Compounds for the targeted degradation of b-cell lymphoma 6 (BCL6)

Abstract

Provided are compounds of the Formula PTM-L-CLM, or a pharmaceutically acceptable salt thereof, wherein the PTM is (PTM-I) These compounds are useful for the degradation of BCL6 and in the treatment cancer.

Description

137508-05920COMPOUNDS FOR THE TARGETED DEGRADATION OF B-CELL LYMPHOMA 6 (BCL6)RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 691,513, filed on September 6, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference.TECHNICAL FIELD

[0002] The description provides compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of using those compounds. The compounds are useful as modulators of targeted ubiquitination, such as B-cell lymphoma 6 protein (BCL6), which is degraded by the compounds of the present disclosure.BACKGROUND

[0003] Most small molecule drugs bind enzymes or receptors in tight and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and therefore, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands which bind to these ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds have been reported that target E3 ligases, but the field remains underdeveloped.

[0004] Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB 1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin1MEl\56615208.vl137508-05920 ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.

[0005] An ongoing need exists in the art for effective treatments for disease associated with (i) aberrant BCL6 expression and / or activity and / or (ii) overexpression or aggregation of B- cell lymphoma 6 protein (BCL6). However, non-specific effects, and the inability to target and modulate BCL6, remain as obstacles to the development of effective treatments. As such, small-molecule therapeutic agents that target BCL6 and that leverage or potentiate E3 ubiquitin ligase (e.g., cereblon’s) substrate specificity would be very useful.SUMMARY

[0006] In one aspect, this application pertains compounds that can be used to treat or ameliorate diffuse large B-cell lymphoma (DLBCL), nodal T-follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI), , high grade B-cell lymphoma, non-Hodgkin lymphoma not otherwise specified, or solid tumors in a subject in need thereof.

[0007] In an aspect, the present disclosure provides compound of Formula (I): PTM-L-CLM (I) or a pharmaceutically acceptable salt thereof, wherein:(a) PTM is (PTM-I):wherein:C- - each Q1, Q2, Q3, and Q4is independently CRP™'2, ® , or N, wherein exactly oneQ5 isNRPTM-3or CRPTM-7RPTM-8. each Q6, Q7, Q8, Q9, and Q10is independently CRPTM'4RP™'5, NRP™'6, or O; each R™’1, Rp™-2, Rp™-4,RPTM-5 ,RPTM-7 ,an(jRp™-8jsindependently H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl;2MEl\56615208.vl137508-05920 each Rp™'3andRp™'6is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; andthe connection to L;(b) L is (L-Ia) or (L-Ib):wherein:* is the connection to PTM and ** is the connection to CLM; each, is independently absent, C3-C10 cycloalkylene,4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, wherein each ofis independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each Y1, Y2, Y3, Y4is independently absent, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene, -O-, -NRL 1-, -(CH2)h-SO2-, -(CH2)g-O-(CH2)P-, or Ci-C6alkoxy; each RL-1is independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each g, h, and p is independently 0, 1, 2, 3, 4 ,5, or 6;(c) CLM is (CLM-I):wherein:3MEl\56615208.vl137508-05920is C3-C10 cycloalkylene, Ce-Cio arylene, 4-12 membered heterocycloalkylene, or 5-10 membered heteroarylene;X is CH2or NH;A is a bond, Ci-Ce alkylene, or -C(O)-NH-; each RCLM-1isindependently H, halogen, CN, C=O, OH, oxo, Ci-Ce alkyl, Ci- Ce alkoxy, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;the connection to L; and m is 0, 1, 2, 3, 4, 5, 6, or 7.

[0008] In some embodiments, PTM is (PTM-II), (PTM-III), (PTM-IV), (PTM-V), (PTM- VI), or (PTM- VII):4MEl\56615208.vl137508-05920wherein each Qla, Q2a, and Q4ais independently CRP™'2or N; and wherein Q6, Q7, Q8, Q9, Q10, Rp™-2, Rp™-4, RP™-5, RPTM-6anj |are asdescribed herein.

[0009] In some embodiments, L is (L-II) or (L-III):wherein:is 4-12 membered heterocycloalkylene optionally substituted with one or more halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy;5MEl\56615208.vl137508-05920, , is independently absent, C3-C10 cycloalkylene,4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Ciois independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each Y2, Y3, Y4is independently absent, Ci-Ce alkylene, C2-C6 alkenylene, C2- C6alkynylene, -O-, -NR'-1-, -(CH2)h-SO2-, -(CH2)g-O-(CH2)P-, or Ci-C6alkoxy; each RL-1and RL'lbis independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each g, h, and p are independently 0, 1, 2, 3, 4 ,5, or 6.

