haloalkyl; hydroxy; -NRaRb;-NRa-C(O)-C(O)-N(Rb)2-NRa-C(O)-C2-C5 alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5 heteroalkyl or -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C2-C6alkenyl substituted with 0, 1, or 2 independently selected halo or C3-C6cycloalkyl; -V-C1-C4 alkyl, wherein the C1-C4 alkyl is substituted with 0, 1, or 2 instances of independently selected halo or CN; and wherein V is a bond, -C(O)-NRa-, - NRa-C(O)-, or -C(O)-; -W-C1-C6 heteroalkyl; wherein W is a bond, -C(O)-NRa-, -NRa-C(O)-, or -C(O)-; -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, C1-C4 heteroalkyl substituted with 1 instance of C2-C3 alkynyl, 5- 6 membered heteroaryl, halo, -OH, oxo, C1-C4haloalkyl, C1-C4alkoxy, C3-C6cycloalkyl, -O-cyclopropyl, -O-C1-C4haloalkyl, C1-C4alkoxy substituted with 1 instance of CN, -CN, C1-C4 cyanoalkyl, -NRaRb, -NRa-C(O)-C1-C4 alkyl-, - C(O)-NRa-S(O)2(C1-C4alkyl), -S(O)2(C1-C4alkyl), -S(O)2NH2, - S(O)(=NH)(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), -C(O)NRaRb, or C3-C7 heterocyclic; and wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, -C(O)- N(Ra)-; -CH(OH)-, -NRa-C(O)-C1-C4alkylene-, or -NRa-C(=NH)-; -Y-3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, - OH, oxo, halo, -C(O)-Ra, 6-10 membered aryl, or 6-10 membered aryl substituted with 1 instance of C1-C4alkoxy; and wherein Y is a bond, -NRa-, - NRa-C(O)-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C2-C4 alkynylene-, or - NRa-C(O)-C2-C4 alkynylene-O-; -Z-3-9 membered cycloalkyl, wherein the 3-9 membered cycloalkyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, C1-C4 haloalkyl, -OH, C1-C4 hydroxyalkyl, CN, C1-C4 cyanoalkyl, C1-C4 heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5 to 10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4alkyl; and wherein Z is a bond, -NRa-C(O)-, -NRa-C(O)-C=, -NRa-C(O)O-, -C(O)-NRa-, -NRa- S(O)2-, -C(O)-, -NRa-C(O)-C2-C4alkynylene-, -NRa-C(O)-C2-C4alkynylene-O-, -NRa-C(O)-C1-C4alkylene-, -NRa-C(O)-C1-C4haloalkylene-, -NRa-C(O)- C1-C4 alkylene-O-, or -N(Ra)-CH(C1-C4 haloalkyl)-; R4is selected from the group consisting of H, -O-R9, -NH-R9, and -R9; and R5is H, -CH3, or -F; or R4is H, -CH3, -NH2, or -F; and R5is selected from the group consisting of H, -OR10, - OR9A, -OR9B, and -NH-R9; R9is -R13-R9A, R9B, R9C, or R9D; R13is a bond, C1-C3alkylene substituted with 0, 1, 2, or 3 halo, or -C(O)-C1-C3alkylene-; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1-C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, =NH, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen or sulfur in the ring atoms, then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1- C4alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; R9Dis 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, oxo, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12; wherein when the 5-10 membered heteroaryl does not contain a nitrogen in the ring atoms then the 5-10 membered heteroaryl is substituted with at least one instance of -NRdRe;R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4 heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra; R10is H, -C1-C4alkylene-NRaRb, or -C1-C4alkyl; R6is H, -CH3, or -NH2; R8is -CH3 substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; R8Ais -H or -CH3; R8Bis -CH3 substituted with 1, 2, or 3 instances of F; R14is -H or -CH3 substituted with 0, 1, 2, or 3 instances of F; R15is -H or C1-C3alkyl; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4 alkyl substituted with 0, 1, 2, or 3 instances of F; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4alkyl substituted with 0 or 1 instance of -O-C1-C4alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4alkyl), C1-C4alkyl, C1- C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, or C1-C4heteroalkyl; or (i) an isotopologue thereof; (ii) a stereoisomer thereof; (iii) a pharmaceutically acceptable salt thereof; or any combination of (i) to (iii); wherein the compound is not:stereoisomer or a pharmaceutically acceptable salt thereof.

[0051] It will be understood that “R4is attached to the rest of the compound through O or N” means that R4is attached to the rest of the compound through O or N, where O or N is part of R4. Similarly, “R4is attached to the rest of the compound through C” means that “R4is attached to the rest of the compound through C, where C is part of R4.

[0052] In some embodiments, “one side of L’ is bound to any chemically possible location on R2” means that one end of L’ covalently connects to R2by replacing any of the hydrogen on R2. In some embodiments, “the other side of L’ is bound to any chemically possible location on R4A” means that when R4Ais not a bond, the other end of L’ covalently connects to R4Aby replacing any of the hydrogen on R4A. It will be understood that when R4Ais a bond, “L’ is bound to any chemically possible location on R4A” means that L’ is directly bound to Z4A.

[0053] It will be understood that any heterocyclyl described herein, unless otherwise specified, can have -S(O)- on the ring. It will also be understood that such heterocyclyl substituted with =NH can result in a heterocycle with a sulfoximine group. For example, a heterocyclyl with -S(O)- on the ring, when substituted with =NH, can result in.

[0054] It will be understood that “an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof” includes any combination of isotopologue, stereoisomer, and pharmaceutically acceptable salt. For example, “an isotopologue, or a stereoisomer or apharmaceutically acceptable salt” of a compound encompasses an isotopologue of a compound that is also a pharmaceutically acceptable salt of the isotopologue.

[0055] In another aspect, provided herein is a compound of Formula (I-P2) or (II-P2):wherein: Z1is N and Z3is CH, or Z1is CH and Z3is N; Z5is N or CR5; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7cycloalkylene-; -CH=CH-C3-C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5alkylene-; -NRa-C1-C3alkylene-O-; -NRa-C1- C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3 alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C3-C6cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; -O- C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; and -C(O)-NRa-C1-C4 alkylene-; E is selected from the group consisting of: H; C1-C4 haloalkyl; hydroxy; -NRaRb; -NRa-C(O)-C(O)-N(Rb)2 -NRa-C(O)-C2-C5 alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5heteroalkyl; -NRa-C(O)-C2-C6 alkenyl substituted with 0, 1, or 2 independently selected halo or C3-C6 cycloalkyl; -V-C1-C4alkyl, wherein the C1-C4alkyl is substituted with 0, 1, or 2 instances of independently selected halo or CN; and wherein V is a bond, -C(O)-NRa-, - NRa-C(O)-, or -C(O)-; -W-C1-C6heteroalkyl; wherein W is a bond, -C(O)-NRa-, -NRa-C(O)-, or -C(O)-; -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C1-C4heteroalkyl substituted with 1 instance of C2-C3alkynyl, 5- 6 membered heteroaryl, halo, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-cyclopropyl, -O-C1-C4 haloalkyl, C1-C4 alkoxy substituted with 1 instance of CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, - S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), -C(O)NRaRb, or C3-C7 heterocyclic; and wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, -C(O)- N(Ra)-; -CH(OH)-, or -NRa-C(O)-C1-C4alkylene-; -Y-3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, - OH, oxo, halo, 6-10 membered aryl, or 6-10 membered aryl substituted with 1 instance of C1-C4alkoxy; and wherein Y is a bond, -NRa-, -NRa-C(O)-, -NRa- C(O)-C1-C4 alkylene-, -NRa-C(O)-C2-C4 alkynylene-, or -NRa-C(O)-C2-C4 alkynylene-O-;-Z-3-9 membered cycloalkyl, wherein the 3-9 membered cycloalkyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, C1-C4 haloalkyl, -OH, C1-C4 hydroxyalkyl, CN, C1-C4 cyanoalkyl, C1-C4 heteroalkyl, or 5 to 10 membered heteroaryl; and wherein Z is a bond, -NRa-C(O)-, -C(O)- NRa-, -NRa-S(O)2-, -C(O)-, -NRa-C(O)-C2-C4alkynylene-, -NRa-C(O)-C2-C4alkynylene-O-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C1-C4 haloalkylene-, - NRa-C(O)-C1-C4 alkylene-O-, or -N(Ra)-CH(C1-C4 haloalkyl)-; R4is selected from the group consisting of H, -O-R9, and -NH-R9; and R5is H, -CH3, or - F; or R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH- R9; R9is -R13-R9A, R9B, R9C, or R9D; R13is a bond or C1-C3 alkylene substituted with 0, 1, 2, or 3 halo; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, C1-C4 cyanoalkyl, hydroxy, C1-C6 heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1- C4 cyanoalkyl, hydroxy, C1-C6 heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4 alkylene-NRdRe, wherein the C1-C4 alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; R9Dis 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, C1-C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12; wherein when the 5-10 membered heteroaryl does not contain a nitrogen in the ring atoms then the 5-10 membered heteroaryl is substituted with at least one instance of -NRdRe; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; R10is H, -C1-C4 alkylene-NRaRb, or -C1-C4 alkyl; R6is H or -NH2; R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4alkyl; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4 alkyl substituted with 0 or 1 instance of -O-C1-C4 alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4alkyl), C1-C4alkyl, C1- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 heteroalkyl; or an isotopologue thereof; or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof; wherein the compound is not:, , , , ,or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, provided herein is a compound of Formula (I-P1) or (II-P1):wherein: Z1is N and Z3is CH, or Z1is CH and Z3is N; Z5is N or CR5; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7cycloalkylene-; -CH=CH-C3-C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1- C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3alkylene)-, -5-6membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3 alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -O-C3-C6 cycloalkylene-; -O-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; and - O-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; E is selected from the group consisting of: H; C1-C4alkyl; C1-C4haloalkyl; C3-C6cycloalkyl; hydroxy; -NRaRb; -NRa-C(O)- C1-C4 alkyl; -C(O)-NRa-C1-C4 alkyl; -C(O)-C1-C4 alkyl; -NRa-C(O)-C3-C6 cycloalkyl; -C(O)-NRa-C3-C6 cycloalkyl; -C(O)-C3-C6 cycloalkyl; -N(Ra)- CH(C3-C6cycloalkyl)(C1-C4haloalkyl); -CH(OH)(5-6 membered heteroaryl); -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, halo, C1-C4haloalkyl, C1-C4alkoxy, C3-C6cycloalkyl, -O- cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -S(O)(=NH)(C1-C4alkyl), - P(O)(C1-C4alkyl)(C1-C4alkyl), -C(O)NRaRb, or C3-C7heterocyclic, wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, or -C(O)-N(Ra)-; and 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4alkyl; R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; or R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH- R9; R9is R9A, R9B, or R9C; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene- C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; wherein when the 3- 9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe;R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; R10is H, -C1-C4alkylene-NRaRb, or -C1-C4alkyl; R6is H or -NH2; R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4alkyl; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4 alkyl substituted with 0 or 1 instance of -O-C1-C4 alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4alkyl), C1-C4alkyl, C1- C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 heteroalkyl; or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof; wherein the compound is not:pharmaceutically acceptable salt thereof.

[0057] In one aspect, provided herein is a compound of Formula (I-P0) or (II-P0):wherein: Z1is N and Z3is CH, or Z1is CH and Z3is N;Z5is N or CR5; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C1-C3 alkylene-NRa-; -NRa-; -NRa-C1-C5 alkylene-; -NRa- C1-C3 alkylene-O-; -NRa-C1-C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1- C3alkylene-C3-C7cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1- C3alkylene; -NRa-5-6 membered aryl or heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl- or -5-6 membered heteroaryl-, wherein the 3-7 membered heterocyclyl or 5- 6 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl or oxo; -C1-C3alkylene-C3-C6cycloalkylene-; -C1-C3alkylene-C3- C7cycloalkylene-C1-C3alkylene-; -O-C3-C6cycloalkylene; -O-C3-C7cycloalkylene-C1- C3 alkylene-; -O-C1-C3 alkylene-C3-C7 cycloalkylene-, and -O-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; E is selected from the group consisting of: H; C1-C4 alkyl; C1-C4 haloalkyl; C3-C6 cycloalkyl; hydroxy; -NRaRb; -NRa-C(O)- C1-C4alkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C3-C6cycloalkyl; -C(O)-C3-C6cycloalkyl;5-10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instances of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or - C(O)NRaRb; -NRa-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instances of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); -S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; -O-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instances of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), - S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb; -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instances of -CN, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb; and 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl; R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; or R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH- R9; R9is R9A, R9B, or R9C; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 1 or 2 instances of -NRdReand 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene- C(O)NRdRe, -NRdRe, or -R12; R9Cis -C1-C4 alkylene-NRdRe, wherein the C1-C4 alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene- C(O)NRdRe, -NRdRe, or -R12; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra; R10is H, -C1-C4 alkylene-NRaRb, or -C1-C4 alkyl; R6is H or -NH2; R8is -CH3 substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; Ra, Rb, and Rcin each instance are independently selected from the group consisting of H and C1-C4alkyl; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4alkyl substituted with 0 or 1 instance of -O-C1-C4alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4 alkyl), C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 heteroalkyl; or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof; wherein the compound is not:stereoisomer or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compound is a compound of Formula (A):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound is a compound of Formula (B):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compound is a compound of Formula (C):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the compound is a compound of Formula (D):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound is a compound of Formula (E):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound is a compound of Formula (F):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the compound is a compound of Formula (G):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound is a compound of Formula (I):or a stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, Formula (I) is Formula (I-P0). In some embodiments, Formula (I) is Formula (I-P1). In some embodiments, Formula (I) is Formula (I-P2).

[0066] In some embodiments, the compound is of Formula (I-1)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound is Formula (I-2)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound is of Formula (I-3)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, R8is -CH3 substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F.

[0070] In some embodiments, R8is -CF3.

[0071] In some embodiments, R8is -CHF2.

[0072] In some embodiments, R8is -CH2F.

[0073] In some embodiments, R8is -CF3and the compound of Formula (I) is a compound of formula (I-A)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, R8is -CHF2 and the compound of Formula (I) is a compound of formula (I-B)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, R8is -CH2F and the compound of Formula (I) is a compound of formula (I-C)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compound is of Formula (I-3A)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, R8is cyclopropyl. In some embodiments, the compound is a compound of Formula (I-D):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, R8is cyclopropyl. In some embodiments, the compound is a compound of Formula (I-E):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, R8is cyclopropyl. In some embodiments, the compound is a compound of Formula (I-F):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound is a compound of Formula (II):or a stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, Formula (II) is Formula (II-P0). In some embodiments, Formula (II) is Formula (II-P1). In some embodiments, Formula (II) is Formula (II-P2).

[0081] In some embodiments, the compound is of Formula (II-1):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound is Formula (II-2)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound is Formula (II-3)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, L is selected from the group consisting of: a bond; -C1-C4alkylene-; -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7 cycloalkylene-; -CH=CH-C3- C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5alkylene-; -NRa-C1-C3alkylene-O- ; -NRa-C1-C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3 alkylene-; -3-7 membered heterocyclyl-, -5- 6 membered heteroaryl-, -6 membered aryl-, -C3-C7cycloalkylene-, -C3-C7cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3 alkylene)-, -C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7cycloalkenylene-(C1-C3alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7 cycloalkylene, or C3-C7 cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo; -C1-C3 alkylene-C3-C6cycloalkylene-; -C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-; -O-C3- C6cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; -O-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; and -C(O)-NRa-C1- C4 alkylene-.

[0085] In some embodiments, L is selected from the group consisting of: a bond; -C1-C4alkylene-; -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7 cycloalkylene-; -CH=CH-C3- C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5alkylene-; -NRa-C1-C3alkylene-O- ; -NRa-C1-C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3 alkylene-; -3-7 membered heterocyclyl-, -5- 6 membered heteroaryl-, -6 membered aryl-, -C3-C7cycloalkylene-, -C3-C7cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3 alkylene)-, -C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -O-C3- C6cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; and -O-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-.In some embodiments, -L-E is selected from the group consisting of: -E; -C1-C4 alkylene-E; -C3-C5 linear alkenylene-E, wherein C3-C5linear alkenylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-E; -CH=C3-C7 cycloalkylene-E; -CH=CH-C3-C7 cycloalkylene-E; -C2-C4 alkynylene-E; -NRa-E; -NRa-C1-C5 alkylene-E; -NRa-C1-C3alkylene-O-E; -NRa-C1-C4hydroxyalkylene-E; -NRa-C3-C7cycloalkylene-E; -NRa-C1-C3alkylene-C3-C7cycloalkylene-E; -NRa-C3-C7cycloalkylene-C1- C3 alkylene-E, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-E; -NRa-6 membered aryl-E; -NRa-5-6 membered heteroaryl-E;-O-C1-C3alkylene-E; -3-7 membered heterocyclyl-E, -5-6 membered heteroaryl-E, -6 membered aryl-E, -C3-C7 cycloalkylene-E, -C3-C7 cycloalkenylene-E, -3-7 membered heterocyclyl-(C1-C3 alkylene)-E, -5-6 membered heteroaryl-(C1-C3 alkylene)-E, -6 membered aryl-(C1-C3alkylene)-E, -C3-C7cycloalkylene-(C1-C3alkylene)-E, or -C3-C7cycloalkenylene-(C1-C3alkylene)-E, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7 cycloalkylene, or C3-C7 cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo; -C1-C3 alkylene-C3-C6cycloalkylene-E; -C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-E; -O- C3-C6 cycloalkylene-E; -O-C3-C7 cycloalkylene-C1-C3 alkylene-E; -O-C1-C3 alkylene-C3-C7 cycloalkylene-E; and -O-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-E.

[0086] In some embodiments, E is selected from the group consisting of: H; C1-C4haloalkyl; hydroxy; -NRaRb; -NRa-C(O)-C(O)-N(Rb)2; -NRa-C(O)-C2-C5 alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5 heteroalkyl or -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C2-C6alkenyl substituted with 0, 1, or 2 independently selected halo or C3- C6cycloalkyl; -V-C1-C4alkyl, wherein the C1-C4alkyl is substituted with 0, 1, or 2 instances of independently selected halo or CN; and wherein V is a bond, -C(O)-NRa-, -NRa-C(O)-, or - C(O)-; -W-C1-C6heteroalkyl; wherein W is a bond, -C(O)-NRa-, -NRa-C(O)-, or -C(O)-; -X- 6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5- 10 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C1-C4heteroalkyl substituted with 1 instance of C2-C3alkynyl, 5-6 membered heteroaryl, halo, -OH, oxo, C1-C4haloalkyl, C1-C4alkoxy, C3-C6 cycloalkyl, -O-cyclopropyl, -O-C1-C4 haloalkyl, C1-C4 alkoxy substituted with 1 instance of CN, -CN, C1-C4 cyanoalkyl, -NRaRb, -NRa-C(O)-C1-C4 alkyl-, -C(O)-NRa- S(O)2(C1-C4alkyl), -S(O)2(C1-C4alkyl), -S(O)2NH2, -S(O)(=NH)(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4 alkyl), -C(O)NRaRb, or C3-C7 heterocyclic; and wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, -C(O)-N(Ra)-; -CH(OH)-, -NRa-C(O)-C1-C4 alkylene-, or -NRa-C(=NH)-; -Y-3- 9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, -OH, oxo, halo, -C(O)-Ra, 6-10 membered aryl, or 6-10 membered aryl substituted with 1 instance of C1-C4 alkoxy; and wherein Y is a bond, -NRa-, -NRa-C(O)-, -NRa-C(O)-C1-C4alkylene-, -NRa-C(O)-C2-C4alkynylene-, or -NRa-C(O)-C2-C4alkynylene-O-;-Z-3-9 membered cycloalkyl, wherein the 3- 9 membered cycloalkyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, C1-C4haloalkyl, -OH, C1-C4hydroxyalkyl, CN, C1-C4cyanoalkyl, C1-C4heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5 to 10 membered heteroarylsubstituted with 0, 1, 2, or 3 independently selected C1-C4alkyl; and wherein Z is a bond, - NRa-C(O)-, -NRa-C(O)-C=, -NRa-C(O)O-, -C(O)-NRa-, -NRa-S(O)2-, -C(O)-, -NRa-C(O)-C2- C4 alkynylene-, -NRa-C(O)-C2-C4 alkynylene-O-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)- C1-C4haloalkylene-, -NRa-C(O)-C1-C4alkylene-O-, or -N(Ra)-CH(C1-C4haloalkyl)-.

[0087] In some embodiments, E is selected from the group consisting of: H; C1-C4alkyl; C1-C4 haloalkyl; C3-C6 cycloalkyl; hydroxy; -NRaRb; -NRa-C(O)-C1-C4 alkyl; -C(O)-NRa-C1- C4 alkyl; -C(O)-C1-C4 alkyl; -NRa-C(O)-C3-C6 cycloalkyl; -C(O)-NRa-C3-C6 cycloalkyl; - C(O)-C3-C6cycloalkyl; -N(Ra)-CH(C3-C6cycloalkyl)(C1-C4haloalkyl); -CH(OH)(5-6 membered heteroaryl); -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, halo, C1-C4haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, - S(O)(=NH)(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), -C(O)NRaRb, or C3-C7heterocyclic, wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, or -C(O)-N(Ra)-; and 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4alkyl.

[0088] In some embodiments of the foregoing, L is a bond. In some embodiments, E is H, C1-C4 alkyl, -NRaRb, 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4alkyl, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, C1-C4alkyl, or -NRa-C(O)-C1-C4alkyl. In some embodiments, E is H, C1-C4 alkyl, -NRaRb, or 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl. In some embodiments, E is H or C1-C3alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, E is -NRaRb, wherein Raand Rbare each independently H, methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, E is -NRa-C(O)-C1-C4 alkyl. In some embodiments, -L-E is H, -CH2CH2CH3, -NH2, -NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,. In some embodiments,-L-E is H, C1-C3alkyl, -NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,, , , o . In some embodiments, -L-E is H, -CH2CH2CH3, -NH2, -NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,, , , ,

[0089] In some embodiments, L is -C1-C3 alkylene-NRa-, such as -CH2-NRa-, -CH2CH2- NRa-, -CH2CH2CH2-NRa-, -CH2CH2(CH3)-NRa-, or -CH2(CH3)CH2-NRa-. In some embodiments, E is 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, or 5-6 membered heteroaryl comprising 1, 2, or 3 annular nitrogen) substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, C1- C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or - C(O)NRaRb. In some embodiments, E is 5-10 membered unsubstituted heteroaryl (e.g., 5-6 membered heteroaryl, or 5-6 membered heteroaryl comprising 1, 2, or 3 annular nitrogen). In some embodiments, E is 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected -C1-C4 alkoxy, -CN, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, -S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb. In some embodiments, E is 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected -C1-C4 alkoxy, -CN, C1-C4 cyanoalkyl, - S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb.

[0090] In some embodiments, -L-E is, ,. In some embodiments, -L-E is

[0091] In some embodiments, L is -C1-C4alkylene-, such as branched or unbranched -C1- C4 alkylene-. In some embodiments, E is -NRa-C(O)-C1-C4 alkyl, -NRaRb, or phenyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or - C(O)NRaRb. In some embodiments, E is -N(Ra)-CH(C3-C6 cycloalkyl)(C1-C4 haloalkyl), - NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl or C1-C4hydroxyalkyl, -NRa-C(O)-C3-C6cycloalkyl, -NRa-5-10 membered heteroaryl, -NRa-C(O)-C1-C4 alkyl, -C(O)-NRa-C1-C4 alkyl, -NRaRb, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl.

[0092] In some embodiments, -L-E is -CH2CH2NH2, -CH2CH2NHC(O)CH3, -CH2CH2- phenyl, -CH2CH2CH2NH2, -CH2CH2CH2NHC(O)CH3, -CH2CH2CH2C(O)NHCH3, -CH2CH2CH2NHC(O)-cyclopropyl, -CH2CH2C(CH3)HNHC(O)-cyclopropyl, - CH2CH2CH2CH2NHC(O)-cyclopropyl,, ,, , ,In some embodiments, -L-E is -CH2CH2NH2, - CH2CH2NHC(O)CH3, -CH2CH2-phenyl, -CH2CH2CH2NH2, -CH2CH2CH2NHC(O)CH3, - CH2CH2CH2C(O)NHCH3, -CH2CH2CH2NHC(O)-cyclopropyl, -CH2CH2C(CH3)HNHC(O)- cyclopropyl, -CH2CH2CH2CH2NHC(O)-cyclopropyl,

[0093] In some embodiments, L is 3-7 membered heterocyclyl-, such as 3-6 membered heterocyclyl or 5-6 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl or oxo.In some embodiments, L is -3-7 membered unsubstituted heterocyclyl-, such as unsubstituted 5-6 membered heterocyclyl. In some embodiments, E is H, -NRa-C(O)-C3-C6 cycloalkyl, or hydroxy. In some embodiments, E is -NRa-C(O)-C3-C6 cycloalkyl, or hydroxy. In some embodiments,.

[0094] In some embodiments, L is -5-6 membered heteroaryl- or -5-6 membered heteroaryl-(C1-C3 alkylene)-, wherein the -5-6 membered heteroaryl- of each is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo. In some embodiments, E is H; hydroxy; C1-C4alkyl; -C(O)-NRa-C1-C4alkyl; -NRa-C(O)-C3-C9cycloalkyl; 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected oxo. In some embodiments, -L-E is, , ,.

[0095] In some embodiments, L is -NRa-. In some embodiments, E is H, C1-C4alkyl, C3-C6cycloalkyl, or 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb. In some embodiments, E is 5-6 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); -S(O)2NH2; or -P(O)(C1-C4alkyl)(C1-C4alkyl). In some embodiments, -L-E iswherein Ring E’ is 6-10 membered aryl or 5-10 membered heteroaryl (e.g., phenyl or 5-6 membered heteroaryl), R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl. In some embodiments, E is unsubstituted 5-6 membered heteroaryl or C3-C6 cycloalkyl.

[0096] In some embodiments, -E is, , ,wherein Ring E’ is 6-10 membered aryl or 5-10 membered heteroaryl (e.g., phenyl or 5-6 membered heteroaryl), R is C1-C4alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl. In some embodiments, E is unsubstituted 5-6 membered heteroaryl or C3-C6 cycloalkyl.

[0097] In some embodiments, E is C3-C6 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of -OH.

[0098] In some embodiments, -L-E is -NHCH2CH2CH3,, ,

[0099] In some embodiments, L is -NRa-C1-C3alkylene-O-, wherein the C1-C3alkylene in L is unbranched or branched. In some embodiments, E is H or C1-C4 alkyl. In some embodiments, -L-E is,

[0100] In some embodiments, L is -NRa-C1-C4hydroxyalkylene-. In some embodiments, E is H, C1-C4 alkyl, or phenyl substituted with 0, 1, or 2 instances of independently selected C1- C4 alkyl, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb. In some embodiments, E is H, or unsubstituted phenyl. In some embodiments, E is H, C1-C4 alkyl, or phenyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl.

[0101] In some embodiments, -L-E is,

[0102] In some embodiments, L is -NRa-C1-C5alkylene-, -NRa-C3-C7cycloalkylene-C1-C3alkylene-, or -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3haloalkyl, halo, or OH. In some embodiments, L is -NRa-C1-C3alkylene-, -NRa- cyclopropylene-C1-C3alkylene-, or -NRa-C1-C3alkylene-cyclopropylene-C1-C3alkylene-. Insome embodiments, L is -NRa-C1-C5alkylene-. In some embodiments, L is -NRa-C1-C5alkylene-, -NRa-C1-C4 alkylene-, -NRa-C1-C3 alkylene-, -NRa-C1-C2 alkylene-, or methylene.

[0103] In some embodiments, E is -H; -C3-C6cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-NRa-C3-C6cycloalkyl; 5-10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or - C(O)NRaRb; 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl; -NRa-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb; -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), - S(O)2NH2, -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb; or -O-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, - P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb.

[0104] In some embodiments, L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene- C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; or -NRa-C1-C3alkylene- C3-C7cycloalkylene-C1-C3alkylene-. In some embodiments, L is -NRa-C1-C3alkylene-, - NRa-cyclopropylene-C1-C3 alkylene-, or -NRa-C1-C3 alkylene-cyclopropylene-C1-C3alkylene-. In some embodiments, L is -NRa-C1-C5alkylene-. In some embodiments, L is - NRa-C1-C5 alkylene-, -NRa-C1-C4 alkylene-, -NRa-C1-C3 alkylene-, -NRa-C1-C2 alkylene-, or methylene. In some embodiments, E is -H; -C3-C6cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-NRa-C3-C6cycloalkyl; 5-10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN, C1-C4 alkyl substituted with 1 instance of CN, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, or - P(O)(C1-C4 alkyl)(C1-C4 alkyl); 5-6 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl; -NRa-5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN, C1-C4 alkyl substituted with 1 instance of CN, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), - S(O)2NH2, or -P(O)(C1-C4alkyl)(C1-C4alkyl); -NRa-C(O)-5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN; or -O-phenyl, wherein the phenyl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN or halo.

[0105] In some embodiments, E is -H; -C3-C6 cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-NRa-C3-C6cycloalkyl; -C(O)- NRa-5-10 membered heteroaryl; 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkoxy; 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected oxo or C1-C4alkyl; -NRa-6-10 membered aryl or -NRa-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkoxy or - C(O)NRaRb; -NRa-C(O)-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl; or -O-5-10membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected halo.

[0106] In some embodiments, L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene- C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3 alkylene-; or -O-C3-C6 cycloalkylene. In some embodiments, L is -NRa- C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3 haloalkyl, halo, or OH; or -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-. In some embodiments, L is -NRa-C1-C3 alkylene-, -NRa-cyclopropylene-C1-C3 alkylene-, or - NRa-C1-C3alkylene-cyclopropylene-C1-C3alkylene-. In some embodiments, L is -NRa-C1-C5alkylene-. In some embodiments, L is -NRa-C1-C5 alkylene-, -NRa-C1-C4 alkylene-, -NRa-C1- C3 alkylene-, -NRa-C1-C2 alkylene-, or methylene. In some embodiments, -E is H, N(CH3)2,, , wherein RE1is C1-C4 alkyl, , wherein RE2is halo,wherein RE3is -O-C1-C4alkyl,, wherein RE1is C1-C4 alkyl,, , wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl.

[0107] In some embodiments, -L-E is -NHCH2CH2CH2N(CH3)2, -O-CH2CH2CH2N(CH3)2, -NHCH2CH2CH2NHCH3,, ,.

[0108] In some embodiments, L is -NRa-C3-C7cycloalkylene-; -NRa-C3-C7cycloalkylene- C1-C3 alkylene-; wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; or -NRa-C1-C3 alkylene- C3-C7cycloalkylene-C1-C3alkylene-. In some embodiments, L is -NRa-cyclopropylene-, -NRa-cyclopropylene-C1-C3alkylene-, or -NRa-C1-C3alkylene-cyclopropylene-C1-C3alkylene-. In some embodiments, L is -NRa-C3-C7 cycloalkylene-, such as -NRa- cyclopropylene-, -NRa- cyclobutylene-, -NRa-C3-C7 cyclopentylene-, or -NRa-cyclohexylene- . In some embodiments, E is hydroxy; C1-C4 haloalkyl;-NRa-C(O)-C1-C4 alkyl; 5-10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or - C(O)NRaRb; -NRa-5-6 membered aryl or heteroaryl, wherein the 5-6 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; -NRa-C(O)-C3-C6cycloalkyl; -NRa-C(O)-5-6 membered aryl or heteroaryl, wherein the 5-6 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), - S(O)2NH2, -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb; or -O-5-6 membered aryl or heteroaryl, wherein the 5-6 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -P(O)(C1- C4alkyl)(C1-C4alkyl), or -C(O)NRaRb.

[0109] In some embodiments, L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene- C1-C3 alkylene-; wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; or -NRa-C1-C3alkylene- C3-C7cycloalkylene-C1-C3alkylene-. In some embodiments, L is -NRa-cyclopropylene-, - NRa-cyclopropylene-C1-C3 alkylene-, or -NRa-C1-C3 alkylene-cyclopropylene-C1-C3 alkylene-. In some embodiments, L is -NRa-C3-C7cycloalkylene-, such as -NRa-cyclopropylene-, -NRa- cyclobutylene-, -NRa-C3-C7cyclopentylene-, or -NRa-cyclohexylene- . In some embodiments, E is hydroxy; C1-C4 haloalkyl; -NRa-C(O)-C1-C4 alkyl; phenyl; -NRa-5-6 membered aryl or heteroaryl, wherein the 5-6 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); -S(O)2NH2; or - P(O)(C1-C4alkyl)(C1-C4alkyl); -NRa-C(O)-C3-C6 cycloalkyl; -NRa-C(O)-5-6 membered aryl or heteroaryl, wherein the 5-6 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl); - S(O)2NH2; or -P(O)(C1-C4alkyl)(C1-C4alkyl); or -O-phenyl.

[0110] In some embodiments, L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene- C1-C3alkylene-; wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; or -NRa-C1-C3alkylene- C3-C7 cycloalkylene-C1-C3 alkylene-. In some embodiments, L is -NRa-cyclopropylene-, - NRa-cyclopropylene-C1-C3alkylene-, or -NRa-C1-C3alkylene-cyclopropylene-C1-C3alkylene-. In some embodiments, L is -NRa-C3-C7cycloalkylene-, such as -NRa- cyclopropylene-, -NRa- cyclobutylene-, -NRa-C3-C7 cyclopentylene-, or -NRa-cyclohexylene- . In some embodiments, -E is -OH, C1-C4haloalkyl,, ,, wherein RE1is C1-C4alkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl,-CN, C1-C4 heteroalkyl, C3-C6 cycloalkyl, or C3-C7 heterocyclic, , wherein RE3is C1-C4 alkyl, , wherein RE4is C3-C6cycloalkyl, , wherein RE2is halo, wherein RE5is C1-C4 alkoxy or -C(O)NRaRb,, or , wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4 alkyl.

[0111] In some embodiments, E is hydroxy; C1-C4haloalkyl; -NRa-C(O)-C1-C4alkyl; - C(O)-NRa-C1-C4 alkyl; 6-10 membered aryl; -NRa-5-10 membered heteroaryl, wherein the 5- 10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected; C1- C4alkoxy or -C(O)NRaRb; -NRa-C(O)-C3-C6cycloalkyl; -NRa-C(O)-5-10 membered heteroaryl, wherein the -NRa-C(O)-5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, C3- C6cycloalkyl, C3-C7heterocyclic, C1-C4alkoxy, or -CN; or -O-6-10 membered aryl.

[0112] In some embodiments, -L-E is, ,. In some embodiments, -L-E is

[0113] In some embodiments, L is -O-C1-C3 alkylene-. In some embodiments, E is H or 5- 10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb. In some embodiments, E is H or phenyl. In some embodiments, E is H or 6-10 membered aryl.

[0114] In some embodiments, -L-E is -OCH2CH2CH3, -OCH2-phenyl, or -OCH2CH2- phenyl.

[0115] In some embodiments, L is -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-. In some embodiments, E is -NRa-C(O)-C3-C6cycloalkyl or -C(O)-NRa-C1-C4alkyl. In someembodiments, -L-E iso.

[0116] In some embodiments, L is -C(O)-NRa-C1-C4 alkylene-. In some embodiments, E is -C(O)-NRa-C1-C4 alkyl or -NRa-C(O)-C3-C6 cycloalkyl. In some embodiments, -L-E is

[0117] In some embodiments, L is -C1-C3alkylene-C3-C6cycloalkylene-. In some embodiments, E is -NRa-C(O)-C3-C6cycloalkyl. In some embodiments, -L-E is.

[0118] In some embodiments, L is -C3-C7cycloalkylene- or -C3-C7cycloalkenylene-. In some embodiments, E is C1-C4alkyl, -C(O)-NRa-C1-C4alkyl, or -NRa-C(O)-C3-C6cycloalkyl. In some embodiments, E is -C(O)-NRa-C1-C4 alkyl or -NRa-C(O)-C3-C6 cycloalkyl. In some embodiments, -L-E is, ,. In some embodiments, -L-E is.

[0119] In some embodiments, L is -6 membered aryl-(C1-C3alkylene)-. In some embodiments, E is -NRa-C(O)-C1-C4alkyl. In some embodiments, -L-E is.

[0120] In some embodiments, L is -C2-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. In some embodiments, L is -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo.

[0121] In some embodiments, L is deuterated at one or more positions. In some embodiments, every H of L is deuterated. In some embodiments, when L is -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo, then L is deuterated at one or more positions. In some embodiments, when L is -C3-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo, every H of L is deuterated.

[0122] In some embodiments, L is -CH=CH-(C1-C3linear alkylene)-, -CH=CH-(C2-C3linear alkenylene)-, or -CH2-CH=CH-, each substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. In some embodiments, L is -CH=CH-(C1-C3 linear alkylene)- or -CH=CH-(C2-C3linear alkenylene)-, each substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. In some embodiments, L is -CH=CH-(C1-C3linear alkylene)- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. In some embodiments, -L-E is -CH=CH-(C1-C3 linear alkylene)- E or -CH=CH-(C2-C3 linear alkenylene)-E, wherein CH=CH-(C1-C3 linear alkylene) or CH=CH-(C2-C3linear alkenylene) is substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo. In some embodiments, -L-E is -CH=CH-(C1-C3linear alkylene)- E, wherein CH=CH-(C1-C3 linear alkylene) is substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo. In some embodiments, L is.

[0123] In some embodiments, E is H; hydroxy; -NRaRb, -C(O)-NRa-C1-C4 alkyl; -NRa- S(O)2-C3-C6cycloalkyl; -NRa-C(O)-C1-C4alkyl substituted with 0, 1, or 2 instances of independently selected halo or CN; -NRa-C(O)-C3-C9cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, C1-C4haloalkyl, -OH, C1-C4hydroxyalkyl, -CN, C1-C4cyanoalkyl, C1-C4 heteroalkyl, -NRa-C(O)-C1-C4 alkyl, -C(O)-NRaRb, or 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4 alkyl; -NRa-C(O)-3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, oxo, or -C(O)-Ra; -NRa-C(O)-C6-C10 membered aryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, -CN, C1-C4alkoxy, C1-C4heteroalkyl, -NRaRb, - C(O)-NRa-S(O)2(C1-C4 alkyl), or -P(O)(C1-C4 alkyl)(C1-C4 alkyl); -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, halo, -OH, C1-C4haloalkyl, C1-C4alkoxy, -O-C1-C4haloalkyl, -NRaRb, -S(O)2(C1-C4alkyl), -NRa-C(O)-C1-C4alkyl-, -C(O)-NRa-S(O)2(C1-C4 alkyl), C3-C6 cycloalkyl, or C3-C7 heterocyclyl ; -NRa-C6-C10membered aryl substituted with 0, 1, 2, or 3 instances of independently selected halo, C1-C4alkoxy, -CN, -S(O)2(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), or - C(O)NRaRb; -NRa-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, C1-C4alkoxy, or -C(O)NRaRb; -NRa-3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected 6-10 membered aryl substituted with 1 instance of C1-C4 alkoxy; -NRa-C(O)-C1-C4alkylene-3-9 membered cycloalkyl; -NRa-C(O)-C1-C4 alkylene-3-9 membered heterocyclyl;-NRa-C(O)-C1-C4alkylene-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl; -NRa-C(O)-C1-C4 alkylene-O-3-9 membered cycloalkyl; -NRa-C(O)-C2-C4alkynylene-3-9 membered cycloalkyl; -NRa-C(O)-C2-C5alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5 heteroalkyl or -NRa-C(O)-C1-C4 alkyl; -C1-C6 heteroalkyl; -NRa-C(O)-C1-C6heteroalkyl; -NRa-C(O)-C1-C4 haloalkylene-3-9 membered cycloalkyl; -NRa-C(O)-C(O)-N(Rb)2; -NRa-C(=NH)-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl; -NRa-C(O)-C=3-9 membered cycloalkyl; -NRa-C(O)O-3-9 membered cycloalkyl; -3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl or oxo; or -5-10 membered heteroaryl.

[0124] In some embodiments, E is -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, or -NRa-C(O)-C3-C6 cycloalkyl. In some embodiments, -L-E is.

[0125] In some embodiments, L is -CH=C3-C7cycloalkylene- or -CH=CH-C3-C7cycloalkylene. In some embodiments, E is -NRa-C(O)-C3-C9 cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, cyclopropyl, or NH2. In some embodiments, E is -NRa-C(O)-3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, cyclopropyl or NH2. In some embodiments, E is -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, cyclopropyl, or NH2. In some embodiments, E is -NRa-C(O)-C3-C6cycloalkyl or -C(O)-NRa-C1-C4alkyl. In some embodiments, -L-E is, ,,

[0126] In some embodiments, R4Acontains one or more secondary or tertiary amines. In some embodiments, L’ is -NH-C2-C10 alkylene-, -C2-C10 alkylene-NH-,,. In some embodiments, L’ is -C2-C12 alkylene-. In some embodiments,R4Ais a bond or -NH-R9. In some embodiments, R9is -R13-R9A. In some embodiments, -R13- R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected halo. In some embodiments,,

[0127] In some embodiments, L is -CH=C3-C7cycloalkylene- or -CH=CH-C3-C7cycloalkylene. In some embodiments, E is H, -NRa-C(O)-C3-C6 cycloalkyl, or -C(O)-NRa-C1-.

[0128] In some embodiments, L is -C2-C4 alkynylene-. In some embodiments, E is H, C1- C4 alkyl, -NRa-C(O)-C1-C4 alkyl, -CH(OH)(5-6 membered heteroaryl), or -NRa-5-10 membered heteroaryl. In some embodiments, E is -NRa-C(O)-C1-C4alkyl, -CH(OH)(5-6 membered heteroaryl), or -NRa-5-10 membered heteroaryl. In some embodiments, -L-E isembodiments, -L-E i

[0129] In some embodiments, Z4is N or CR4; Z4Ais C; Z5is N or CR5; Z6is N or CR6; and Z7is N or CH.

[0130] In some embodiments, Z4is NR4, CR4H, or C(R4)R4B; Z4Ais N or CH; Z5is NR5or CHR5; Z6is NR6or CHR6; and Z7is NH or CH2.

[0131] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH.

[0132] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is N, Z6is CR6; and Z7is CH.

[0133] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4Ais CR4; Z5is CR5; Z6is CR6; and Z7is CH.

[0134] In some embodiments, Z1is N; Z2is CR2; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH.

[0135] In some embodiments, Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH.

[0136] In some embodiments, Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is N.

[0137] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2.

[0138] In some embodiments, Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2.

[0139] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is NH.

[0140] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2.

[0141] In some embodiments, Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is NR6; and Z7is CH2.

[0142] In some embodiments, Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is NR5; Z6is CHR6; and Z7is CH2.

[0143] In some embodiments, Z1is CH; Z3is N; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2.

[0144] In some embodiments, Z1is N and Z3is CH. In some embodiments, Z1is CH and Z3is N.

[0145] In some embodiments, Z5is N. In some embodiments, Z5is CR5. In some embodiments, Z5is CH.

[0146] In some embodiments, R5is H, -OR10, or -NH-R9.

[0147] In some embodiments, Z6and Z7are each CH.

[0148] In some embodiments, R6is H or -NH2.

[0149] In some embodiments, Z4is CR4and Z5is CR5. In some embodiments, the compound is of Formula (I-G)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound is of Formula (I-3G)or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F. In some embodiments, R4is selected from the group consisting of Hand -NH-R9; and R5is H. In some embodiments, R4is -NH-R9. In some embodiments, R5is H.

[0152] In some embodiments, R9is: a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1- C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with - NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; or -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, - C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12.

[0153] In some embodiments, R9is: 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, hydroxy, C1-C6heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; 3-9 membered cycloalkyl substituted with 1 or 2 instances of -NRdReand with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene- C(O)NRdRe, -NRdRe, or -R12; or-C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene- C(O)NRdRe, -NRdRe, or -R12.