[0010] In some embodiments, CLM is (CLM-II), (CLM-III), (CLM-IV), (CLM-V), (CLM- VI), or (CLM- VII):6MEl\56615208.vl137508-05920wherein:W is CRCLM'la’ RCLM-la” or C=O;is Ce arylene, 6-membered heterocycloalkylene, or 6 membered heteroarylene;X’ is CH or N;A’ is a bond or Ci-Ce alkylene; each of RCLM'laRCLM'lbRCLM-lc RCLM-M j^CLM-leand RCLM'lfis independently halogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;7MEl\56615208.vl137508-05920 each RCLM-la’and RCLM- ” jsindependently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; each of RCLM'leand RCLM-lfisindependently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; each mame, and mfis independently 0, 1, 2, or 3; each mb, mc, and mdis independently 0, 1, 2, 3, or 4;anddescribed herein.DETAILED DESCRIPTIONDefinitions

[0011] The following is a detailed description provided to aid those skilled in the art in practicing the present disclosure. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, figures and other references mentioned herein are expressly incorporated by reference in their entirety.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for describing particular embodiments only, and is not intended to be limiting of the disclosure.

[0013] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0014] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0015] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article8MEl\56615208.vl137508-05920 unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0016] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0017] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

[0018] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of and “consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0019] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.

[0020] The term “ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For9MEl\56615208.vl137508-05920 example, without wishing to be bound by theory, cereblon, an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0021] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In preferred embodiments, the patient is human.

[0022] The term “effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result. The term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.

[0023] A compound of the disclosure may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protective groups, as can be obtained from the relevant scientific literature or from standard reference textbooks in the field in view of this disclosure. Although not limited to any one or several sources, recognized reference textbooks of organic synthesis include: Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thed.; John Wiley & Sons: New York, 2001; and Greene, T.W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, 3rd; John10MEl\56615208.vl137508-05920Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2022 / 0395576 and International Publication No. 2022 / 221673 are incorporated herein by reference in their entireties.

[0024] The term “independently” is used herein to indicate that the variable, such as atom or functional group, which is independently applied, varies independently from application to application. For example, where more than one substituent or atom (carbon or heteroatom, such as oxygen (O), sulfur (S), or nitrogen (N)) occurs, each substituent or atom is independent of another substituent or atom and such substituents or atom can also alternate.

[0025] The term “alkyl”, as used herein, refers to saturated, straight-chain or branched hydrocarbon radicals containing, in certain embodiments, between one and twenty, including between one and ten, or between one and six, carbon atoms. Branched means that one or more lower Ci-Ce alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Examples of Ci-Ce alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of Ci-Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. Examples of C1-C20 alkyl radicals include but are not limited to hexadecamethyl, hexadecaethyl, hexadecopropyl, octadecamethyl, octadecaethyl, octadecapropyl and the like.

[0026] The term “alkenyl”, as used herein, denotes a monovalent straight or branched group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight, or two to twenty carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Examples of C2- Cs alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten-l-yl, heptenyl, octenyl and the like. As defined herein, “akenyl” groups include both cis- and trans-i somers.

[0027] The term “alkynyl”, as used herein, denotes a monovalent straight or branched group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight, or two to twenty carbon atoms having at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group. Examples of C2- Cs alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl and the like.

[0028] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen11MEl\56615208.vl137508-05920 atom from the alkyl. As herein defined, alkylene may also be a Ci-Ce alkylene. An alkylene may further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2- , -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, and the like.

[0029] Similarly, the terms “alkenylene,” “alkynylene,” “cycloalkylene,” “arylene,” “heteroarylene,” and “heterocyclene” denote a divalent radical derived from the monovalent alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle, respectively, by the abstraction of a second hydrogen atom from the respective monovalent radical.