[0154] In some embodiments, R9is 3-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected -OH, C1-C4 alkyl, halo, C1-C4 alkoxy, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene- SO2-(C1-C4alkyl), C1-C4hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5- 6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4 heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; 3-9 membered cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, C1-C4 alkoxy, or -NRdRe; or -C1-C4alkylene-NRdRe.

[0155] In some embodiments, R9is R9A.

[0156] In some embodiments, -NH-R9is -NH-C1-C4 alkylene-N(CH3)2, or -NH-C1-C4 alkylene-NHCH3. In some embodiments,, wherein R90is -OH, -CN, C1-C4alkyl, halo, C1-C4alkoxy, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4 alkyl), C1-C4 hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra.

[0157] In some embodiments, -NH-R9is -NHCH2CH2CH2N(CH3)2, or - NHCH2CH2CH2NHCH3. In some embodiments,,,, In some embodiments, -NH-R9is

[0158] In some embodiments,

[0159] In some embodiments, -NH-R9is 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, -CN, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe.

[0160] In some embodiments, -NH-R9is -NH-CH2CH2CH2N(CH3)2 or -NH- CH2CH2CH2NHCH3. In some embodiments, -NH-R9is,.

[0161] In some embodiments, R9is R9B.

[0162] In some embodiments, -NH-R9is, , , wh91erein each R is independently C1-C4 alkyl or halo;, wherein Ring DE is 4-11 membered heterocyclyl and each R92is independently -OH, halo, oxo, C1-C4 haloalkyl, C1-C4alkoxy, or -SO2(C1-C4alkyl).

[0163] In some embodiments, -NH-R9is,.

[0164] In some embodiments, R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, -NRdRe, or -R12. In some embodiments,

[0165] In some embodiments, R9is R9C. In some embodiments, R9is -C1-C4 alkylene- NRdRe. In some embodiments, -NH-R9is -NHCH2CH2CH2N(CH3)2or - NHCH2CH2CH2NHCH3.

[0166] In some embodiments, R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH-R9. In some embodiments, R5is H, -OH, -O-C1-C4alkylene- NRaRb, or -O-C1-C4alkyl. In some embodiments, R5is H, -OCH3, -OH, or - OCH2CH2CH2N(CH3)2.

[0167] In some embodiments, R6is H. In some embodiments, R6is -NH2.

[0168] In some embodiments, R8Ais -H. In some embodiments, R8Ais -CH3.

[0169] In some embodiments, R8Bis -CH3 substituted with three instances of F.

[0170] In some embodiments, R14is -H. In some embodiments, R14is -CH3 substituted with 0, 1, 2, or 3 instances of F.

[0171] In some embodiments, R15is -H. In some embodiments, R15is C1-C3alkyl.

[0172] In some embodiments, the compound is of Formula (I), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; (ii) L is -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1-C4 hydroxyalkylene- ; -NRa-C3-C7cycloalkylene-; -NRa-C1-C3alkylene-C3-C7cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7cycloalkylene-C1-C3alkylene, or -NRa-5-6 membered aryl or heteroaryl-; (iii) -E is, , ,wherein Ring E’ is 5-10 membered aryl or heteroaryl, R is C1-C4alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4 alkyl; (iv) E is -NRa-C(O)-C1-C4alkyl, -NRa-C(O)-C3-C6 cycloalkyl, 5-10 membered aryl or heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4alkoxy, -O-cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, -P(O)(C1-C4alkyl)(C1-C4alkyl), or - C(O)NRaRb; -NRa-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, substituted with 0 or 1 instance of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); -S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; -O-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN, halo, C1-C4 alkoxy, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4alkyl), -S(O)2NH2, - P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb; or -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb; and (v) R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F.

[0173] In some embodiments, the compound is of Formula (I), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; (ii) L is -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1-C4 hydroxyalkylene- ; -NRa-C3-C7cycloalkylene-; -NRa-C1-C3alkylene-C3-C7cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7cycloalkylene-C1-C3alkylene, or -NRa-5-6 membered aryl or heteroaryl-; (iii) -E is, o , wherein Ring E’ is 5-10 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4 alkyl; (iv) E is -NRa-C(O)-C1-C4 alkyl, -NRa-C(O)-C3-C6 cycloalkyl, -NRa-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); -S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; or -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb; and (v) R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; and (vi) -NH-R9is, wherein R90is -OH, C1-C4alkyl, halo, C1-C4alkoxy, - C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), C1-C4hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; or, wherein R91is halo; or, wherein Ring DE is 4-11 membered heterocyclyl and each R92is independently -OH, halo, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, or -SO2(C1-C4 alkyl).

[0174] In some embodiments, the compound is of Formula (I), or a salt thereof, wherein at least one, two three, four or all of (i) to (v) applies: (i) R8is -CF3or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; (ii) L is -NRa-; -NRa-C1-C5alkylene-; -NRa-C1-C3alkylene-O-; -NRa-C1-C4hydroxyalkylene- ; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7 cycloalkylene-C1-C3 alkylene, or -NRa-5-6 membered aryl or heteroaryl-; (iv) E is -NRa-C(O)-C1-C4alkyl, -NRa-C(O)-C3-C6 cycloalkyl,-NRa-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); -S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb; or -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4 cyanoalkyl; -S(O)2(C1-C4 alkyl); - S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; and (v) R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; and (vi) -NH-R9is, wherein R90is -OH, C1-C4 alkyl, halo, C1-C4 alkoxy, - C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), C1-C4hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra.

[0175] In some embodiments, the compound is of Formula (I-4):wherein L is -NRa-,-NRa-C1-C5alkylene-, -NRa-C1-C3 alkylene-O-, -NRa-C1-C4 hydroxyalkylene-, -NRa-C3-C7cycloalkylene-, -NRa-C1-C3alkylene-C3-C7cycloalkylene-, -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene, or -NRa-5-6 membered aryl or heteroaryl-; E is -NRa-C(O)-C1-C4 alkyl, -NRa-C(O)-C3-C6 cycloalkyl, or -NRa-C(O)-5-10 membered aryl or heteroaryl, wherein the 5-10 membered aryl or heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl substituted with 0 or 1 instance of -CN; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); -S(O)2NH2; -P(O)(C1-C4alkyl)(C1-C4alkyl); or -C(O)NRaRb; and R4is -NH-R9, wherein R9is a 5-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, or halo.

[0176] In some embodiments, the compound is a compound of the formula:, ,or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, provided herein are compounds and pharmaceutically acceptable salts thereof described in Table 1. Table 1

[0178] In one aspect, provided herein are synthetic intermediates for obtaining any of the compounds described herein. In some embodiments, provided herein is a compound selected from Table 2, or a stereoisomer thereof, or a salt thereof. Table 2

[0179] Any variation or embodiment of the variables provided herein, including R2, R4, R5, R6, R8, R8A, R8B, R9, R9A, R9B, R9C, R9D, R10, R12, R13, R14, R15, Z1, Z2, Z3, Z4, Z5, Z6, Z7, L, L’, E, Ra, Rb, Rd, Re, V, W, X, Y, or Z provided herein can be combined with every other variation or embodiment of the variables provided herein, including R2, R4, R5, R6, R8, R8A, R8B, R9, R9A, R9B, R9C, R9D, R10, R12, R13, R14, R15, Z1, Z2, Z3, Z4, Z5, Z6, Z7, L, L’, E, Ra, Rb, Rd, Re, V, W, X, Y, or Z as if each combination had been individually and specifically described.

[0180] All the compounds described herein or a pharmaceutically acceptable salt thereof, can be used in the methods provided herein. The methods can be in vitro methods, such as in vitro methods of administering a compound to cells for screening purposes and / or for conducting quality control assays. The methods can also be in vivo methods, such as in vivo methods of administering a compound to a subject in need thereof for treating certain disorders. III. Method of Use

[0181] Certain bicyclic compounds containing a vinyl have been found to be effective in binding to p53 proteins having a Y220C mutation, and these compounds may be useful in stabilizing the protein and in treating conditions associated with this mutation. In one aspect, provided herein are methods comprising contacting a mutant p53 protein with an effective amount of a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a salt thereof, as described herein. P53 Protein

[0182] The p53 protein, a tumor suppressor, is an amino acid transcription factor that can regulate cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. P53 protein has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. Due to the critical role of p53 protein in tumor suppression, p53 protein is inactivated in almost all cancers either by direct mutation or through perturbation of associated signaling pathways involved in tumor suppression. The presence of certain p53protein mutations in several types of human cancer can correlate with less favorable patient prognosis.

[0183] In an unstressed cell, p53 protein levels are maintained at low levels via the interaction of p53 protein with Mdm2, an E3 ubiquitin ligase, and Mdm2 can target p53 protein for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 protein is disrupted, and p53 protein accumulates. The critical event leading to the activation of p53 protein is phosphorylation of the N-terminal domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53 results in a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. P53 protein can activate proteins involved in the above pathways including, for example, Fas / Apo, KILLER / DRS, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAFl). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD51, and hTERT.

[0184] Each chain of the p53 protein tetramer is composed of several functional domains including the transactivation domain (amino acids 1-100), the DNA-binding domain (amino acids 101-306), and the tetramerization domain (amino acids 307-355), which are highly mobile and largely unstructured. Most p53 protein mutations related to proliferative disorders are located in the DNA-binding core domain of the protein, which contains a central β- sandwich of anti-parallel β-sheets that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two β-turn loops, L2 and L3, which are stabilized by a zinc ion, for example, at Arg175 and Arg248, and a loop-sheet-helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively- charged amino acids, and makes specific contact with various p53 protein response elements.

[0185] Due to the prevalence of p53 protein mutations in many types of cancer, the reactivation of wild type p53 protein function in a cancerous cell can be an effective therapy. Mutations in p53 located in the DNA-binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. P53 mutations that can abrogate the activity of p53 include, for example, Rl75H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 protein mutations can either distort the structure of the DNA- binding site or thermodynamically destabilize the folded protein at body temperature.Without being bound by theory, wild-type function of p53 mutants can be recovered by binding of the p53 protein mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization. With the wild-type function of p53 protein recovered, downstream targets involved in tumor suppression can be further activated. Restore wild-type function of p53 mutants

[0186] In one aspect, provided herein is a method of modulating the conformation of a mutant p53 protein. In some embodiments, provided herein is a method of restoring wild-type activity of a mutant p53 protein including, for example, DNA binding function and activation of downstream targets involved in tumor suppression, wherein the method comprises selectively binding a compound described herein to the p53 mutant. In some embodiments, before contacted with the compounds described herein (e.g., a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I- C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1), the p53 mutant has a conformation that is not pro-apoptotic, and the compound described herein can bind to the binding site on the p53 mutant and modulate the conformation of the p53 mutant to a form that is pro-apoptotic. In some embodiments, the modulation of the conformation of the p53 mutant comprises forming a covalent bond between the compounds provided herein (e.g., a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1) and the p53 mutant. In some embodiments, the p53 mutant is Y220C. In some embodiments, the method of modulating the conformation of a mutant p53 protein comprises contacting the mutant p53 protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula e.g., a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the Formulas, e.g., Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), and (I-3G), is as defined herein. In some embodiments, the method of restoring wild-type function of a mutant p53 protein comprises contacting the mutant p53protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula, e.g., a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the Formulas, e.g., Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I- C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), and (I- 3G), is as defined herein.

[0187] In some embodiments, provided herein is a method of binding a compound described herein to a p53 protein containing a Y220C mutation. In some embodiments, the compound described herein selectively binds to (e.g., has a higher binding affinity for) a p53 protein containing a Y220C mutation over a p53 protein that lacks the Y220C mutation. In some embodiments, the compound described herein has higher binding affinity for the Y220C residue on a p53 protein over other residues on the protein. In some embodiments, the compound described herein has higher binding affinity for the cysteine at position 220 in a p53 Y220C mutant protein compared to other cysteine residues in the protein. In some embodiments, provided herein is a method of stabilizing the Y220C mutant, optionally to reduce the likelihood of denaturation or misfolding of the protein at body temperature with a compound provided herein. The Y220C mutant is a temperature sensitive mutant, which binds to DNA at lower temperature and is denatured at body temperature. Located in the periphery of the p53 β-sandwich connecting β-strands S7 and S8, the aromatic ring of Y220 is an integral part of the hydrophobic core of the β-sandwich. The Y220C mutation can be highly destabilizing, due to the formation of an internal surface cavity. In some embodiments, the compounds described herein can bind to and occupy this surface crevice to stabilize the sandwich, thereby restoring wild-type p53 DNA-binding activity.

[0188] In some embodiments, the method comprises determining the ability of a compound described herein to bind and stabilize mutant p53. In some embodiments, assays can be employed to detect, for example, a conformational change in the p53 mutant or activation of wild-type p53 targets. Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectrometry (NMR), or X-ray crystallography. Additionally, antibodies specific for the wild type of mutant conformation of p53 can be used to detect a conformational change via, for example, immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting.

[0189] In some embodiments, provided herein is a method of reactivating the transcriptional activity of p53. In some embodiments, the method is to activate downstream targets in the p53 signaling cascade. In some embodiments, the method is to activate p53 effector proteins. In some embodiments, the potency and efficacy of the compounds described herein in reactivating the transcriptional activity of p53 can be measured by, for example, immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction (RT-PCR), and immununoblotting. The activation of p53 can also be measured by the induction of apoptosis via the caspase cascade and using methods including, for example, Annexin V staining, TUNEL assays, pro-caspase and caspase levels, and cytochrome c levels. Another consequence of p53 activation is senescence, which can be measured using methods such as galactosidase staining.

[0190] In some embodiments, the method provided herein is in vitro, wherein the method comprises contacting the mutant p53 protein with an effective amount of a compound or a salt thereof described herein. In some embodiments, the method is in vivo, wherein the method comprises contacting the mutant p53 protein in a subject in need thereof with an effective amount or a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described herein.

[0191] In some embodiments, the method provided herein increases the ability of a p53 mutant to bind to DNA by at least about 0.1%, such as at least about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the ability of the p53 mutant to bind to DNA in the absence of the method. In some embodiments, the method provided herein increases the ability of a p53 mutant to bind to DNA by up to about 0.1%, such as up to about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the ability of the p53 mutant to bind to DNA in the absence of the method. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations.

[0192] In some embodiments, the method provided herein increases the DNA-binding activity of the Y220C mutant by at least about 2-fold, such as by at least about any of 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, at least or up to about 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, at least or up to about 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 160-fold, 170-fold, 180-fold, 190-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450- fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold, 1,000-fold, 1,500-fold, 2.000-fold, 3,000-fold, 4,000-fold, 5,000-fold, 6,000-fold, 7,000-fold, 8,000-fold, 9,000-fold, or 10,000-fold compared to the ability of Y220C to bind DNA in the absence of the method. In some embodiments, the method provided herein increases the DNA-binding activity of the Y220C mutant by up to about 2-fold, such as by up to about any of 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, at least or up to about 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, at least or up to about 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 110-fold, 120-fold, 130- fold, 140-fold, 150-fold, 160-fold, 170-fold, 180-fold, 190-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800- fold, 850-fold, 900-fold, 950-fold, 1,000-fold, 1,500-fold, 2.000-fold, 3,000-fold, 4,000-fold, 5,000-fold, 6,000-fold, 7,000-fold, 8,000-fold, 9,000-fold, or 10,000-fold compared to the ability of Y220C to bind DNA in the absence of the method.

[0193] In some embodiments, the method provided herein increases the stability of a p53 mutant by at least about 0.1%, such as at least about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the stability of the p53 mutant in the absence of the method. In some embodiments, the method provided herein increases the stability of a p53 mutant by up to about 0.1%, such as up to about any of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 125%, 150%, 175%, 200%, 225%, or 250%, as compared to the stability of the p53 mutant in the absence of the method. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations.

[0194] In some embodiments, the method provided herein restores the wild-type function of a p53 mutant by at least about 5%, such as at least about any of 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%. In some embodiments, the method provided herein restores the wild-type function of a p53 mutant by up to about 5%, such as up to about any of 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%. In some embodiments, the p53 mutant comprises a Y220C mutation, with or without other mutations.Treating proliferative disorders

[0195] In some embodiments, provided herein is a method of inducing apoptosis, cell cycle arrest, and / or senescence in a cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell carries a mutation in p53. In some embodiments, the method is in vitro. In some embodiments, the method is in vivo.

[0196] In some embodiments, provided herein is a method of treating a proliferative disorder comprising administering an effective amount or a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0197] In some aspects, provided herein is a method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0198] In some embodiments, the proliferative disorder is associated with a mutant p53 protein. In some embodiments, also provided herein is a method of preventing a proliferative disorder. In some embodiments, the mutant p53 protein comprises a Y220C mutation, with or without other mutations. In some embodiments, the proliferative disorder is a cancer.

[0199] In some embodiments, provided herein is a method of treating cancer.

[0200] In some embodiments, provided herein is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0201] In some embodiments, the method is to slow the proliferation of cancer cell lines, or kill cancer cells. In some embodiments, also provided herein is a method of preventing cancer. In some embodiments, the cancer is associated with a p53 protein comprising a Y220C mutation, with or without other mutations.

[0202] In some embodiments, the method of treating a proliferative disorder comprises comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II- P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein each of the Formula(A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I- 3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I- E), (I-F), (I-G), and (I-3G) is as defined herein. In some embodiments, the method of treating cancer comprises comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein each of the Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I- P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I-3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II- 1), (II-2), (II-3), (I-E), (I-F), (I-G), and (I-3G) is as defined herein.

[0203] In some embodiments, the method provided herein slows the progression of cancer in a subject in need thereof by at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method provided herein slows the progression of cancer in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method.

[0204] In some embodiments, the method provided herein reduces the likelihood of development of a proliferative disorder or any symptom thereof in a subject in need thereofby at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method provided herein reduces the likelihood of development of a proliferative disorder or any symptom thereof in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method.

[0205] In some embodiments, the method provided herein delays the development of a proliferative disorder or any symptom thereof in a subject in need thereof by at least about 0.5%, such as at least about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. In some embodiments, the method provided herein delays the development of a proliferative disorder or any symptom thereof in a subject in need thereof by up to about 0.5%, such as up to about any of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9%, when compared to not using the method. IV. Composition

[0206] In some aspects, provided herein is a composition comprising a mutant p53 protein and a p53 stabilizer having a covalent bond to the mutant p53 protein, wherein the mutant p53 protein comprises a Y220C mutation, and the covalent bond is formed between a vinyl group of the p53 stabilizer and the cysteine at position 220 in the mutant p53 protein. In some embodiments, the mutant p53 protein has greater wild-type function compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments, the mutant p53 protein has a greater wild-type conformation compared to a composition comprising the mutant p53 protein without the p53 stabilizer having a covalent bond to the mutant p53 protein. In some embodiments, the stabilizer selectively binds to the cysteine at position 220 in the mutant p53 protein compared to other positions within the protein (e.g., compared to other cysteines in the protein). In some embodiments, the p53 stabilizer is a compound of Formula (A), (B), (C), (D), (E), (F), (G), (I), (I-P0), (I-P1), (I-P2), (I-1), (I-2), (I-3), (I-4), (I-A), (I-B), (I-C), (I- 3A), (I-D), (II), (II-P0), (II-P1), (II-P2), (II-1), (II-2), (II-3), (I-E), (I-F), (I-G), (I-3G), or Table 1, or a pharmaceutically acceptable salt thereof. V. Formulation

[0207] In some embodiments, the compounds provided herein can be formulated in a formulation, such as a pharmaceutical formulation. In some embodiments, the formulation further comprises one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical formulation includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are formulations, such as pharmaceutical formulations that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the formulation may be sterile or contains components that are sterile. Sterilization can be achieved by methods known in the art. In some embodiments, the formulation comprises one or more compounds that are substantially pure (e.g., with a purity of at least about any of 85%, 90%, 95%, 98%, 99%,99.5%, 99.9%, or 99.99%). In some embodiments, especially wherein a formulation is administered by inhalation, injection, or other parenteral administration including the routes listed herein, or wherein a formulation is used for oral, gastric, gastrointestinal, or enteric administration, the formulations and preparations used in the methods disclosed herein are sterile. Methods for preparing sterile, pharmaceutically acceptable compositions include steam sterilization, dry-heat sterilization, gas sterilization, ionizing radiation, or sterile filtration. Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Code of Federal Regulations 211) known to those of skill in the art. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0209] Also provided are packaged pharmaceutical formulations, comprising a pharmaceutical formulation as described herein and instructions for using the formulation to treat a patient suffering from a disease or condition described herein. VI. Dose and method of administration

[0210] The compounds and compositions described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg / kg of body weight; in some embodiments, from about 0.05 to 10.0 mg / kg of body weight, and in some embodiments,from about 0.10 to 1.4 mg / kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetics.

[0211] Administration of the compounds and compositions described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0212] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0213] The compounds disclosed and / or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and / or described herein. Actualmethods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0214] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and / or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.

[0215] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and / or described herein in solution.

[0216] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0217] In addition, pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.VII. Kits

[0218] Also provided herein are kits for carrying out the methods described herein, which comprises one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of any of the diseases described herein.

[0219] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.

[0220] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., cancer) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0221] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods described herein. The instructions included with the kit generally include information as to the components and their administration to an individual. ENUMERATED EMBODIMENTS

[0222] The following enumerated embodiments are representative of some aspects of the invention. A1. A compound of Formula (I-P1) or (II-P1):wherein: Z1is N and Z3is CH, or Z1is CH and Z3is N; Z5is N or CR5; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo; -C1-C3alkylene-NRa-; - CH=C3-C7cycloalkylene-; -CH=CH-C3-C7cycloalkylene-; -C2-C4alkynylene-; -NRa- ; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1-C4 hydroxyalkylene-; - NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -NRa-6 membered aryl-; - NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5- 6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, -C3-C7cycloalkylene-(C1-C3alkylene)-, or -C3-C7cycloalkenylene-(C1-C3alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3alkylene-C3- C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -O-C3-C6 cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; and -O-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-; E is selected from the group consisting of: H; C1-C4 alkyl; C1-C4 haloalkyl; C3-C6 cycloalkyl; hydroxy; -NRaRb; -NRa-C(O)- C1-C4alkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl;-C(O)-NRa-C3-C6cycloalkyl; -C(O)-C3-C6cycloalkyl; -N(Ra)-CH(C3-C6cycloalkyl)(C1-C4 haloalkyl); -CH(OH)(5-6 membered heteroaryl); -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, halo, C1- C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-cyclopropyl, C1-C4 alkoxy substituted with 1 instance of F or CN, -CN, C1-C4 cyanoalkyl, -S(O)2(C1-C4 alkyl), - S(O)2NH2, -S(O)(=NH)(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), -C(O)NRaRb, or C3-C7 heterocyclic, wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, or -C(O)-N(Ra)-; and 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl; R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; or R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH-R9; R9is R9A, R9B, or R9C; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4 alkylene-NRdRe, wherein the C1-C4 alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1- C4haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4 heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra; R10is H, -C1-C4 alkylene-NRaRb, or -C1-C4 alkyl; R6is H or -NH2; R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; Raand Rbin each instance are independently selected from the group consisting of H and C1- C4alkyl; and Rdand Rein each instance are independently selected from the group consisting of H; C1-C4 alkyl substituted with 0 or 1 instance of -O-C1-C4 alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4alkyl), C1-C4alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 heteroalkyl; or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof; wherein the compound is not:; or a stereoisomer or a pharmaceutically acceptable salt thereof. A2. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-1) or (II-1):A3. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is Formula (I-2) or (II-2)A4. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-P1). A5. The compound of embodiment A4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CH3 substituted with 1, 2, or 3 instances of F. A6. The compound of embodiment A5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CF3 and the compound of Formula (I-P1) is a compound of formula (I-A)A7. The compound of embodiment A5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CHF2 and the compound of Formula (I-P1) is a compound of formula (I-B)A8. The compound of embodiment A5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CH2F and the compound of Formula (I-P1) is a compound of formula (I-C)A9. The compound of embodiment A4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is cyclopropyl substituted with one F. A10. The compound of embodiment A4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is cyclopropyl. A11. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-P1). A12. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is a bond. A13. The compound of embodiment A12, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, C1-C4 alkyl, -NRaRb, or 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4alkyl. A14. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is H, -CH2CH2CH3, -NH2, - NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,A15. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C3 alkylene-NRa-. A16. The compound of embodiment A15, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected -C1-C4 alkoxy, -CN, C1-C4 cyanoalkyl, -S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or -C(O)NRaRb. A17. The compound of embodiment A15, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is 5-10 membered unsubstituted heteroaryl.A18. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,A19. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C4alkylene-. A20. The compound of embodiment A19, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -N(Ra)-CH(C3-C6cycloalkyl)(C1-C4haloalkyl), -NRa- C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl or C1-C4 hydroxyalkyl, -NRa-C(O)-C3-C6 cycloalkyl, -NRa-5-10 membered heteroaryl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRa-C1-C4alkyl, -NRaRb, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl. A21. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -CH2CH2NH2, - CH2CH2NHC(O)CH3, -CH2CH2-phenyl, -CH2CH2CH2NH2, -CH2CH2CH2NHC(O)CH3, -CH2CH2CH2C(O)NHCH3, -CH2CH2CH2NHC(O)-cyclopropyl, -CH2CH2C(CH3)HNHC(O)- cyclopropyl, -CH2CH2CH2CH2NHC(O)-cyclopropyl,,A22. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -3-7 membered heterocyclyl-, wherein the -3-7 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo. A23. The compound of embodiment A22, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -3-7 membered unsubstituted heterocyclyl-. A24. The compound of embodiment A22 or embodiment A23, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, -NRa-C(O)-C3-C6cycloalkyl, or hydroxy. A25. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isA26. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-.A27. The compound of embodiment A26, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is C3-C6 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of -OH. A28. The compound of embodiment A1 or A26, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,, , ,, wherein Ring E’ is 6-10 membered aryl or 5-10 membered heteroaryl, R is C1-C4alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently C1-C4alkyl. A29. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -NHCH2CH2CH3,. A30. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C3alkylene-O-.A31. The compound of embodiment A30, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H or C1-C4 alkyl. A32. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -. A33. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C4 hydroxyalkylene-. A34. The compound of embodiment A33, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, C1-C4 alkyl, or phenyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl. A35. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,A36. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C5 alkylene-. A37. The compound of embodiment A36, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -H; -C3-C6 cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C3-C6 cycloalkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-NRa-C3-C6cycloalkyl; -C(O)-NRa-5-10 membered heteroaryl; 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkoxy; 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected oxo or C1-C4 alkyl;-NRa-6-10 membered aryl or -NRa-5-10 membered heteroaryl, wherein the 6- 10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkoxy or -C(O)NRaRb; -NRa-C(O)-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl; or -O-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected halo. A38. The compound of embodiment A36, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -E is H, N(CH3)2, NHCH3,, wherein RE1is C1-C4 alkyl, , wherein RE2is halo, wherein RE3is -O-C1-C4 alkyl,, wherein RE1is C1-C4 alkyl,, , wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl. A39. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -NHCH2CH2CH2N(CH3)2, - NHCH2CH2CH2NHCH3,. A40. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C3-C7 cycloalkylene-; -NRa-C3- C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; or -NRa- C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-. A41. The compound of embodiment A40, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C3-C7cycloalkylene-.A42. The compound of embodiment A40 or A41, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is hydroxy; C1-C4 haloalkyl; -NRa-C(O)-C1-C4 alkyl; -C(O)-NRa-C1-C4 alkyl; 6-10 membered aryl; -NRa-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected; C1-C4 alkoxy or - C(O)NRaRb; -NRa-C(O)-C3-C6cycloalkyl; -NRa-C(O)-5-10 membered heteroaryl, wherein the -NRa-C(O)-5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C3-C6cycloalkyl, C3-C7heterocyclic, C1-C4 alkoxy, or -CN; or -O-6-10 membered aryl. A43. The compound of any one of embodiments A40-A41, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -E is -OH, C1-C4haloalkyl,wheE1rein R is C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl,-CN, C1-C4heteroalkyl, C3-C6cycloalkyl, or C3-C7heterocyclic, wherein RE3is C1-C4 alkyl,, wherein RE4is C3-C6 cycloalkyl, , wherein RE2is halo, wherein RE5is C1-C4a balkoxy or -C(O)NR R ,, , wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4 alkyl. A44. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,A45. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -O-C1-C3alkylene-. A46. The compound of embodiment A45, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H or 6-10 membered aryl. A47. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -OCH2CH2CH3, -OCH2-phenyl, or - OCH2CH2-phenyl. A48. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C3alkylene-C3-C7cycloalkylene-. A49. The compound of embodiment A48, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C6cycloalkyl or -C(O)-NRa-C1-C4alkyl. A50. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is.A51. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C3 alkylene-C3-C6 cycloalkylene-.A52. The compound of embodiment A51, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C6 cycloalkyl. A53. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is, A54. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C3-C7cycloalkylene- or -C3-C7cycloalkenylene-. A55. The compound of embodiment A54, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -C(O)-NRa-C1-C4alkyl or -NRa-C(O)-C3-C6cycloalkyl. A56. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -,. A57. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -6 membered aryl-(C1-C3 alkylene)-. A58. The compound of embodiment A57, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C1-C4alkyl.A59. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -. A60. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C3-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. A61. The compound of embodiment A60, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is deuterated at one or more positions. A62. The compound of embodiment A60 or A61, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -CH=CH-(C1-C3 linear alkylene)- or -CH=CH-(C2-C3 linear alkenylene)-, each substituted with 0, 1, 2, or 3 instances of independently selected C1- C3 alkyl or halo. A63. The compound of embodiment A60 or A61, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, or -NRa-C(O)-C3- C6 cycloalkyl. A64. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is, , ,A65. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -CH=C3-C7 cycloalkylene- or - CH=CH-C3-C7cycloalkylene. A66. The compound of embodiment A65, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C6 cycloalkyl or -C(O)-NRa-C1-C4 alkyl. A67. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isA68. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C2-C4alkynylene-.A69. The compound of embodiment A68, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C1-C4 alkyl, -CH(OH)(5-6 membered heteroaryl), or -NRa-5-10 membered heteroaryl. A70. The compound of any one of embodiments A1-A11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,A71. The compound of any one of embodiments A1 and A4-A70, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N and Z3is CH. A72. The compound of any one of embodiments A1 and A4-A70, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH and Z3is N. A73. The compound of any one of embodiments A1-A72, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is N. A74. The compound of any one of embodiments A1-A72, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is CR5. A75. The compound of embodiment A74, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F. A76. The compound of embodiment A75, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H. A77. The compound of embodiment A75 or 76, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9A.A78. The compound of any one of embodiments A1-A77, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -, wherein R90is -OH, -CN, C1-C4 alkyl, halo, C1-C4 alkoxy, -C1-C4 alkylene-C(O)NRdRe, -C1- C4 alkylene-SO2-(C1-C4 alkyl), C1-C4 hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra. A79. The compound of embodiment A77, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is, ,. A80. The compound of embodiment A77, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, -CN, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe. A81. The compound of embodiment A77, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is, ,. A82. The compound of embodiment A75 or A76, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9B. A83. The compound of embodiment A82, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,,, wherein each R91is independently C1-C4alkyl or halo; or -NH-R9is, wherein Ring DE is 4-11 membered heterocyclyl and each R92is independently -OH, halo, oxo, C1-C4haloalkyl, C1-C4alkoxy, or -SO2(C1-C4 alkyl). A84. The compound of embodiment A82, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is,. A85. The compound of embodiment A82, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2instances of independently selected C1-C4alkyl, halo, -NRdRe, or -R12. A86. The compound of embodiment A82, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is,A87. The compound of embodiment A75 or A76, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9C. A88. The compound of embodiment A87, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is -C1-C4 alkylene-NRdRe. A89. The compound of embodiment A87, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is -NHCH2CH2CH2N(CH3)2or - NHCH2CH2CH2NHCH3. A90. The compound of embodiment A74, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH-R9. A91. The compound of embodiment A90, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is H. A92. The compound of embodiment A89 or A90, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H, -OH, -O-C1-C4 alkylene-NRaRb, or -O-C1-C4 alkyl. A93. The compound of embodiment A89 or A90, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H, -OCH3, -OH, or -OCH2CH2CH2N(CH3)2.A94. The compound of any one of embodiments A1-A93, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6is H. A95. The compound of any one of embodiments A1-A93, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6is -NH2. A96. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-4):wherein L is -NRa-, -NRa-C1-C5alkylene-, -NRa-C1-C3 alkylene-O-, -NRa-C1-C4 hydroxyalkylene-, -NRa-C3-C7cycloalkylene-, -NRa-C1-C3alkylene-C3-C7cycloalkylene-, -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene, or -NRa-5-6 membered aryl or heteroaryl-; E is -NRa-C(O)-C1-C4 alkyl, -NRa-C(O)-C3-C6 cycloalkyl, or -NRa-C(O)-6-10 membered aryl or 5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl; halo; C1-C4 alkoxy; -O-cyclopropyl; C1-C4 alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); - S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; and R4is-NH-R9, wherein R9is a 5-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, or halo. A97. The compound of embodiment A1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1. A98. A pharmaceutical composition comprising a compound of any one of embodiments A1-A97, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A99. The composition of embodiment A98, wherein the composition is sterile. A100. A method of modulating the conformation of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of embodiments A1-A97, or the composition of embodiment A98 or A99. A101. A method of restoring wild-type function of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of embodiments A1-A97, or a salt thereof, or the composition of embodiment A98 or A99. A102. A method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments A1-A97, or a salt thereof, or the composition of embodiment A98 or A99. A103. The method of embodiment A102, wherein the proliferative disorder is associated with a mutant p53 protein. A104. The method of embodiment A103, wherein the mutant p53 protein comprises a Y220C mutation. A105. The method of any one of embodiments A102-A104, wherein the proliferative disorder is cancer. A106. A compound of the formula: ,thereof.

[0223] The embodiment numbers referenced in this set refer to those within set B. For example, “embodiment 1” recited in embodiment B2 refers to embodiment B1. B1. A compound of Formula (A), (B), (C), (D), (E), (F), or (G):wherein: each ring bond represented by a dashed line is independently a single bond or a double bond; Z1is N or CH; Z2is N or CR2; Z3is N or CH; wherein at least one of Z1, Z2when present, and Z3is N; Z4is N, NR4, CR4, CR4H, or C(R4)R4B, wherein when Z4is C(R4)R4Band R4is attached to the rest of the compound through O or N, then R4Bis C1-C2alkyl, or C1-C2haloalkyl, and when Z4is C(R4)R4Band R4is attached to the rest of the compound through C, then R4Bis C1-C2 alkyl, C1-C2 haloalkyl, F, -OH, -OMe, -OCF3, -OCH2F, - OCHF2, -NH2, -NHMe, or NMe2; Z4Ais N, C, or CH;Z5is N, NR5, CR5, or CHR5; Z6is N, NR6, CR6, or CHR6; Z7is N, NH, CH, or CH2; when the compound is of Formula (B) and R8Ais -H and R15is C1-C3alkyl, then Z1is N; when the compound is of Formula (B), (C), or (D), then: (a) Z5and Z6are N, NH, or CH; and (b) R2 and R4 are not -H, -F, -NH2, -CH3, or -CF3; when the compound is of Formula (E), then (a) Z4is CR4wherein R4is not -H and / or (b) Z5is CR5wherein R5is not -H; when the compound is of Formula (F), then R2is not -H, -CH3, or -CF3; when the compound is of Formula (G), then: (a) L is -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo; (b) R4Ais R4or a bond; (c) one side of L' is bound to any chemically possible location on R2, and the other side of L' is bound to any chemically possible location on R4A; and (d) L' is selected from the group consisting of: -(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-, -C2-C12alkylene-, -NH-C2-C10 alkylene-, -C2-C10 alkylene-NH-,,, , -O-C2-C10alkylene-, -C2-C10alkylene-O-, -NH-C(O)-C2-C10alkylene-, -C2-C10 alkylene-C(O)-NH-, -NH-C(O)-C2-C10 alkylene-C(O)-NH-, -C(O)- C2-C10alkylene-, -C2-C10alkylene-C(O)-, -C(O)-C2-C10alkylene-C(O)-, -C(O)-C2- C10alkylene-C(O)-NH-, and -NH-C(O)-C2-C10alkylene-C(O)-, wherein any terminal -C(O)- group in L’, when present, is directly attached to a nitrogen atom in R2or R4A, or Z4Awhen R4Ais a bond; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo; -C1-C3alkylene-NRa-; -CH=C3-C7 cycloalkylene-; -CH=CH-C3-C7 cycloalkylene-; -C2-C4 alkynylene-; -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1- C4hydroxyalkylene-; -NRa-C3-C7cycloalkylene-; -NRa-C1-C3alkylene-C3-C7cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3 alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C3-C6cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; -O- C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; and -C(O)-NRa-C1-C4 alkylene-; E is selected from the group consisting of: H; C1-C4haloalkyl; hydroxy; -NRaRb; -NRa-C(O)-C(O)-N(Rb)2 -NRa-C(O)-C2-C5alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5 heteroalkyl or -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C2-C6 alkenyl substituted with 0, 1, or 2 independently selected halo or C3-C6cycloalkyl; -V-C1-C4 alkyl, wherein the C1-C4 alkyl is substituted with 0, 1, or 2 instances of independently selected halo or CN; and wherein V is a bond, -C(O)-NRa-, - NRa-C(O)-, or -C(O)-; -W-C1-C6heteroalkyl; wherein W is a bond, -C(O)-NRa-, -NRa-C(O)-, or -C(O)-; -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C1-C4heteroalkyl substituted with 1 instance of C2-C3alkynyl, 5- 6 membered heteroaryl, halo, -OH, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-cyclopropyl, -O-C1-C4 haloalkyl, C1-C4 alkoxy substituted with 1 instance of CN, -CN, C1-C4cyanoalkyl, -NRaRb, -NRa-C(O)-C1-C4alkyl-, - C(O)-NRa-S(O)2(C1-C4alkyl), -S(O)2(C1-C4alkyl), -S(O)2NH2, - S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), -C(O)NRaRb, or C3-C7 heterocyclic; and wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, -C(O)- N(Ra)-; -CH(OH)-, -NRa-C(O)-C1-C4alkylene-, or -NRa-C(=NH)-; -Y-3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, - OH, oxo, halo, -C(O)-Ra, 6-10 membered aryl, or 6-10 membered aryl substituted with 1 instance of C1-C4 alkoxy; and wherein Y is a bond, -NRa-, - NRa-C(O)-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C2-C4 alkynylene-, or - NRa-C(O)-C2-C4alkynylene-O-; -Z-3-9 membered cycloalkyl, wherein the 3-9 membered cycloalkyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, C1-C4 haloalkyl, -OH, C1-C4hydroxyalkyl, CN, C1-C4cyanoalkyl, C1-C4heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5 to 10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4 alkyl; and wherein Z is a bond, -NRa-C(O)-, -NRa-C(O)-C=, -NRa-C(O)O-, -C(O)-NRa-, -NRa- S(O)2-, -C(O)-, -NRa-C(O)-C2-C4alkynylene-, -NRa-C(O)-C2-C4alkynylene- O-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C1-C4 haloalkylene-, -NRa-C(O)- C1-C4 alkylene-O-, or -N(Ra)-CH(C1-C4 haloalkyl)-; R4is selected from the group consisting of H, -O-R9, -NH-R9, and -R9; and R5is H, -CH3, or -F; or R4is H, -CH3, -NH2, or -F; and R5is selected from the group consisting of H, -OR10, - OR9A, -OR9B, and -NH-R9; R9is -R13-R9A, R9B, R9C, or R9D; R13is a bond, C1-C3 alkylene substituted with 0, 1, 2, or 3 halo, or -C(O)-C1-C3 alkylene-; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, C1-C4 cyanoalkyl, hydroxy, C1-C6 heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, =NH, or -R12; wherein when the 3-9 memberedheterocyclyl does not contain a nitrogen or sulfur in the ring atoms, then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; R9Dis 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, oxo, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12; wherein when the 5-10 membered heteroaryl does not contain a nitrogen in the ring atoms then the 5-10 membered heteroaryl is substituted with at least one instance of -NRdRe; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; R10is H, -C1-C4 alkylene-NRaRb, or -C1-C4 alkyl; R6is H, -CH3, or -NH2; R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; R8Ais -H or -CH3; R8Bis -CH3substituted with 1, 2, or 3 instances of F; R14is -H or -CH3substituted with 0, 1, 2, or 3 instances of F; R15is -H or C1-C3 alkyl; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4alkyl substituted with 0, 1, 2, or 3 instances of F; andRdand Rein each instance are independently selected from the group consisting of H; C1- C4 alkyl substituted with 0 or 1 instance of -O-C1-C4 alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4 alkyl), C1-C4 alkyl, C1- C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, or C1-C4heteroalkyl; or (i) an isotopologue thereof; (ii) a stereoisomer thereof; (iii) a pharmaceutically acceptable salt thereof; or any combination of (i) to (iii); wherein the compound is not:stereoisomer or a pharmaceutically acceptable salt thereof. B2. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (A). B3. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (B). B4. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (C). B5. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (D). B6. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (E).B7. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (F). B8. The compound of embodiment 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (G). B9. A compound of Formula (I) or (II):wherein: Z1is N and Z3is CH, or Z1is CH and Z3is N; Z5is N or CR5; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C3-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo; -C1-C3 alkylene-NRa-; -CH=C3-C7cycloalkylene-; -CH=CH-C3-C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1- C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3 alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substitutedwith 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -O-C3-C6 cycloalkylene-; -O-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; and - O-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-; E is selected from the group consisting of: H; C1-C4 alkyl; C1-C4 haloalkyl; C3-C6 cycloalkyl; hydroxy; -NRaRb; -NRa-C(O)- C1-C4alkyl; -C(O)-NRa-C1-C4alkyl; -C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C3-C6 cycloalkyl; -C(O)-C3-C6 cycloalkyl; -N(Ra)- CH(C3-C6 cycloalkyl)(C1-C4 haloalkyl); -CH(OH)(5-6 membered heteroaryl); -X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, halo, C1-C4haloalkyl, C1-C4alkoxy, C3-C6cycloalkyl, -O- cyclopropyl, C1-C4alkoxy substituted with 1 instance of F or CN, -CN, C1-C4cyanoalkyl, -S(O)2(C1-C4 alkyl), -S(O)2NH2, -S(O)(=NH)(C1-C4 alkyl), - P(O)(C1-C4alkyl)(C1-C4alkyl), -C(O)NRaRb, or C3-C7heterocyclic, wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, or -C(O)-N(Ra)-; and 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4alkyl; R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F; or R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH- R9; R9is R9A, R9B, or R9C; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene- C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; wherein when the 3- 9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, hydroxy, C1-C6heteroalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12, wherein when the 3-9 memberedcycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, or -R12; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4 heteroalkyl, C1-C4 haloalkyl, or -C(O)Ra; R10is H, -C1-C4alkylene-NRaRb, or -C1-C4alkyl; R6is H or -NH2; R8is -CH3 substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4 alkyl; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4alkyl substituted with 0 or 1 instance of -O-C1-C4alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4 alkyl), C1-C4 alkyl, C1- C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, or C1-C4heteroalkyl; or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof; wherein the compound is not:stereoisomer or apharmaceutically acceptable salt thereof.B10. The compound of embodiment 1, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-1) or (II-1):B11. The compound of embodiment 1, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-2) or (II-2)B12. The compound of embodiment 9, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I). B13. The compound of any one of embodiments 1, 2, and 8-12, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CH3 substituted with 1, 2, or 3 instances of F. B14. The compound of any one of embodiments 1, 2, and 8-12, an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CF3. B15. The compound of any one of embodiments 1, 2, and 8-12, an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CHF2. B16. The compound of any one of embodiments 1, 2, and 8-12, an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CH2F. B17. The compound of any one of embodiments 1, 2, and 8-12, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is cyclopropyl substituted with one F.B18. The compound of any one of embodiments 1, 2, and 8-12, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is cyclopropyl. B19. The compound of embodiment 9, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II). B20. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is a bond. B21. The compound of embodiment 20, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, C1-C4alkyl, -NRaRb, 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected - OH, oxo, or C1-C4 alkyl, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, C1-C4alkyl, or -NRa-C(O)-C1-C4alkyl. B22. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is H, - CH2CH2CH3, -NH2, -NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,B23. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C3alkylene- NRa-. B24. The compound of embodiment 23, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected -C1- C4 alkoxy, -CN, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, -S(O)(=NH)(C1-C4 alkyl), - P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb. B25. The compound of embodiment 23, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is 5-10 membered unsubstituted heteroaryl. B26. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is. B27. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C4 alkylene-. B28. The compound of embodiment 27, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -N(Ra)-CH(C3-C6cycloalkyl)(C1- C4 haloalkyl), -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl or C1-C4 hydroxyalkyl, -NRa-C(O)-C3-C6 cycloalkyl, -NRa-5-10 membered heteroaryl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRa-C1-C4alkyl, -NRaRb, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl. B29. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -CH2CH2NH2, -CH2CH2NHC(O)CH3, -CH2CH2-phenyl, -CH2CH2CH2NH2, -CH2CH2CH2NHC(O)CH3, -CH2CH2CH2C(O)NHCH3, -CH2CH2CH2NHC(O)-cyclopropyl, - CH2CH2C(CH3)HNHC(O)-cyclopropyl, -CH2CH2CH2CH2NHC(O)-cyclopropyl,,B30. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -3-7 membered heterocyclyl-, wherein the -3-7 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo. B31. The compound of embodiment 30, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -3-7 membered unsubstituted heterocyclyl-. B32. The compound of embodiment 30 or embodiment 31, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, -NRa-C(O)- C3-C6 cycloalkyl, or hydroxy. B33. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is. B34. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -5-6 membered heteroaryl- or -5-6 membered heteroaryl-(C1-C3alkylene)-, wherein the -5-6 membered heteroaryl- of each is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo. B35. The compound of embodiment 34, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H; hydroxy; C1-C4 alkyl; -C(O)- NRa-C1-C4 alkyl; -NRa-C(O)-C3-C9 cycloalkyl; 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected oxo.B36. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,, , B37. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-. B38. The compound of embodiment 37, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is C3-C6 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of -OH. B39. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E iswherein Ring E’ is 6-10 membered aryl or 5-10 membered heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently C1-C4 alkyl. B40. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is -B41. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C3 alkylene-O-. B42. The compound of embodiment 41, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H or C1-C4 alkyl. B43. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is. B44. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C4 hydroxyalkylene-. B45. The compound of embodiment 44, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, C1-C4 alkyl, or phenyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl. B46. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isB47. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C5alkylene-. B48. The compound of embodiment 47, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is-H; -C3-C6cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C1-C4 alkyl; -C(O)-NRa-C3-C6 cycloalkyl; -C(O)-NRa-5-10 membered heteroaryl; 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkoxy; 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected oxo or C1-C4 alkyl; -NRa-6-10 membered aryl or -NRa-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkoxy or -C(O)NRaRb; -NRa-C(O)-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl; or -O-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected halo. B49. The compound of embodiment 47, or an isotopologue, or a stereoisomer or apharmaceutically acceptable salt thereof, wherein -E is H, N(CH3)2, NHCH3, ,, wherein RE1is C1-C4 alkyl, wherein RE2is halo, wherein RE3is -O-C1-C4 alkyl,, wherein RE1is C1-C4alkyl,, , wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl. B50. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is - NHCH2CH2CH2N(CH3)2, -NHCH2CH2CH2NHCH3,,B51. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7 cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7cycloalkylene-C1-C3alkylene-; or -O-C3-C6 cycloalkylene. B52. The compound of embodiment 51, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C3-C7cycloalkylene- or -O- C3-C6 cycloalkylene. B53. The compound of embodiment 51 or 52, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is hydroxy; C1-C4 haloalkyl; -NRa-C(O)-C1-C4 alkyl; -C(O)-NRa-C1-C4 alkyl; 6-10 membered aryl; -NRa-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected; C1-C4 alkoxy or -C(O)NRaRb; -NRa-C(O)-C3-C6 cycloalkyl; -NRa-C(O)-5-10 membered heteroaryl, wherein the -NRa-C(O)-5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, C3-C7 heterocyclic, C1-C4 alkoxy, or -CN; or -O-6-10 membered aryl. B54. The compound of embodiment 51 or 52, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -E is -OH, C1-C4 haloalkyl,,, wherein RE1is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl,- CN, C1-C4heteroalkyl, C3-C6cycloalkyl, or C3-C7heterocyclic, , wherein RE3is C1-C4alkyl,wherein RE4is C3-C6 cycloalkyl, whereiE2n R is halo,, wherein RE5is C1-C4 alkoxy or -C(O)NRaRb,wherein Ring E’ is 5-6 membered aryl or heteroaryl, R is C1-C4 alkyl substituted with 0 or 1 instance of F or CN, or cyclopropyl, and R’ and R’’ are each independently selected C1-C4alkyl. B55. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,B56. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -O-C1-C3alkylene-. B57. The compound of embodiment 56, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H or 6-10 membered aryl. B58. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is - OCH2CH2CH3, -OCH2-phenyl, or -OCH2CH2-phenyl. B59. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NRa-C1-C3 alkylene-C3-C7cycloalkylene-. B60. The compound of embodiment 59, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C6 cycloalkyl or - C(O)-NRa-C1-C4alkyl. B61. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is.B62. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C(O)-NRa-C1-C4 alkylene-.B63. The compound of embodiment 62, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -C(O)-NRa-C1-C4 alkyl, -NRa- C(O)-C3-C6 cycloalkyl, B64. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isB65. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C1-C3 alkylene- C3-C6cycloalkylene-. B66. The compound of embodiment 65, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C6 cycloalkyl. B67. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is, B68. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C3-C7 cycloalkylene- or -C3-C7cycloalkenylene-. B69. The compound of embodiment 68, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is C1-C4 alkyl, -C(O)-NRa-C1-C4 alkyl, or -NRa-C(O)-C3-C6 cycloalkyl. B70. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is, , .B71. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -6 membered aryl-(C1-C3 alkylene)-. B72. The compound of embodiment 71, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C1-C4alkyl. B73. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is. B74. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C2-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3 alkyl or halo. B75. The compound of embodiment 74, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is deuterated at one or more positions. B76. The compound of embodiment 74 or 75, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -CH=CH-(C1-C3 linear alkylene)-, -CH=CH-(C2-C3 linear alkenylene)-, or -CH2-CH=CH-, each substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo. B77. The compound of embodiment 74 or 75, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is. B78. The compound of any one of embodiments 74 to 77, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H; hydroxy; -NRaRb,-C(O)-NRa-C1-C4alkyl; -NRa-S(O)2-C3-C6cycloalkyl; -NRa-C(O)-C1-C4 alkyl substituted with 0, 1, or 2 instances of independently selected halo or CN; -NRa-C(O)-C3-C9cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, C1-C4haloalkyl, -OH, C1-C4hydroxyalkyl, -CN, C1-C4cyanoalkyl, C1-C4heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4 alkyl; -NRa-C(O)-3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, oxo, or -C(O)-Ra; -NRa-C(O)-C6-C10membered aryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, -CN, C1-C4 alkoxy, C1-C4 heteroalkyl, -NRaRb, -C(O)- NRa-S(O)2(C1-C4 alkyl), or -P(O)(C1-C4 alkyl)(C1-C4 alkyl); -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, halo, - OH, C1-C4 haloalkyl, C1-C4 alkoxy, -O-C1-C4 haloalkyl, -NRaRb, -S(O)2(C1-C4 alkyl), -NRa-C(O)-C1-C4alkyl-, -C(O)-NRa-S(O)2(C1-C4alkyl), C3-C6cycloalkyl, or C3-C7heterocyclyl ; -NRa-C6-C10 membered aryl substituted with 0, 1, 2, or 3 instances of independently selected halo, C1-C4alkoxy, -CN, -S(O)2(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb; -NRa-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, C1-C4alkoxy, or -C(O)NRaRb; -NRa-3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected 6-10 membered aryl substituted with 1 instance of C1-C4 alkoxy; -NRa-C(O)-C1-C4alkylene-3-9 membered cycloalkyl; -NRa-C(O)-C1-C4alkylene-3-9 membered heterocyclyl; -NRa-C(O)-C1-C4 alkylene-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl; -NRa-C(O)-C1-C4alkylene-O-3-9 membered cycloalkyl; -NRa-C(O)-C2-C4 alkynylene-3-9 membered cycloalkyl; -NRa-C(O)-C2-C5 alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5heteroalkyl or -NRa-C(O)-C1-C4alkyl; -C1-C6 heteroalkyl; -NRa-C(O)-C1-C6 heteroalkyl;-NRa-C(O)-C1-C4haloalkylene-3-9 membered cycloalkyl; -NRa-C(O)-C(O)-N(Rb)2; -NRa-C(=NH)-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl; -NRa-C(O)-C=3-9 membered cycloalkyl; -NRa-C(O)O-3-9 membered cycloalkyl; -3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl or oxo; or -5-10 membered heteroaryl. B79. The compound of any one of embodiments 74 to 77, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C9cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, cyclopropyl, or NH2. B80. The compound of any one of embodiments 74 to 77, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1- C4alkyl, halo, cyclopropyl or NH2. B81. The compound of any one of embodiments 74 to 77, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, cyclopropyl, or NH2. B82. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,,,,. B83. The compound of any one of embodiments 74 to 82, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L’ is -NH-C2-C10. B84. The compound of any one of embodiments 74 to 82, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L’ is -C2-C12alkylene-. B85. The compound of any one of embodiments 74 to 84, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4Acontains one or more secondary or tertiary amines. B86. The compound of any one of embodiments 74 to 85, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4Ais a bond or -NH- R9. B87. The compound of any one of embodiments 74 to 86, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is -R13-R9A. B88. The compound of embodiment 87, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -R13-R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected halo.B89. The compound of any one of embodiments 1, 8, and 13 to 18, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E-L’-R4A- is ,. B90. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -CH=C3-C7 cycloalkylene- or -CH=CH-C3-C7 cycloalkylene. B91. The compound of embodiment 90, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, -NRa-C(O)-C3-C6 cycloalkyl, or -C(O)-NRa-C1-C4 alkyl. B92. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isB93. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C2-C4alkynylene-. B94. The compound of embodiment 93, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H, C1-C4alkyl, -NRa-C(O)-C1-C4alkyl, -CH(OH)(5-6 membered heteroaryl), or -NRa-5-10 membered heteroaryl.B95. The compound of any one of embodiments 1-19, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E isB96. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z4is N or CR4; Z4Ais C; Z5is N or CR5; Z6is N or CR6; and Z7is N or CH. B97. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z4is NR4, CR4H, or C(R4)R4B; Z4Ais N or CH; Z5is NR5or CHR5; Z6is NR6or CHR6; and Z7is NH or CH2. B98. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH. B99. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is N, Z6is CR6; and Z7is CH. B100. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4Ais CR4; Z5is CR5; Z6is CR6; and Z7is CH. B101. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH. B102. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH. B103. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is N.B104. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2. B105. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2. B106. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is NH. B107. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2. B108. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is NR6; and Z7is CH2. B109. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is NR5; Z6is CHR6; and Z7is CH2. B110. The compound of any one of embodiments 1-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH; Z3is N; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2. B111. The compound of any one of embodiments 1-9 and 12-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N and Z3is CH. B112. The compound of any one of embodiments 1-9 and 12-95, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is CH and Z3is N. B113. The compound of any one of embodiments 1-95, 111, and 112, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is N. B114. The compound of any one of embodiments 1-95, 111, and 112, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is CR5.B115. The compound of embodiment 114, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H, -OR10, or -NH-R9. B116. The compound of embodiment 114, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is CH. B117. The compound any one of embodiments 1-95 and 111-116, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z6and Z7are each CH. B118. The compound of any one of embodiments 1-95 and 111-117, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of H and -NH-R9; and R5is H, -CH3, or -F. B119. The compound of embodiment 118, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is -NH-R9. B120. The compound of embodiment 118 or 119, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H. B121. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is -R13-R9A. B122. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is, wherein R90is -OH, -CN, C1-C4 alkyl, halo, C1-C4 alkoxy, -C1-C4 alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), C1-C4hydroxyalkyl, 3-9 membered heterocyclyl substituted with 0 or 1 instance of -C(O)Ra, 3-9 membered cycloalkyl substituted with 0 or 1 instance of hydroxy, 5-6 membered heteroaryl substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or - C(O)Ra. B123. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4or R5isB124. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, -CN, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen in the ring atoms then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe. B125. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is ,B126. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein. B127. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9B. B128. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9isindependently C1-C4alkyl or halo;, wherein Ring DE is 4-11 membered heterocyclyl and each R92is independently -OH, halo, oxo, C1-C4 haloalkyl, C1-C4alkoxy, or -SO2(C1-C4alkyl). B129. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is ,B130. The compound of embodiment 127, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, -NRdRe, or -R12. B131. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is. B132. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9C. B133. The compound of embodiment 132, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is -C1-C4alkylene-NRdRe. B134. The compound of embodiment 132, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -NH-R9is -NHCH2CH2CH2N(CH3)2or -NHCH2CH2CH2NHCH3. B135. The compound of any one of embodiments 1-120, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R9is R9D. B136. The compound of any one of embodiments 1-117, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is H, -CH3, or -F; and R5is selected from the group consisting of H, -OR10, and -NH-R9. B137. The compound of embodiment 136, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is H. B138. The compound of embodiment 136 or 137, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H, -OH, -O-C1-C4 alkylene- NRaRb, or -O-C1-C4 alkyl. B139. The compound of embodiment 136 or 137, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5is H, -OCH3, -OH, or - OCH2CH2CH2N(CH3)2. B140. The compound of any one of embodiments 1-139, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6is H.B141. The compound of any one of embodiments 1-140, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6is -NH2. B142. The compound of any one of embodiments 1-141, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8Ais -H. B143. The compound of any one of embodiments 1-141, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8Ais -CH3. B144. The compound of any one of embodiments 1-141, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8Bis -CH3substituted with three instances of F. B145. The compound of any one of embodiments 1-144, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R14is -H. B146. The compound of any one of embodiments 1-144, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R14is -CH3 substituted with 0, 1, 2, or 3 instances of F. B147. The compound of any one of embodiments 1-145, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R15is -H. B148. The compound of any one of embodiments 1-145, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R15is C1-C3 alkyl. B149. The compound of embodiment 1 or 9, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-4):wherein L is -NRa-, -NRa-C1-C5alkylene-, -NRa-C1-C3 alkylene-O-,-NRa-C1-C4hydroxyalkylene-, -NRa-C3-C7 cycloalkylene-, -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-, -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene, or -NRa-5-6 membered aryl or heteroaryl-; E is -NRa-C(O)-C1-C4 alkyl, -NRa-C(O)-C3-C6cycloalkyl, or -NRa-C(O)-6-10 membered aryl or 5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl; halo; C1-C4alkoxy; -O-cyclopropyl; C1-C4alkoxy substituted with 1 instance of F or CN; -CN; C1-C4cyanoalkyl; -S(O)2(C1-C4alkyl); - S(O)2NH2; -P(O)(C1-C4 alkyl)(C1-C4 alkyl); or -C(O)NRaRb; and R4is -NH-R9, wherein R9is a 5-6 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, or halo. B150. The compound of embodiment 1, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1. B151. A pharmaceutical composition comprising a compound of any one of embodiments 1- 150, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. B152. The composition of embodiment 151, wherein the composition is sterile. B153. A method of modulating the conformation of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of embodiments 1-150, or the composition of embodiment 151 or 152. B154. A method of restoring wild-type function of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of embodiments 1-150, or a salt thereof, or the composition of embodiment 151 or 152.B155. A method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-150, or a salt thereof, or the composition of embodiment 151 or 152. B156. The method of embodiment 155, wherein the proliferative disorder is associated with a mutant p53 protein. B157. The method of embodiment 156, wherein the mutant p53 protein comprises a Y220C mutation. B158. The method of any one of embodiments 155-107, wherein the proliferative disorder is cancer. B159. A compound of the formula:, , , ,; or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof. GENERAL SYNTHETIC EXAMPLES

[0224] The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[0225] Compounds provided herein may be prepared according to Schemes, as exemplified herein. Minor variations in temperatures, concentrations, reaction times, and other parameters can be made when following the Examples and Methods, which do not substantially affect the results of the procedures. EXAMPLE Abbreviations: DIAD – Diisopropyl azodicarboxylate MeCN – acetonitrile ACN – acetonitrile AcOH – acetic acid TFAA – trifluoroacetic anhydride TFA – trifluoroacetic acid MeOH – methyl alcohol BINAP – Bis(diphenylphosphino)-1,1'-binaphthyl DBU – 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM – dichloromethane NBS - N-Bromosuccinimide THF – tetrahydrofuran DPPF – 1,1′-Bis(diphenylphosphino)ferrocene DMSO – dimethyl sulfoxide HATU – Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium DMF – dimethylformamide DIEA – N,N-diisopropylethylamine TCFH – Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate NMI – N-methylimidazole TEA – triethylamine MOMBr – bromomethylmethylether LDA - Lithium diisopropylamide MTBE, MtBE – tert-Butyl methyl ether PE– petroleum ether EtOAc – ethyl acetateNIS – N-Iodosuccinimide FA – formic acid STAB – sodium triacetoxyborohydride DCE – dichloroethane DAST – Diethylaminosulfur trifluoride NMP – N-Methyl-2-pyrrolidone DMAP – N N-dimethyl-4-pyridylamine DMA – N,N-Dimethylacetamide BBBPY – 4,4′-Di-tert-butyl-2,2′-dipyridyl TBAF – Tetrabutylammonium fluoride BSA – Bovine serum albumin HEPES – 4-(2-Hydroxyethyl)piperazine-1-ethane-sulfonic acid LED – light-emitting diode HPLC – High-performance liquid chromatography LCMS – Liquid chromatography mass spectrometry NMR – Nuclear magnetic resonance BCA – bicinchoninic acid ATP – adenosine triphosphate TR-FRET – Time-resolved fluorescence resonance energy transferExample 1. Preparation of Intermediates Intermediate 1, 2 (Compound Int-1, Compound Int-2)1. Synthesis of 3-chloro-5-nitro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline

[0226] A mixture of 1,3-dichloro-5-nitroisoquinoline (7 g, 28.80 mmol, 1 eq), 4,4,6- trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (6.39 g, 28.80 mmol, 1 eq), Cs2CO3(28.15 g, 86.40mmol, 3 eq) and Pd(dppf)2Cl2DCM (2.35 g, 2.88 mmol, 0.1 eq) in dioxane (120 mL) and H2O (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 1 hr under N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0- 100% ethyl acetate in petroleum ether) affording title compound (8.5 g, 97.52%) as a yellow solid. LCMS: [M+H]+303.0, 305.0. 2. Synthesis of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-1

[0227] To a solution of 3-chloro-5-nitro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline (4 g, 13.22 mmol, 1 eq) and NH4Cl (2.12 g, 39.65 mmol, 3 eq) in EtOH (30 mL), THF (30 mL) and H2O (10 mL) was added Fe (4.43 g, 79.30 mmol, 6 eq) at 50°C. The mixture was stirred at 80°C for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulphateand concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (3 g, 83.25%) as a yellow solid. LCMS: [M+H]+273.0, 275.0.1H NMR (400 MHz, MeCN-d3) δ 7.97 (s, 1H), 7.49 - 7.39 (m, 2H), 7.03 (dd, J = 1.8, 6.7 Hz, 1H), 6.54 (d, J = 1.1 Hz, 1H), 5.98 (s, 1H). 3. Synthesis of 3-chloro-N-(1-methylpiperidin-4-yl)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-amine, Int-2

[0228] To a solution of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (3.5 g, 12.84 mmol, 1 eq) and 1-methylpiperidin-4-one (2.91 g, 25.67 mmol, 2 eq) in DCM (100 mL) and AcOH (50 mL) was added BH3.THF (1 M in THF, 64.18 mL,5 eq) at 0°C under N2atmosphere. The mixture was stirred at 25°C for 12 hrs under N2atmosphere. The reaction mixture was quenched by 1N HCl (60 mL) at 0°C. The mixture was stirred at 30°C for 1 hr. The mixture adjusted to pH=8 with saturated Na2CO3 (100 mL) at 0°C and extracted with DCM (3 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording title compound (2.6 g, 54.77%) as a yellow solid. LCMS: [M+H]+370.1, 372.1. 1H NMR (400 MHz, MeCN -d3) δ 8.06 (s, 1H), 7.53 - 7.45 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 1.1 Hz, 1H), 5.96 (s, 1H), 3.61 - 3.43 (m, 1H), 2.87 (br d, J = 11.9 Hz, 2H), 2.28 (s, 3H), 2.16 (br t, J = 11.7 Hz, 2H), 2.12 - 2.05 (m, 2H), 1.71 - 1.61 (m, 2H).Intermediate 3 (Compound Int-3)1. Synthesis of tert-butyl 3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop-1- en-2-yl)isoquinolin-3-yl)amino)propanoate

[0229] A mixture of 3-chloro-N-(1-methylpiperidin-4-yl)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-amine (50 mg, 135.20 μmol, 1 eq), tert-butyl 3-aminopropanoate (49.08 mg, 338.01 μmol, 2.5 eq), Cs2CO3 (132.16 mg, 405.61 μmol, 3 eq), Pd-PEPPSI-IPentCl (11.36 mg, 13.52 μmol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 1 hr under N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure affording title compound (120 mg, crude) (2 batches) as a yellow oil and used in next step without any further purification. LCMS: [M+H]+479.3. 2. Synthesis of 3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-3-yl)amino)propanoic acid, Int-3

[0230] A mixture of tert-butyl 3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-3-yl)amino)propanoate (30 mg, 62.69 μmol, 1 eq) in DCM (1 mL) and TFA (0.4 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1% TFA)- MeCN];gradient:15%-45% B over 8.0 min) affording title compound (4.07 mg, 11.61%, TFA salt) as a yellow oil. LCMS: [M+H]+423.2.1H NMR (400 MHz, MeCN-d3) δ 9.79 - 9.14 (m, 1H), 7.29 - 7.19 (m, 1H), 7.18 - 7.10 (m, 1H), 6.89 (s, 1H), 6.78 - 6.66 (m, 1H),6.51 (s, 1H), 5.95 (s, 1H), 4.02 - 3.89 (m, 1H), 3.80 - 3.62 (m, 3H), 3.61 - 3.53 (m, 2H), 3.43 - 3.32 (m, 1H), 3.15 - 3.03 (m, 1H), 2.88 - 2.81 (m, 2H), 2.77 - 2.67 (m, 2H), 2.36 (br d, J = 13.9 Hz, 2H), 2.31 - 2.11 (m, 2H). Intermediate 15 and 17 (Compound Int-15, Compound Int-17)1. Synthesis of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine

[0231] A mixture of 1,3-dichloroisoquinolin-5-amine (1.8 g, 8.45 mmol, 1 eq), 4,4,6- trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (1.89 g, 8.53 mmol, 1.01 eq), Pd(dppf)Cl2 (689.91 mg, 844.82 μmol, 0.1 eq) and Cs2CO3 (5.51 g, 16.90 mmol, 2 eq) in dioxane (30 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 1 hr under N2atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (2.13 g, 92.47%) as a yellow oil. LCMS: [M+H]+273.0, 275.0.1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.49 - 7.44 (m, 1H), 7.42 - 7.37 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 1.1 Hz, 1H), 5.84 (s, 1H), 4.24 (br s, 2H). 2. Synthesis of 5-bromo-3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline, Int-17

[0232] To a solution of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (2.13 g, 7.81 mmol, 1 eq) in MeCN (100 mL) was added camphorsulfonic acid (3.63 g, 15.62 mmol, 2 eq), TBAB (251.84 mg, 781.21 μmol, 0.1 eq), CuBr (1.34 g, 9.37 mmol, 285.52 μL, 1.2 eq) and NaNO2 (1.08 g, 15.62 mmol, 2 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. The reaction mixture was quenched with saturated sodium bicarbonate (30 mL) at0°C and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (2 g, 76.07%) as a yellow solid. LCMS: [M+H]+335.9 / 337.9.1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.06 - 8.01 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H), 6.50 (s, 1H), 5.87 (s, 1H). 3. Synthesis of 3-chloro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-15

[0233] A mixture of 5-bromo-3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline Int-17 (6.37 g, 18.91 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (4.5 g, 34.04 mmol, 1.8 eq), RuPhos Pd G4 (1.61 g, 1.89 mmol, 0.1 eq) and Cs2CO3 (18.49 g, 56.74 mmol, 3 eq) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo.The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). The residue was diluted with a (10 : 1) mixture of petroleum ether : ethyl acetate (22 mL) and the resulting precipitate was filtered affording title compound (4.83 g, 65.85%) as a yellow solid. LCMS: [M+H]+388.1 / 390.1.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.51 - 7.43 (m, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.58 (s, 1H), 6.31 (br d, J = 7.9 Hz, 1H), 6.09 (s, 1H), 4.98 - 4.79 (m, 1H), 3.78 - 3.65 (m, 1H), 3.07 (br t, J = 10.7 Hz, 1H), 2.90 - 2.80 (m, 1H), 2.35 - 2.24 (m, 1H), 2.21 (s, 3H), 2.15 - 2.08 (m, 2H), 1.76 - 1.71 (m, 1H). Intermediate 18 (Compound Int-18)1. Synthesis of 3-bromo-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-18

[0234] A mixture of 1,3-dibromoisoquinolin-5-amine (33 g, 109.28 mmol, 1 eq), 4,4,6- trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (24.26 g, 109.28 mmol, 1 eq), Na2CO3 (34.75 g, 327.85 mmol, 3 eq) and Pd(PPh3)2Cl2 (15.34 g, 21.86 mmol, 0.2 eq) in dioxane (800 mL) and H2O (270 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2atmosphere. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (25 g, 72.14%) as a yellow oil. LCMS: [M+H]+317.0, 319.0.1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.42 - 7.30 (m, 2H), 6.91 (d, J = 7.1 Hz, 1H), 6.36 (d, J = 1.1 Hz, 1H), 5.76 (s, 1H), 4.14 (br s, 2H). Intermediate 19 (Compound Int-19)1. Synthesis of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(((4- methoxybenzyl)oxy)methyl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine

[0235] A mixture of 3-chloro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-5-amine Int-15 (1 g, 2.58 mmol, 1 eq), potassium trifluoro(((4-methoxybenzyl)oxy)methyl)borate (1.33 g, 5.16 mmol, 2 eq), Cs2CO3(2.52 g, 7.74 mmol, 3 eq) and cataCXium A Pd G3 (187.79 mg, 257.86 μmol, 0.1 eq) in Tol. (20 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hrs under N2atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were driedover sodium sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18250*50mm*15um; mobile phase: [H2O (0.1% TFA)-MeCN]; gradient: 40%-60% B over 10.0 min) affording title compound (900 mg, 56.52%, TFA salt) as a yellow oil. LCMS: [M+H]+504.1. 2. Synthesis of (5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-3-yl)methanol

[0236] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(((4- methoxybenzyl)oxy)methyl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (900 mg, 1.46 mmol, 1 eq, TFA salt) in TFA (4 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated in vacuo affording title compound (800 mg, crude, TFA salt) as a yellow oil, used in next step without any further purification. LCMS: [M+H]+384.1. 3. Synthesis of 5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3-carbaldehyde

[0237] To a solution of (5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-3-yl)methanol (50 mg, 100.52 μmol, 1 eq, TFA salt), DIEA (51.97 mg, 402.09 μmol, 4 eq) and DMSO (31.42 mg, 402.09 μmol, 4 eq) in DCM (1 mL) was added SO3.Py (64.00 mg, 402.09 μmol, 4 eq) at 0°C. The mixture was stirred at 25°C for 1 h. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1% TFA)-MeCN]; gradient: 5%-35% B over 8.0 min) affording title compound (27 mg, 54.22%, TFA salt) as a yellow oil. LCMS: [M+H]+382.1. 4. Synthesis of 5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3-carboxylic acid, Int-19

[0238] To a solution of 5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3-carbaldehyde (27 mg, 54.50 μmol, 1 eq, TFA salt) in DMF (0.5 mL) was added Oxone (167.53 mg, 272.51 μmol, 5 eq). The mixture was stirred at 40°C for 1 h. The reaction mixture was concentrated to dryness in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1% TFA)-MeCN]; gradient: 15%-45% B over 8.0 min) affording title compound (7 mg, 25.11%, TFA salt) as a yellow oil. LCMS: [M+H]+398.1.Intermediates 20, 21, 22 (Compound Int-20, Compound Int-21, Compound Int-22)1. Synthesis of tert-butyl N-[(E)-3-[5-amino-1-[1-(trifluoromethyl)vinyl]-3- isoquinolyl]allyl]carbamate, Int-21

[0239] A mixture of 3-bromo-1-[1-(trifluoromethyl)vinyl]isoquinolin-5-amine Int-18 (50 mg, 157.68 μmol, 1 eq), tert-butyl N-[(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)allyl]carbamate (53.58 mg, 189.21 μmol, 1.2 eq), Pd(dtbpf)Cl2 (10.28 mg, 15.77 μmol, 0.1 eq), K3PO4 (66.94 mg, 315.35 μmol, 2 eq) in dioxane (1 mL) and H2O (0.3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 1hr under N2 atmosphere. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) affording title compound (50 mg, 80.61%) as a yellow oil. LCMS: [M+H]+394.1. 2. Synthesis of 3-[(E)-3-aminoprop-1-enyl]-1-[1-(trifluoromethyl)vinyl]isoquinolin-5- amine, Int-22

[0240] A mixture of tert-butyl N-[(E)-3-[5-amino-1-[1-(trifluoromethyl)vinyl]-3- isoquinolyl]allyl]carbamate (50 mg, 127.10 μmol, 1 eq) in DCM (1 mL) and TFA (0.3 mL) was stirred at 25°C for 1 hr. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.1%TFA)-MeCN]; gradient: 5%-35% B over 8.0 min affording title compound (TFA salt, 18 mg, 34.96%) as a white solid. LCMS: [M+H]+294.1.1H NMR (400 MHz, MeCN-d3) δ = 7.98 (s, 1H), 7.65 - 7.42 (m, 2H), 7.19(br d, J = 7.1 Hz, 1H), 7.05 - 6.89 (m, 1H), 6.86 - 6.70 (m, 1H), 6.56 (br s, 1H), 5.97 (br s, 1H), 3.79 (br s, 2H). 3. Synthesis of N-[(E)-3-[5-amino-1-[1-(trifluoromethyl)vinyl]-3- isoquinolyl]allyl]cyclopropanecarboxamide, Int-20

[0241] To a solution of 3-[(E)-3-aminoprop-1-enyl]-1-[1- (trifluoromethyl)vinyl]isoquinolin-5-amine (40 mg, 98.21 μmol, 1eq, TFA), NaHCO3 (20.62 mg, 245.51 μmol, 2.5 eq) in THF (1 mL) and H2O (1 mL) was added cyclopropanecarbonyl chloride (9.24 mg, 88.38 μmol, 8.02 μL, 0.9 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.1% TFA)-MeCN]; gradient:25%-65% B over 8.0 min affording title compound (TFA salt, 5.4 mg, 97.16%) as a white solid. LCMS: [M+H]+362.1.1H NMR (400 MHz, MeCN-d3) δ 7.82 (s, 1H), 7.40 (d, J =4.6 Hz, 2H), 7.07 - 7.00 (m, 1H), 6.90 - 6.78 (m, 1H), 6.78 - 6.71 (m, 1H), 6.53 (d, J =1.3 Hz, 1H), 5.96 (s, 1H), 4.04 (br d, J =5.0 Hz, 2H), 1.62 - 1.53 (m, 1H), 0.88 - 0.80 (m, 2H), 0.79 - 0.70 (m, 2H).Intermediates 23, 24, 25, 26 (Compound Int-23, Compound Int-24, Compound Int-25, Compound Int-26)1. Synthesis of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline, Int-23

[0242] A mixture of 1,3-dichloroisoquinoline (120 g, 605.92 mmol, 1 eq), 4,4,6-trimethyl- 2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (174.88 g, 787.68 mmol, 1.3 eq), Pd(dppf)Cl2.DCM (49.48 g, 60.60 mmol, 0.1 eq) and Cs2CO3(394.84 g, 1.21 mol, 2 eq) in dioxane (2.4 L) and H2O (500 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The mixture was diluted with water (600 mL) and extracted with ethyl acetate (2 x 1 L). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (130 g, 82.44%) as a yellow oil. LCMS: [M+H]+258.1, 259.9.1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.09 (t, J = 7.6 Hz, 2H), 7.91 (t, J = 7.6 Hz, 1H), 7.80 - 7.73 (m, 1H), 6.68 (s, 1H), 6.21 (s, 1H). 2. Synthesis of 3-chloro-5-iodo-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline, Int-24

[0243] To a solution of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline (130 g, 504.58 mmol, 1 eq) in trifluoromethanesulfonic acid (1 L) was added NIS (170.28 g, 756.88 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. The mixture was quenched with saturated Na2SO3(1 L) and then the solid was filtered and the filter cake was dried under reduced pressure. The residue was triturated with hexanes (50 mL) and the resulting solid was collected by filtration and dried under reduced pressure to afford title compound (140 g, 69.45%) as a white solid. LCMS: [M+H]+383.9, 385.9.1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 7.3 Hz, 1H), 8.17 - 8.12 (m, 1H), 8.00 (s, 1H), 7.53 (dd, J = 7.5, 8.4 Hz, 1H), 6.70 (s, 1H), 6.22 (s, 1H). 3. Synthesis of 3-chloro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-15

[0244] A mixture of 3-chloro-5-iodo-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline (30 g, 75.09 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (12.90 g, 97.62 mmol, 1.3 eq), RuPhos Pd G4 (6.39 g, 7.51 mmol, 0.1 eq) and Cs2CO3(61.17 g, 187.73 mmol, 2.5 eq) in 2-methylbutan-2-ol (600 mL) was degassed and purged with N2for 3 times, the mixture was stirred at 125°C for 2 hrs under N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording title compound (27 g, 42.48%) as a white solid. LCMS: [M+H]+388.0, 390.0.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.55 - 7.44 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.59 (s, 1H), 6.33 (br d, J = 7.9 Hz, 1H), 6.10 (s, 1H), 4.99 - 4.79 (m, 1H), 3.80 - 3.63 (m, 1H), 3.14 - 3.03 (m, 1H), 2.86 (br d, J = 6.1 Hz, 1H), 2.36 - 2.19 (m, 4H), 2.16 - 2.08 (m, 2H), 1.75 (br t, J = 8.6 Hz, 1H). 4. Synthesis of tert-butyl ((E)-3-(5-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1- (3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-3-yl)allyl)carbamate, Int-25

[0245] A mixture of 3-chloro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-5-amine (3.3 g, 8.51 mmol, 1 eq), (E)-tert-butyl (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (3.37 g, 11.91 mmol, 1.4 eq), Pd(dtbpf)Cl2(555 mg, 851 μmol, 0.1 eq) and K3PO4(3.61 g, 17.02 mmol, 2 eq) in dioxane (33 mL) and H2O (11 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording title compound (3.7 g, 85.50%) as a yellow solid. LCMS: [M+H]+509.2.1H NMR (400 MHz, MeCN-d3) δ 7.80 (s, 1H), 7.46 - 7.34 (m, 2H), 6.91 - 6.80 (m, 2H), 6.77 - 6.70 (m, 1H), 6.50 (d, J = 1.0 Hz, 1H), 5.92 (s, 1H), 5.62 (br s, 1H), 5.09 (br d, J = 8.5 Hz, 1H), 5.00 - 4.79 (m, 1H), 3.92 (br t, J = 5.4 Hz, 2H), 3.79 - 3.63 (m, 1H), 3.12 (br d, J = 1.7 Hz, 1H), 2.90 (br dd, J = 1.5, 11.3 Hz, 1H), 2.37 - 2.25 (m, 4H), 2.23 - 2.13 (m, 2H), 2.08 - 1.99 (m, 1H), 1.46 (s, 9H). 5. Synthesis of 3-((E)-3-aminoprop-1-en-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-26

[0246] To a solution of tert-butyl ((E)-3-(5-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-3-yl)allyl)carbamate (4 g, 7.86 mmol, 1 eq) in DCM (18 mL) was added TFA (6 mL) and the mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with EtOAc (150 mL) and basified by sat.aq.Na2CO3at 0°C until pH>12. The combined organic layers were extracted with 2-Me THF (3 x 200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford title compound (3.5 g, crude) as a yellow solid. LCMS: [M+H]+409.1.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.78 (br d, J = 2.6 Hz, 2H), 7.47 - 7.41 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.55 (s, 1H), 6.15 (br d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 4.98 - 4.82 (m, 1H), 3.78 - 3.68 (m, 3H), 3.13 - 3.03 (m, 1H), 2.87 (br d, J = 8.3 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.22 (s, 3H), 2.16 - 2.08 (m, 2H), 1.79 (br d, J = 10.9 Hz, 1H).Intermediates 27, 28, 29, 30, 31 (Compound Int-27, Compound Int-28, Compound Int-29, Compound Int-30, Compound Int-31)1. Synthesis of (1S,2R,3R,5R)-tert-butyl 3-((3-chloro-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate, Int-27

[0247] A mixture of 5-bromo-3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline (600 mg, 1.78 mmol, 1 eq), (1S,2R,3R,5R)-tert-butyl 3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (479.13 mg, 1.96 mmol, 1.1 eq), Cs2CO3 (1.45 g, 4.47 mmol, 2.5 eq) and Pd-PEPPSI-IPentCl (149.79 mg, 178.29 μmol, 0.1 eq) in dioxane (12 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100°C for 12 hrs under nitrogen atmosphere. The mixture was diluted with H2O (10 mL) and washed with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethylacetate in commercial hexanes) affording title compound (600 mg, 67.32%) as a yellow solid. LCMS: [M+H]+500.1, 502.1. 2. Synthesis of 3-chloro-N-((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)-1- (3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-28

[0248] To a solution of (1S,2R,3R,5R)-tert-butyl 3-((3-chloro-1-(3,3,3-trifluoroprop-1-en- 2-yl)isoquinolin-5-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.20 mmol, 1 eq) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 20°C for 1 hr. The mixture was concentrated under reduced pressure affording title compound (650 mg, crude, TFA salt) as a yellow oil. LCMS: [M+H]+400.2, 402.2. 3. Synthesis of 3-chloro-N-((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octan- 3-yl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-29

[0249] To a solution of 3-chloro-N-((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (600 mg, 1.17 mmol, 1 eq) in MeOH (5 mL) was added DIEA (226.37 mg, 1.75 mmol, 1.5 eq), AcOH (105.18 mg, 1.75 mmol, 1.5 eq), HCHO (104.24 mg, 1.28 mmol, 37% purity in H2O, 1.1 eq) and NaBH3CN (146.76 mg, 2.34 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched with saturated sodium bicarbonate (5 mL) at 0°C and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*15um;mobile phase: [H2O(0.1% TFA)-MeCN];gradient:15%-55% B over 10.0 min), and concentrated under reduced pressure to remove MeCN and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording title compound (260 mg, 53.80%) as a yellow solid. LCMS: [M+H]+414.3, 416.3.1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.38 - 7.29 (m, 2H), 6.73 (dd, J = 0.9, 6.8 Hz, 1H), 6.36 (d, J = 1.1 Hz, 1H), 5.75 (s, 1H), 4.65 - 4.50 (m, 1H), 3.78 - 3.62 (m, 1H), 3.49 (br d, J = 2.5 Hz, 1H), 3.28 (br s, 1H), 2.34 (s, 3H), 2.20 (s, 1H), 2.03 (ddd, J = 3.3, 5.8, 12.9 Hz, 2H), 1.85 - 1.77 (m, 1H), 1.70 - 1.61 (m, 1H), 1.55 - 1.45 (m, 1H). 4. Synthesis of tert-butyl ((E)-3-(5-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-3- yl)allyl)carbamate, Int-30

[0250] A mixture of 3-chloro-N-((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (50 mg, 120.82 μmol, 1 eq), (E)-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (41.06 mg, 144.98 μmol, 1.2 eq), cataCXiumA Pd-G3 (8.80 mg, 12.08 μmol, 0.1 eq), K3PO4 (51.29 mg, 241.64 μmol, 2 eq) in Tol. (1 mL) and H2O (0.3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) affording title compound (60 mg, 92.90%) as a yellow solid. LCMS: [M+H]+535.4. 5. Synthesis of 3-((E)-3-aminoprop-1-en-1-yl)-N-((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine, Int-31

[0251] To a solution of tert-butyl ((E)-3-(5-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-3- yl)allyl)carbamate (60 mg, 112.24 μmol, 1 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 30°C for 0.5 hr. The mixture was concentrated under reduced pressure affording title compound (60 mg, crude, TFA salt) as a brown oil. LCMS: [M+H]+435.4. Intermediate 32 (Compound Int-32)1. Synthesis of 1,3-dichloro-6-((1-methylpiperidin-4-yl)oxy)isoquinoline

[0252] A mixture of 1,3-dichloroisoquinolin-6-ol (300 mg, 1.40 mmol, 1 eq), 1- methylpiperidin-4-ol (242.13 mg, 2.10 mmol, 245.82 μL, 1.5 eq), PPh3(551.42 mg, 2.10 mmol, 1.5 eq) and DIAD (425.11 mg, 2.10 mmol, 407.59 μL, 1.5 eq) in THF (6 mL) was degassed and purged with N2 for 3 times at 0°C, and then the mixture was stirred at 25°Cfor 12 hrs under N2atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: WePure Biotech XP tC18150*40*10um;mobile phase: [H2O(10mM NH4HCO3)- MeCN];gradient:60%-90% B over 8.0 min) affording title compound (230 mg, 52.73%) as a yellow solid. LCMS: [M+H]+311.0, 313.0.1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.05 (m, 1H), 7.95 - 7.91 (m, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.46 - 7.20 (m, 1H), 4.60 (tt, J = 3.9, 8.2 Hz, 1H), 2.64 (br t, J = 7.2 Hz, 2H), 2.32 (q, J = 6.9 Hz, 1H), 2.22 (br s, 1H), 2.20 (s, 3H), 2.10 - 1.96 (m, 2H), 1.85 - 1.56 (m, 2H). 2. Synthesis of 3-chloro-6-((1-methylpiperidin-4-yl)oxy)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinoline, Int-32

[0253] A mixture of 1,3-dichloro-6-[(1-methyl-4-piperidyl)oxy]isoquinoline (210 mg, 674.79 μmol, 1 eq), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (194.76 mg, 877.23 μmol, 1.3 eq), Pd(dppf)Cl2.CH2Cl2(110.21 mg, 134.96 μmol, 0.2 eq), K3PO4(429.71 mg, 2.02 mmol, 3 eq) in dioxane (9 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: WePure Biotech XP tC18150*40*10um;mobile phase: [H2O(10mM NH4HCO3)-MeCN];gradient:40%-70% B over 8.0 min) affording title compound (150 mg, 59.95%) as a yellow solid. LCMS: [M+H]+371.1, 373.1.1H NMR (400 MHz, MeCN-d3) δ 7.90 (br d, J = 9.0 Hz, 1H), 7.66 (s, 1H), 7.30 - 7.00 (m, 2H), 6.45 (br s, 1H), 5.88 (s, 1H), 4.48 (br s, 1H), 2.60 (br s, 2H), 2.26 - 2.19 (m, 2H), 1.97 (br s, 2H), 1.86 (br s, 3H), 1.70 (br d, J = 9.0 Hz, 2H).Intermediate 33 (Compound Int-33)1. Synthesis of 1,3-dichloroisoquinolin-5-ol

[0254] To a solution of 1,3-dichloro-5-methoxyisoquinoline (1 g, 4.38 mmol, 1 eq) in DCM (7 mL) was added BBr3 (6.58 mL, 1 M in DCM, 6.58 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 10 hrs. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL) at 0°C and adjusted to pH=8, and then extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in Commercial hexanes) affording title compound (700 mg, 74.59%) as a white solid. LCMS: [M+H]+214.0, 215.9.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.01 (s, 1H), 7.73 - 7.60 (m, 2H), 7.23 (d, J = 7.5 Hz, 1H). 2. Synthesis of tert-butyl (3S,4R)-4-((1,3-dichloroisoquinolin-5-yl)oxy)-3- fluoropiperidine-1-carboxylate

[0255] To a solution of 1,3-dichloroisoquinolin-5-ol (350 mg, 1.64 mmol, 1 eq) and tert- butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (537.77 mg, 2.45 mmol, 1.5 eq) in Tol. (7 mL) was added CMBP (986.62 mg, 4.09 mmol, 2.5 eq). The mixture was stirred at 80°C for 1 hr. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in Commercial hexanes) affording title compound (500 mg, 73.63%) as a yellow solid. LCMS: [M+H]+415.1, 416.9.1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.15 (d, J = 7.9 Hz,1H), 4.83 - 4.73 (m, 2H), 3.95 - 3.83 (m, 2H), 2.99 - 2.90 (m, 2H), 2.24 - 2.19 (m, 1H), 2.00 (br d, J = 4.8 Hz, 1H), 1.50 (s, 9H). 4. Synthesis of tert-butyl (3S,4R)-4-((3-chloro-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-yl)oxy)-3-fluoropiperidine-1-carboxylate, Int-33

[0256] A mixture of tert-butyl (3S,4R)-4-((1,3-dichloroisoquinolin-5-yl)oxy)-3- fluoropiperidine-1-carboxylate (450 mg, 1.08 mmol, 1 eq), 4,4,6-trimethyl-2-(3,3,3- trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (242.98 mg, 1.09 mmol, 1.01 eq), K3PO4 (460.02 mg, 2.17 mmol, 2 eq) and Pd(dppf)2Cl2.DCM (88.49 mg, 108.36 μmol, 0.1 eq in dioxane (3 mL) and H2O (1 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80°C for 2 hrs under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in Commercial hexanes) affording title compound (300 mg, 58.49%) as a yellow solid. LCMS: [M+H]+475.3, 477.3.1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 1.1 Hz, 1H), 5.85 (d, J = 0.8 Hz, 1H), 4.85 - 4.74 (m, 2H), 3.21 (br s, 2H), 2.27 - 2.17 (m, 2H), 2.02 - 1.97 (m, 2H), 1.46 (s, 9H). Example 2. General methods for preparation of 1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinoline 3,5-diamines Method 1 (M1)

[0257] Int-2 coupled with amine M1-1 (obtained commercially or synthesized according to methods known in the art) under Pd-catalyzed conditions to provide 3,5 -disubstituted 1- (3,3,3-trifluoroprop-1-en-2-yl)isoquinoline M1-2. In some cases, M1-2 is final compound, in some cases further chemistry was performed to obtain final compound:The following compounds were prepared following Method 1 starting with Int-2: Compound 91. Synthesis of N5-(1-methylpiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinoline-3,5-diamine (Compound 9)

[0258] A mixture of 3-chloro-N-(1-methyl-4-piperidyl)-1-[1- (trifluoromethyl)vinyl]isoquinolin-5-amine (30 mg, 81.12 μmol, 1 eq), propan-1-amine (23.98 mg, 405.61 μmol, 5 eq), Cs2CO3(79.29 mg, 243.37 μmol, 3 eq), Pd-PEPPSI-IPent- Cl (6.82 mg, 8.11 μmol, 0.1 eq) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 1 hr under N2 atmosphere. The reaction mixture was added H2O (2 mL) and extracted with 2Me-THF (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1% TFA)- MeCN];gradient:15%-45% B over 8.0 min) affording title compound (4.42mg, 10.62%, TFA salt) as a yellow oil. LCMS: [M+H]+393.2.1H NMR (400 MHz, MeCN-d3) δ 10.43 - 9.85 (m, 1H), 7.27 - 7.18 (m, 1H), 7.15 - 7.09 (m, 1H), 6.77 - 6.68 (m, 2H), 6.50 (d, J = 1.1 Hz, 1H), 5.94 (s, 1H), 3.74 (tdd, J = 3.9, 7.6, 15.0 Hz, 1H), 3.58 (br d, J = 12.9 Hz, 2H), 3.38 - 3.30 (m, 2H), 3.14 - 3.02 (m, 2H), 2.86 - 2.81 (m, 3H), 2.42 - 2.30 (m, 2H), 2.23 - 2.17 (m, 1H), 1.92 (br d, J = 2.6 Hz, 1H), 1.80 - 1.68 (m, 2H), 1.10 - 1.01 (m, 3H). Compound 381. Synthesis of N5-(1-methylpiperidin-4-yl)-N3-(3-(pyridin-2-ylamino)propyl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3,5-diamine (Compound 38)

[0259] A mixture of 3-chloro-N-(1-methylpiperidin-4-yl)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-amine (100 mg, 270.41 μmol, 1 eq), N1-(pyridin-2-yl)propane-1,3-diamine (81.78 mg, 540.82 μmol, 2 eq), Cs2CO3(264.31 mg, 811.23 μmol, 3 eq) and Pd-PEPPSI- IPentCl (45.44 mg, 54.08 μmol, 0.2 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere.The reaction mixture was added H2O (3 mL) at 0°C and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: 3_Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.1% TFA)- MeCN];gradient:10%-40% B over 8.0 min) affording title compound (40.75 mg, 25.18%, TFA salt) as a yellow amorphous solid. LCMS: [M+H]+485.2.1H NMR (400 MHz, MeCN-d3) δ 10.99 - 10.40 (m, 1H), 7.88 - 7.69 (m, 2H), 7.27 - 7.04 (m, 2H), 6.99 - 6.88 (m, 1H), 6.83 - 6.64 (m, 3H), 6.48 (s, 1H), 5.94 - 5.87 (m, 1H), 3.96 - 3.65 (m, 1H), 3.62 - 3.52 (m, 3H), 3.51 - 3.46 (m, 2H), 3.35 (br s, 1H), 3.06 (br d, J = 5.8 Hz, 2H), 2.82 (br s, 3H), 2.34 (br d, J = 13.9 Hz, 1H), 2.20 (br d, J = 3.5 Hz, 1H), 2.06 (quin, J = 6.5 Hz, 2H), 1.95 - 1.87 (m, 2H). Compound 79 and stereoisomers thereof1. Synthesis of tert-butyl (3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop- 1-en-2-yl)isoquinolin-3-yl)amino)cyclopentyl)carbamate

[0260] A mixture of 3-chloro-N-(1-methylpiperidin-4-yl)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-amine (50 mg, 135.20 μmol, 1 eq), tert-butyl N-(3- aminocyclopentyl)carbamate (40.62 mg, 202.81 μmol, 1.5 eq), Pd-PEPPSI-IPentCl (11.36mg, 13.52 μmol, 0.1 eq), Cs2CO3(132.16 mg, 405.61 μmol, 3 eq) in dioxane (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 105°C for 1 hour under nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% MeOH in DCM) affording title compound (70 mg, 97.02%) as a yellow solid. LCMS: [M+H]+534.3. 2. Synthesis of N3-(3-aminocyclopentyl)-N5-(1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3,5-diamine

[0261] To a solution of tert-butyl (3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinolin-3-yl)amino)cyclopentyl)carbamate (70 mg, 131.18 μmol, 1 eq) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25°C for 0.5 hr. The mixture was concentrated under reduced pressure affording title compound (70 mg, crude, TFA salt) as a yellow oil. LCMS: [M+H]+434.2. 3. Synthesis of N-(trans-3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop-1- en-2-yl)isoquinolin-3-yl)amino)cyclopentyl)cyclopropanecarboxamide (Compound 79) and N-(cis-3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-3-yl)amino)cyclopentyl)cyclopropanecarboxamide (Compound 79- stereoisomer-1) and N-(3-((5-((1-methylpiperidin-4-yl)amino)-1-(3,3,3-trifluoroprop-1- en-2-yl)isoquinolin-3-yl)amino)cyclopentyl)cyclopropanecarboxamide (Compound 79- stereoisomer-2)

[0262] To a solution of N3-(3-aminocyclopentyl)-N5-(1-methylpiperidin-4-yl)-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3,5-diamine (60 mg, 109.58 μmol, 1 eq, TFA salt), cyclopropanecarboxylic acid (14.15 mg, 164.37 μmol, 1.5 eq) and DIEA EtOAc (42.49 mg, 328.75 μmol, 3 eq) in DMF (1 mL) was added HATU (83.33 mg, 219.16 μmol, 2 eq). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.1%TFA)- MeCN];gradient:15%-45% B over 8.0 min) affording title compounds.

[0263] Title compound Compound 79-stereoisomer-2 (8.47 mg, 12.56%, TFA salt) as a yellow solid. LCMS: [M+H]+502.2.1H NMR (400 MHz, MeCN-d3) δ 9.36 - 8.74 (m, 1H), 7.27 - 7.13 (m, 2H), 7.11 - 6.98 (m, 1H), 6.97 - 6.83 (m, 1H), 6.80 - 6.74 (m, 1H), 6.62 - 6.54 (m, 1H), 6.08 - 5.98 (m, 1H), 4.36 - 4.15 (m, 2H), 3.75 (ddd, J = 3.9, 7.3, 15.0 Hz, 1H), 3.65 - 3.54 (m, 2H), 3.42 - 3.28 (m, 2H), 2.87 - 2.83 (m, 3H), 2.69 - 2.55 (m, 1H), 2.37(br d, J = 15.0 Hz, 2H), 2.22 - 2.16 (m, 1H), 2.15 - 2.05 (m, 1H), 2.02 (br d, J = 6.6 Hz, 1H), 1.92 - 1.78 (m, 2H), 1.77 - 1.64 (m, 1H), 1.57 (dt, J = 6.8, 13.6 Hz, 1H), 1.47 (dq, J = 4.8, 8.0 Hz, 1H), 0.80 - 0.74 (m, 2H), 0.73 - 0.66 (m, 2H).

[0264] Title compound Compound 79 (12.94 mg, 19.18%, TFA salt) as a yellow solid. LCMS: [M+H]+502.3.1H NMR (400 MHz, MeCN-d3) δ 9.46 - 8.73 (m, 1H), 7.29 - 7.12 (m, 2H), 6.83 (s, 1H), 6.80 - 6.68 (m, 2H), 6.54 (s, 1H), 5.99 (s, 1H), 4.40 - 4.25 (m, 2H), 3.81 - 3.69 (m, 1H), 3.58 (br d, J = 12.1 Hz, 2H), 3.10 (br d, J = 12.4 Hz, 2H), 2.84 (d, J = 4.6 Hz, 3H), 2.41 - 2.29 (m, 3H), 2.22 - 2.13 (m, 2H), 2.04 - 2.00 (m, 2H), 1.91 (br d, J = 10.8 Hz, 1H), 1.70 - 1.46 (m, 3H), 0.80 - 0.75 (m, 2H), 0.73 - 0.67 (m, 2H).

[0265] Title compound Compound 79-stereoisomer-1 (8.56 mg, 12.69%, TFA salt) as a yellow solid. LCMS: [M+H]+502.3.1H NMR (400 MHz, MeCN-d3) δ 9.21 - 8.68 (m, 1H), 7.27 - 7.15 (m, 2H), 7.09 (br s, 1H), 6.98 - 6.85 (m, 1H), 6.83 - 6.73 (m, 1H), 6.63 - 6.54 (m, 1H), 6.10 - 5.99 (m, 1H), 4.35 - 4.25 (m, 1H), 4.25 - 4.14 (m, 1H), 3.75 (tdd, J = 3.8, 7.4, 11.0 Hz, 1H), 3.59 (br d, J = 11.8 Hz, 2H), 3.11 (br d, J = 12.3 Hz, 2H), 2.88 - 2.83 (m, 3H), 2.65 - 2.56 (m, 1H), 2.37 (br d, J = 12.8 Hz, 2H), 2.22 - 2.15 (m, 1H), 2.15 - 2.08 (m, 1H), 2.08 - 2.01 (m, 1H), 1.92 - 1.78 (m, 2H), 1.73 (td, J = 7.4, 12.1 Hz, 1H), 1.56 (br dd, J = 6.5, 13.3 Hz, 1H), 1.51 - 1.44 (m, 1H), 0.79 - 0.73 (m, 2H), 0.73 - 0.66 (m, 2H). Table S-1AThe following compounds were prepared following Method 1 starting with Int-15. Table S-1BCompounds with differentiated substitution in position 5 were prepared according to the procedures described below.

[0266] 5-amino substitution was introduced via reductive amination of Int-1, Int-18 and analogs of thereof or via Pd-catalyzed C-N coupling of 5-halo-1-(3,3,3-trifluoroprop-1-en- 2-yl)isoquinoline intermediate.Compound 74, Compound 110, Compound 110a, Compound 110b, Compound 110c, Compound 110d1. Synthesis of tert-butyl 4-((3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5- yl)amino)-3-fluoropiperidine-1-carboxylate

[0267] A mixture of 3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5-amine (2 g, 7.34 mmol, 1 eq), tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (3.19 g, 14.67 mmol, 2eq) in DCM (50 mL) and AcOH (20 mL) was degassed and purged with N2for 3 times, then BH3.THF (1 M, 40.34 mL, 5.5 eq) was added at 0°C, and then the mixture was stirred at 25°C for 12 hrs under N2 atmosphere. The reaction mixture was quenched with 1 N HCl (60 mL) at 0°C and adjusted to pH=8 with saturated aq.NaOH at 0°C carefully, followed by extraction with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) affording title compound (2 g, 57.54%) as a yellow solid. LCMS: [M+H]+474.2, 476.2.1H NMR (400 MHz, CDCl3) δ 7.77 - 7.70 (m, 1H), 7.48 - 7.42 (m, 2H), 6.99 - 6.79 (m, 1H), 6.45 (s, 1H), 5.84 (s, 1H), 4.97 - 4.73 (m, 1H), 4.62 - 4.46 (m, 1H), 4.38 - 4.20 (m, 1H), 3.78 - 3.66 (m, 1H), 3.27 - 2.87 (m, 2H), 2.05 - 2.00 (m, 1H), 1.92 - 1.81 (m, 1H), 1.51 - 1.49 (m, 9H). 2. Synthesis of tert-butyl 3-fluoro-4-((3-(propylamino)-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinolin-5-yl)amino)piperidine-1-carboxylate

[0268] A mixture of tert-butyl 4-((3-chloro-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-5- yl)amino)-3-fluoropiperidine-1-carboxylate (100 mg, 211.02 μmol, 1 eq), propan-1-amine (24.95 mg, 422.04 μmol, 34.70 μL, 2 eq), Pd-PEPPSI-IPentCI (17.73 mg, 21.10 μmol, 0.1 eq) and Cs2CO3(206.26 mg, 633.06 μmol, 3 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2 atmosphere. Three batches were combined, and the mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% tetrahydrofuran in petroleum ether) affording title compound (160 mg, 50.90%) (3 batches) as a yellow oil. LCMS: [M+H]+497.3. 3. Synthesis of N5-(3-fluoropiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1-en-2- yl)isoquinoline-3,5-diamine (Compound 74)

[0269] To a solution of tert-butyl 3-fluoro-4-((3-(propylamino)-1-(3,3,3-trifluoroprop-1-en- 2-yl)isoquinolin-5-yl)amino)piperidine-1-carboxylate (80 mg, 131.03 μmol, 1 eq) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25°C for 0.5 hr. The reaction mixture was concentrated to dryness in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O (0.1% TFA)-MeCN];gradient:13%-43% B over 8.0 min) affording title compound (45 mg, 67.28%, TFA salt) as a yellow solid. LCMS: [M+H]+397.2.1H NMR (400 MHz, MeCN-d3) δ 8.97 - 8.72 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.82 - 6.71 (m, 2H), 6.46 (d, J = 1.4 Hz, 1H), 5.90 (d, J = 1.0 Hz, 1H), 5.22 - 5.08 (m, 1H), 4.03 - 3.90 (m, 1H), 3.74 - 3.66 (m, 1H), 3.52 (br d, J = 12.9 Hz, 1H), 3.46 - 3.28 (m, 3H), 3.24 - 3.14 (m, 1H), 2.42 - 2.09 (m, 2H), 1.78 - 1.65 (m, 2H), 1.07 - 0.96 (m, 3H). 4. Synthesis of N5-(3-fluoro-1-methylpiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1- en-2-yl)isoquinoline-3,5-diamine (Compound 110) & (trans)-N5-((3S,4S)-3-fluoro-1- methylpiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-3,5- diamine (Compound 110a) & (cis)-N5-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-N3- propyl-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline-3,5-diamine (Compound 110b)

[0270] To a solution of N5-(3-fluoropiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1-en- 2-yl)isoquinoline-3,5-diamine (30 mg, 58.77 μmol, 1 eq, TFA salt) in MeOH (2 mL) was added DIEA EtOAc (22.79 mg, 176.32 μmol, 3 eq) at 0°C, formaldehyde (4.77 mg, 58.77 μmol, 1 eq) and AcOH (3.53 mg, 58.77 μmol, 1 eq) were added to the mixture. The mixture was stirred at 25°C for 0.5 hr. Then NaBH3CN (11.08 mg, 176.32 μmol, 3 eq) was added at 0°C and the mixture was stirred at 25°C for 0.5 hr. The reaction mixture was quenched with saturated sodium bicarbonate (2 mL) at 0°C and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1% TFA)-MeCN]; gradient: 20%-50% B over 8.0 min) affording title compound Compound 110 (6.69 mg, 20.71%, TFA salt) as a yellow solid. LCMS: [M+H]+411.2.1H NMR (400 MHz, MeCN-d3) δ 9.95 - 9.13 (m, 1H), 7.29 - 7.18 (m, 1H), 7.17 - 7.11 (m, 1H), 7.02 - 6.74 (m, 2H), 6.54 (s, 1H), 5.99 (s, 1H), 5.23 - 5.08 (m, 1H), 4.06 - 3.87 (m, 1H), 3.85 - 3.73 (m, 1H), 3.63 (br d, J = 12.4 Hz, 1H), 3.46 - 3.24 (m, 3H), 3.16 (br t, J = 12.3 Hz, 1H), 2.96 - 2.82 (m, 3H), 2.46 - 2.30 (m, 1H), 2.20 (br d, J = 12.6 Hz, 1H), 1.79 - 1.66 (m, 2H), 1.09 - 0.97 (m, 3H).

[0271] Title compound Compound 110a (4.71 mg, 11.68%) as a yellow solid. LCMS: [M+H]+411.2.1H NMR (400 MHz, MeCN-d3) δ 9.98 - 9.60 (m, 1H), 7.24 - 7.20 (m, 1H), 7.17 - 7.12 (m, 1H), 6.89 (s, 1H), 6.77 (br d, J = 7.4 Hz, 1H), 6.56 (s, 1H), 6.02 (s, 1H), 5.24 - 5.07 (m, 1H), 4.03 - 3.88 (m, 1H), 3.85 - 3.76 (m, 1H), 3.63 (br d, J = 12.6 Hz, 1H), 3.45 - 3.25 (m, 3H), 3.15 (br t, J = 12.1 Hz, 1H), 2.87 (s, 3H), 2.45 - 2.29 (m, 1H), 2.20 (br d, J = 12.8 Hz, 1H), 1.72 (sxt, J = 7.3 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H).

[0272] Title compound Compound 110b (10 mg, 21.34%, TFA salt) as a yellow solid. LCMS: [M+H]+411.2.1H NMR (400 MHz, MeCN-d3) δ 9.98 - 9.60 (m, 1H), 7.24 - 7.20 (m, 1H), 7.17 - 7.12 (m, 1H), 6.89 (s, 1H), 6.77 (br d, J = 7.4 Hz, 1H), 6.56 (s, 1H), 6.02 (s,1H), 5.24 - 5.07 (m, 1H), 4.03 - 3.88 (m, 1H), 3.85 - 3.76 (m, 1H), 3.63 (br d, J = 12.6 Hz, 1H), 3.45 - 3.25 (m, 3H), 3.15 (br t, J = 12.1 Hz, 1H), 2.87 (s, 3H), 2.45 - 2.29 (m, 1H), 2.20 (br d, J = 12.8 Hz, 1H), 1.72 (sxt, J = 7.3 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 5. Synthesis of N5-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-N3-propyl-1-(3,3,3- trifluoroprop-1-en-2-yl)isoquinoline-3,5-diamine (Compound 110c) & N5-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-N3-propyl-1-(3,3,3-trifluoroprop-1-en-2-yl)isoquinoline- 3,5-diamine (Compound 110d)

[0273] The racemic material was further purified by SFC to give arbitrarily assigned: Title compound 110c (Peak 1, retention time = 1.789) (5.33 mg, 25.50%) as a yellow solid. LCMS: [M+H]...

Claims

1. CLAIMS 1. A compound of Formula (A), (B), (C), (D), (E), (F), or (G):wherein: each ring bond represented by a dashed line is independently a single bond or a double bond; Z1is N or CH; Z2is N or CR2; Z3is N or CH; wherein at least one of Z1, Z2when present, and Z3is N; Z4is N, NR4, CR4, CR4H, or C(R4)R4B, wherein when Z4is C(R4)R4Band R4is attached to the rest of the compound through O or N, then R4Bis C1-C2 alkyl, or C1-C2 haloalkyl, and when Z4is C(R4)R4Band R4is attached to the rest of the compoundthrough C, then R4Bis C1-C2alkyl, C1-C2haloalkyl, F, -OH, -OMe, -OCF3, -OCH2F, - OCHF2, -NH2, -NHMe, or NMe2; Z4Ais N, C, or CH; Z5is N, NR5, CR5, or CHR5; Z6is N, NR6, CR6, or CHR6; Z7is N, NH, CH, or CH2; when the compound is of Formula (B) and R8Ais -H and R15is C1-C3 alkyl, then Z1is N; when the compound is of Formula (B), (C), or (D), then: (a) Z5and Z6are N, NH, or CH; and (b) R2 and R4 are not -H, -F, -NH2, -CH3, or -CF3; when the compound is of Formula (E), then (a) Z4is CR4wherein R4is not -H and / or (b) Z5is CR5wherein R5is not -H; when the compound is of Formula (F), then R2is not -H, -CH3, or -CF3; when the compound is of Formula (G), then: (a) L is -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo; (b) R4Ais R4or a bond; (c) one side of L' is bound to any chemically possible location on R2, and the other side of L' is bound to any chemically possible location on R4A; and (d) L' is selected from the group consisting of: -(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-, -C2-C12alkylene-, -NH-C2-C10 alkylene-, -C2-C10 alkylene-NH--O-C2-C10alkylene-, -C2-C10alkylene-O-, -NH-C(O)-C2-C10alkylene-, -C2-C10 alkylene-C(O)-NH-, -NH-C(O)-C2-C10 alkylene-C(O)-NH-, -C(O)- C2-C10alkylene-, -C2-C10alkylene-C(O)-, -C(O)-C2-C10alkylene-C(O)-, -C(O)-C2- C10alkylene-C(O)-NH-, and -NH-C(O)-C2-C10alkylene-C(O)-, wherein any terminal -C(O)- group in L’, when present, is directly attached to a nitrogen atom in R2or R4A, or Z4Awhen R4Ais a bond; R2is -L-E; L is selected from the group consisting of: a bond; -C1-C4 alkylene-; -C2-C5 linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo; -C1-C3alkylene-NRa-;-CH=C3-C7cycloalkylene-; -CH=CH-C3-C7cycloalkylene-; -C2-C4alkynylene-; -NRa-; -NRa-C1-C5 alkylene-; -NRa-C1-C3 alkylene-O-; -NRa-C1- C4 hydroxyalkylene-; -NRa-C3-C7 cycloalkylene-; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; -NRa-C3-C7cycloalkylene-C1-C3alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances of independently selected C1-C3 alkyl, C1-C3 haloalkyl, halo, or OH; -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; -NRa-6 membered aryl-; -NRa-5-6 membered heteroaryl-; -O-C1-C3alkylene-; -3-7 membered heterocyclyl-, -5-6 membered heteroaryl-, -6 membered aryl-, -C3-C7 cycloalkylene-, -C3-C7 cycloalkenylene-, -3-7 membered heterocyclyl-(C1-C3 alkylene)-, -5-6 membered heteroaryl-(C1-C3alkylene)-, -6 membered aryl-(C1-C3alkylene)-, - C3-C7 cycloalkylene-(C1-C3 alkylene)-, or -C3-C7 cycloalkenylene-(C1-C3 alkylene)-, wherein the 3-7 membered heterocyclyl, 5-6 membered heteroaryl, 6 membered aryl, C3-C7cycloalkylene, or C3-C7cycloalkenylene is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; -C1-C3 alkylene-C3-C6 cycloalkylene-; -C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3alkylene-; -O-C3-C6cycloalkylene-; -O-C3-C7cycloalkylene-C1-C3alkylene-; -O-C1-C3alkylene-C3-C7cycloalkylene-; -O- C1-C3 alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; and -C(O)-NRa-C1-C4 alkylene-; E is selected from the group consisting of: H; C1-C4 haloalkyl; hydroxy; -NRaRb; -NRa-C(O)-C(O)-N(Rb)2 -NRa-C(O)-C2-C5alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5 heteroalkyl or -NRa-C(O)-C1-C4 alkyl; -NRa-C(O)-C2-C6 alkenyl substituted with 0, 1, or 2 independently selected halo or C3-C6cycloalkyl; -V-C1-C4alkyl, wherein the C1-C4alkyl is substituted with 0, 1, or 2 instances of independently selected halo or CN; and wherein V is a bond, -C(O)-NRa-, - NRa-C(O)-, or -C(O)-; -W-C1-C6heteroalkyl; wherein W is a bond, -C(O)-NRa-, -NRa-C(O)-, or -C(O)-;-X-6-10 membered aryl or -X-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 heteroalkyl, C1-C4heteroalkyl substituted with 1 instance of C2-C3alkynyl, 5- 6 membered heteroaryl, halo, -OH, oxo, C1-C4haloalkyl, C1-C4alkoxy, C3-C6cycloalkyl, -O-cyclopropyl, -O-C1-C4 haloalkyl, C1-C4 alkoxy substituted with 1 instance of CN, -CN, C1-C4 cyanoalkyl, -NRaRb, -NRa-C(O)-C1-C4 alkyl-, - C(O)-NRa-S(O)2(C1-C4alkyl), -S(O)2(C1-C4alkyl), -S(O)2NH2, - S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), -C(O)NRaRb, or C3-C7 heterocyclic; and wherein X is a bond, -NRa-, -O-, -NRa-C(O)-, -C(O)- N(Ra)-; -CH(OH)-, -NRa-C(O)-C1-C4alkylene-, or -NRa-C(=NH)-; -Y-3-9 membered heterocyclyl, wherein the 3-9 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, - OH, oxo, halo, -C(O)-Ra, 6-10 membered aryl, or 6-10 membered aryl substituted with 1 instance of C1-C4alkoxy; and wherein Y is a bond, -NRa-, - NRa-C(O)-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C2-C4 alkynylene-, or - NRa-C(O)-C2-C4alkynylene-O-; -Z-3-9 membered cycloalkyl, wherein the 3-9 membered cycloalkyl is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, halo, C1-C4 haloalkyl, -OH, C1-C4hydroxyalkyl, CN, C1-C4cyanoalkyl, C1-C4heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5 to 10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4 alkyl; and wherein Z is a bond, -NRa-C(O)-, -NRa-C(O)-C=, -NRa-C(O)O-, -C(O)-NRa-, -NRa- S(O)2-, -C(O)-, -NRa-C(O)-C2-C4alkynylene-, -NRa-C(O)-C2-C4alkynylene- O-, -NRa-C(O)-C1-C4 alkylene-, -NRa-C(O)-C1-C4 haloalkylene-, -NRa-C(O)- C1-C4 alkylene-O-, or -N(Ra)-CH(C1-C4 haloalkyl)-; R4is selected from the group consisting of H, -O-R9, -NH-R9, and -R9; and R5is H, -CH3, or -F; or R4is H, -CH3, -NH2, or -F; and R5is selected from the group consisting of H, -OR10, - OR9A, -OR9B, and -NH-R9; R9is -R13-R9A, R9B, R9C, or R9D; R13is a bond, C1-C3 alkylene substituted with 0, 1, 2, or 3 halo, or -C(O)-C1-C3 alkylene-; R9Ais a 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy,halo, -CN, C1-C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1-C4 alkyl), -NRdRe, =NH, or -R12; wherein when the 3-9 membered heterocyclyl does not contain a nitrogen or sulfur in the ring atoms, then the 3-9 membered heterocyclyl is substituted with at least one instance of -NRdRe; R9Bis a 3-9 membered cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4 alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12, wherein when the 3-9 membered cycloalkyl is not substituted with -NRdRe, then the 3-9 membered cycloalkyl is substituted with at least one instance of 5-6 membered heteroaryl or 3-9 membered heterocyclyl that contains at least one N as a ring atom; R9Cis -C1-C4alkylene-NRdRe, wherein the C1-C4alkylene is substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, halo, -CN, hydroxy, C1-C6 heteroalkyl, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1-C4alkyl), -NRdRe, or -R12; R9Dis 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, -CN, C1- C4cyanoalkyl, hydroxy, oxo, C1-C6heteroalkyl substituted with 0 or 1 instance of hydroxy, C1-C4hydroxyalkyl, -C1-C4alkylene-C(O)NRdRe, -C1-C4alkylene-SO2-(C1- C4 alkyl), -NRdRe, or -R12; wherein when the 5-10 membered heteroaryl does not contain a nitrogen in the ring atoms then the 5-10 membered heteroaryl is substituted with at least one instance of -NRdRe; R12is 5-6 membered heteroaryl, 6 membered aryl, 3-9 membered heterocyclyl, or 3-9 membered cycloalkyl, each of which is substituted with 0, 1, or 2 instances of hydroxy, C1-C4heteroalkyl, C1-C4haloalkyl, or -C(O)Ra; R10is H, -C1-C4 alkylene-NRaRb, or -C1-C4 alkyl; R6is H, -CH3, or -NH2; R8is -CH3substituted with 1, 2, or 3 instances of F, or R8is cyclopropyl substituted with 0, 1, 2, or 3 instances of F; R8Ais -H or -CH3; R8Bis -CH3substituted with 1, 2, or 3 instances of F; R14is -H or -CH3substituted with 0, 1, 2, or 3 instances of F;R15is -H or C1-C3alkyl; Raand Rbin each instance are independently selected from the group consisting of H and C1-C4 alkyl substituted with 0, 1, 2, or 3 instances of F; and Rdand Rein each instance are independently selected from the group consisting of H; C1- C4alkyl substituted with 0 or 1 instance of -O-C1-C4alkyl; 3-11 membered cycloalkyl; and 3-11 membered heterocyclyl; or Rdand Retogether with the nitrogen to which they are attached form a 3-11 membered heterocyclyl, wherein the 3-11 membered cycloalkyl or 3-11 membered heterocyclyl of Rdand Reor the 3-11 membered heterocyclyl formed by Rdand Reis independently substituted with 0, 1, or 2 instances of independently selected -OH, oxo, S(O)2(C1-C4 alkyl), C1-C4 alkyl, C1- C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, or C1-C4heteroalkyl; or (i) an isotopologue thereof; (ii) a stereoisomer thereof; (iii) a pharmaceutically acceptable salt thereof; or any combination of (i) to (iii); wherein the compound is not:stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (A).

3. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (B).

4. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (C).

5. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (D).

6. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (E).

7. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (F).

8. The compound of claim 1, or an isotopologue, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (G).

9. The compound of any one of claims 1, 2, and 8, an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is -CF3.

10. The compound of any one of claims 1, 2, and 8, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R8is cyclopropyl substituted with 0 or 1 F.

11. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: (i) L is a bond; and E is H, C1-C4alkyl, -NRaRb, 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, or C1-C4 alkyl, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected -OH, oxo, C1- C4alkyl, or -NRa-C(O)-C1-C4alkyl; (ii) L is -3-7 membered heterocyclyl-, wherein the -3-7 membered heterocyclyl is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3alkyl, or oxo; and E is H, -NRa-C(O)-C3-C6 cycloalkyl, or hydroxy; (iii) L is -5-6 membered heteroaryl- or -5-6 membered heteroaryl-(C1-C3 alkylene)-, wherein the -5-6 membered heteroaryl- of each is substituted with 0, 1, 2, or 3 instances of independently selected hydroxy, C1-C3 alkyl, or oxo; and E is H; hydroxy; C1-C4 alkyl; -C(O)-NRa-C1-C4 alkyl; -NRa-C(O)-C3-C9 cycloalkyl; 3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected oxo; (iv) L is -C3-C7 cycloalkylene- or -C3-C7 cycloalkenylene-; and E is C1-C4alkyl, -C(O)-NRa-C1-C4alkyl, or -NRa-C(O)-C3-C6cycloalkyl; or(v) L is -6 membered aryl-(C1-C3alkylene)-; and E is -NRa-C(O)-C1-C4 alkyl.

12. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is H, -CH2CH2CH3, -NH2, - NHCH2CH2CH3, -NHCH2CH3, -N(CH3)CH2CH2CH3,13. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein (i) L is -C1-C3 alkylene-NRa-; and E is 6-10 membered aryl or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected -C1-C4 alkoxy, -CN, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, -S(O)(=NH)(C1-C4 alkyl), -P(O)(C1-C4 alkyl)(C1-C4 alkyl), or - C(O)NRaRb;(ii) L is -C1-C4alkylene-; and E is -N(Ra)-CH(C3-C6 cycloalkyl)(C1-C4 haloalkyl), -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl or C1-C4hydroxyalkyl, -NRa-C(O)-C3-C6cycloalkyl, -NRa-5-10 membered heteroaryl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRa-C1-C4alkyl, -NRaRb, or 6-10 membered aryl substituted with 0, 1, or 2 instances of independently selected C1- C4 alkyl; (iii) L is -NRa-; and E is C3-C6 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of -OH; (iv) -NRa-C1-C3alkylene-O-; and E is H or C1-C4 alkyl; (v) L is -NRa-C1-C4 hydroxyalkylene-; and E is H, C1-C4alkyl, or phenyl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl; (vi) L is -NRa-C1-C5 alkylene-; and E is -H; -C3-C6cycloalkyl; -NRaRb; -NRa-C(O)-C1-C4alkyl; -NRa-C(O)-C3-C6cycloalkyl; -C(O)-NRa-C1-C4 alkyl; -C(O)-NRa-C3-C6 cycloalkyl; -C(O)-NRa-5-10 membered heteroaryl; 5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkoxy; 3-7 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected oxo or C1-C4alkyl; - NRa-6-10 membered aryl or -NRa-5-10 membered heteroaryl, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkoxy or -C(O)NRaRb; -NRa-C(O)-5- 10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl; or -O-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected halo; (vii) L is -NRa-C3-C7 cycloalkylene-; -NRa-C3-C7 cycloalkylene-C1-C3 alkylene-, wherein the C3-C7cycloalkylene is substituted with 0, 1, or 2 instances ofindependently selected C1-C3alkyl, C1-C3haloalkyl, halo, or OH; -NRa-C1-C3alkylene-C3-C7 cycloalkylene-C1-C3 alkylene-; or -O-C3-C6 cycloalkylene; and E is hydroxy; C1-C4 haloalkyl; -NRa-C(O)-C1-C4 alkyl; -C(O)-NRa-C1-C4 alkyl; 6- 10 membered aryl; -NRa-5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected; C1-C4alkoxy or -C(O)NRaRb; -NRa-C(O)-C3-C6 cycloalkyl; -NRa-C(O)-5-10 membered heteroaryl, wherein the -NRa-C(O)-5-10 membered heteroaryl is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C3-C7 heterocyclic, C1-C4 alkoxy, or -CN; or -O- 6-10 membered aryl; (viii) L is -O-C1-C3alkylene-; and E is H or 6-10 membered aryl; (ix) L is -NRa-C1-C3 alkylene-C3-C7 cycloalkylene-; and E is -NRa-C(O)-C3-C6cycloalkyl or -C(O)-NRa-C1-C4alkyl; (x) L is -C(O)-NRa-C1-C4alkylene-; and E is -C(O)-NRa-C1-C4 alkyl or -NRa-C(O)-C3-C6 cycloalkyl; or (xi) L is -C1-C3alkylene-C3-C6cycloalkylene-; and E is -NRa-C(O)-C3-C6 cycloalkyl.

14. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,, , -CH2CH2NH2, - CH2CH2NHC(O)CH3, -CH2CH2-phenyl, -CH2CH2CH2NH2, -CH2CH2CH2NHC(O)CH3, - CH2CH2CH2C(O)NHCH3, -CH2CH2CH2NHC(O)-cyclopropyl, - CH2CH2C(CH3)HNHC(O)-cyclopropyl, -CH2CH2CH2CH2NHC(O)-cyclopropyl,,, , , OCH2CH2CH3, -OCH2-phenyl, -OCH2CH2-phenyl,.

15. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -C2-C5linear alkenylene- substituted with 0, 1, 2, or 3 instances of independently selected C1-C3alkyl or halo.

16. The compound of claim 15, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is deuterated at one or more positions.

17. The compound of claim 15 or 16, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is.

18. The compound of any one of claims 15 to 17, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is H; hydroxy; -NRaRb, -C(O)-NRa-C1-C4 alkyl; -NRa-S(O)2-C3-C6 cycloalkyl; -NRa-C(O)-C1-C4alkyl substituted with 0, 1, or 2 instances of independently selected halo or CN; -NRa-C(O)-C3-C9 cycloalkyl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, C1-C4haloalkyl, -OH, C1-C4hydroxyalkyl, -CN, C1-C4cyanoalkyl, C1-C4heteroalkyl, -NRa-C(O)-C1-C4alkyl, -C(O)-NRaRb, or 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 independently selected C1-C4 alkyl; -NRa-C(O)-3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, oxo, or -C(O)-Ra; -NRa-C(O)-C6-C10 membered aryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4alkyl, halo, -CN, C1-C4alkoxy, C1-C4heteroalkyl, -NRaRb, -C(O)- NRa-S(O)2(C1-C4alkyl), or -P(O)(C1-C4alkyl)(C1-C4alkyl); -NRa-C(O)-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, halo, - OH, C1-C4haloalkyl, C1-C4alkoxy, -O-C1-C4haloalkyl, -NRaRb, -S(O)2(C1-C4alkyl),-NRa-C(O)-C1-C4alkyl-, -C(O)-NRa-S(O)2(C1-C4alkyl), C3-C6cycloalkyl, or C3-C7heterocyclyl ; -NRa-C6-C10 membered aryl substituted with 0, 1, 2, or 3 instances of independently selected halo, C1-C4alkoxy, -CN, -S(O)2(C1-C4alkyl), -P(O)(C1-C4alkyl)(C1-C4alkyl), or -C(O)NRaRb; -NRa-5-10 membered heteroaryl substituted with 0, 1, or 2 instances of independently selected C1-C4 alkyl, halo, C1-C4 alkoxy, or -C(O)NRaRb; -NRa-3-9 membered heterocyclyl substituted with 0, 1, 2, or 3 instances of independently selected 6-10 membered aryl substituted with 1 instance of C1-C4 alkoxy; -NRa-C(O)-C1-C4 alkylene-3-9 membered cycloalkyl; -NRa-C(O)-C1-C4alkylene-3-9 membered heterocyclyl; -NRa-C(O)-C1-C4 alkylene-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl; -NRa-C(O)-C1-C4alkylene-O-3-9 membered cycloalkyl; -NRa-C(O)-C2-C4 alkynylene-3-9 membered cycloalkyl; -NRa-C(O)-C2-C5 alkynyl substituted with 0, 1, or 2 instances of independently selected C2-C5heteroalkyl or -NRa-C(O)-C1-C4alkyl; -C1-C6 heteroalkyl; -NRa-C(O)-C1-C6 heteroalkyl; -NRa-C(O)-C1-C4haloalkylene-3-9 membered cycloalkyl; -NRa-C(O)-C(O)-N(Rb)2; -NRa-C(=NH)-5-10 membered heteroaryl substituted with 0, 1, 2, or 3 instances of independently selected C1-C4 alkyl; -NRa-C(O)-C=3-9 membered cycloalkyl; -NRa-C(O)O-3-9 membered cycloalkyl; -3-9 membered heterocyclyl substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl or oxo; or -5-10 membered heteroaryl.

19. The compound of any one of claims 15 to 18, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein E is -NRa-C(O)-C3-C9 cycloalkyl, -NRa- C(O)-3-9 membered heterocyclyl, or -NRa-C(O)-5-10 membered heteroaryl, each of which is substituted with 0, 1, or 2 instances of independently selected C1-C4alkyl, halo, cyclopropyl, or NH2.

20. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is,,, , ,, ,, , ,, , ,,,.

21. The compound of any one of claims 15 to 20, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L’ is -NH-C2-C10alkylene-, -C2-C10C2-C12alkylene- and R4Acontains one or more secondary or tertiary amines.

22. The compound of any one of claims 1 and 8 to 10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E-L’-R4A- is,.

23. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: (i) L is -CH=C3-C7cycloalkylene- or -CH=CH-C3-C7cycloalkylene; and E is H, -NRa-C(O)-C3-C6 cycloalkyl, or -C(O)-NRa-C1-C4 alkyl; or (ii) L is -C2-C4 alkynylene-; and E is H, C1-C4alkyl, -NRa-C(O)-C1-C4alkyl, -CH(OH)(5-6 membered heteroaryl), or -NRa-5-10 membered heteroaryl.

24. The compound of any one of claims 1-10, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein -L-E is, ,25. The compound of any one of claims 1-24, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein(i) Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH; (ii) Z1is N; Z2is CR2; Z3is CH; Z4is CR4; Z5is N, Z6is CR6; and Z7is CH; (iii) Z1is N; Z2is CR2; Z3is CH; Z4Ais CR4; Z5is CR5; Z6is CR6; and Z7is CH; (iv) Z1is N; Z2is CR2; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH; (v) Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is CH; (vi) Z1is CH; Z3is N; Z4is CR4; Z5is CR5; Z6is CR6; and Z7is N; (vii) Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2; (viii) Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is CH2; (ix) Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is CHR5; Z6is CHR6; and Z7is NH; (x) Z1is N; Z2is CR2; Z3is CH; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2; (xi) Z1is CH; Z3is N; Z4is CR4H; Z5is CHR5; Z6is NR6; and Z7is CH2; (xii) Z1is N; Z2is CR2; Z3is CH; Z4is CR4H; Z5is NR5; Z6is CHR6; and Z7is CH2; or (xiii) Z1is CH; Z3is N; Z4is NR4; Z5is CHR5; Z6is CHR6; and Z7is CH2.

26. The compound of any one of claims 1-25, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z1is N and Z3is CH; or Z1is CH and Z3is N.

27. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is -NH-R9A, -OR9A, or R9A; or R5is - NH-R9Aor -OR9A.

28. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is -NH-R9B, -OR9B, or R9B; or R5is - NH-R9Bor -OR9B.

29. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, R4is -NH-R9C, -OR9C, or R9C; or R5is -NH-R9C.

30. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4is -NH-R9D, -OR9D, or R9D; or R5is - NH-R9D.

31. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R4or R5is,, ,NHCH2CH2CH2N(CH3)2, or -NHCH2CH2CH2NHCH3.

32. The compound of any one of claims 1-26, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein.

33. The compound of any one of claims 1-32, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z5is CH.

34. The compound of any one of claims 1-33, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z6and Z7are each CH.

35. The compound of claim 1, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

36. A pharmaceutical composition comprising a compound of any one of claims 1-35, or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

37. A method of modulating the conformation of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of claims 1- 35, or the composition of claim 36.

38. A method of restoring wild-type function of a mutant p53 protein, comprising contacting the mutant p53 protein with an effective amount of the compound of any one of claims 1- 35, or a salt thereof, or the composition of claim 36.

39. A method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1- 35, or a salt thereof, or the composition of claim 36.

40. The method of claim 39, wherein the proliferative disorder is associated with a mutant p53 protein.

41. The method of claim 40, wherein the mutant p53 protein comprises a Y220C mutation.

42. The method of any one of claims 39-41, wherein the proliferative disorder is cancer.

43. A compound of the formula:or an isotopologue, or a stereoisomer or a pharmaceutically acceptable salt thereof.

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