[0030] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0031] The term “substituted” or “optionally substituted” shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent) one or more substituents (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (ON), nitro (NO2), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, C1-C10 , more preferably, Ci-Ce), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl), alkoxy group (preferably, Ci-Ce alkyl or aryl, including phenyl and substituted phenyl), thioether (Ci-Ce alkyl or aryl), acyl (preferably, Ci-Ce acyl), ester or thioester (preferably, Ci-Ce alkyl or aryl) including alkylene ester (such that attachment is on the alkylene group, rather than at the ester function which is preferably substituted with a Ci-Ce alkyl or aryl group), preferably, Ci-Ce alkyl or aryl, halogen (preferably, F or Cl), amine (including a five- or six-membered cyclic alkylene amine, further including a Ci-Ce alkyl amine or a Ci-Ce dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups) or an optionally substituted -N(Co-Ce alkyl)C(O)(O-Ci-Ce alkyl) group (which may be optionally substituted with a polyethylene glycol chain to which is further bound an alkyl group containing a single halogen, preferably chlorine substituent), hydrazine, amido, which is preferably substituted with one or two Ci-Ce alkyl groups (including a carboxamide which is optionally substituted with one or two Ci-Ce alkyl groups), alkanol (preferably, Ci-Ce alkyl or aryl), or alkanoic acid (preferably, Ci-Ce alkyl or aryl). Substituents according to the present disclosure may include, for example -SiRiR2R3groups where each of Ri and R2 is as otherwise described herein and R3is H or a Ci-Ce alkyl group, preferably Ri, R2, R3in this context is a12MEl\56615208.vl137508-05920C1-C3 alkyl group (including an isopropyl or t-butyl group). Each of the above-described groups may be linked directly to the substituted moiety or alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted -(CH2)m- or alternatively an optionally substituted -(0CH2)m-, - (OCH2CH2)m- or -(CH2CH2O)m- group, which may be substituted with any one or more of the above-described substituents. Alkylene groups -(CH2)m- or -(CH2)n- groups or other chains such as ethylene glycol chains, as identified above, may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or Ci-Ce (preferably C1-C3) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-Ci-Ce groups), up to three halo groups (preferably F), or a sidechain of an amino acid as otherwise described herein and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two Co-Ce alkyl substituents, which group(s) may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted Ci- Ce alkyl groups, preferably C1-C4 alkyl group, most often methyl or O-methyl groups or a sidechain of an amino acid as otherwise described herein. In the present disclosure, a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure moieties which are substituted are substituted with one or two substituents.

[0032] The term “substituted” (each substituent being independent of any other substituent) shall also mean within its context of use Ci-Ce alkyl, Ci-Ce alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, Ci-Ce ester (oxyester or carbonylester), Ci-Ce keto, urethane -O-C(O)-NRIR2 or -N(Ri)-C(O)-O-Ri, nitro, cyano and amine (especially including a Ci-Ce alkylene-NRiR2, a mono- or di- Ci-Ce alkyl substituted amines which may be optionally substituted with one or two hydroxyl groups). Each of these groups contain unless otherwise indicated, within context, between 1 and 6 carbon atoms. In certain embodiments, preferred substituents will include for example, -NH-, -NHC(O)-, -O-, =0, -(CH2)m- (here, m and n are in context, 1, 2, 3, 4, 5 or 6), -S-, -S(O)-, SO2- or -NH-C(O)- NH-, -(CH2)n0H, -(CH2)nSH, -(CH2)nC00H, Ci-C6alkyl, -(CH2)nO-(Ci-C6alkyl), - (CH2)nC(O)-(Ci-C6alkyl), -(CH2)nOC(O)-(Ci-C6alkyl), -(CH2)nC(O)O-(Ci-C6alkyl), - (CH2)nNHC(0)-Ri, -(CH2)nC(O)-NRiR2, -(OCH2)nOH, -(CH2O)nCOOH, Ci-C6alkyl, - (OCH2)nO-(Ci-C6alkyl), -(CH2O)nC(O)-(Ci-C6alkyl), -(0CH2)nNHC(0)-Ri, -(CH2O)nC(O)- NR1R2, -S(O)2-Rs, -S(O)-RS (Rs is Ci-C6alkyl or a -(CH2)m-NRiR2 group), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of the use of the substituent.13MEl\56615208.vl137508-05920Ri and R2 are each, within context, H or a Ci-Ce alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term “substituted” shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted Ci-Ce alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), a sidechain of an amino acid group as otherwise described herein, an amido group as described hereinabove, or a urethane group 0-C(0)-NRIR2 group where Ri and R2 are as otherwise described herein, although numerous other groups may also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents. It is noted that in instances where, in a compound at a particular position of the molecule substitution is required (principally, because of valency), but no substitution is indicated, then that substituent is construed or understood to be H, unless the context of the substitution suggests otherwise.

[0033] The term “aryl” or “aromatic”, in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present disclosure at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented. Other examples of aryl groups, in context, may include heterocyclic aromatic ring systems, “heteroaryl” groups having one or more (i.e. 1 to 4) nitrogen, oxygen, or sulfur atoms in the ring (monocyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above. Among the heteroaryl groups which may be mentioned include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic14MEl\56615208.vl137508-05920 heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles comprising 2 or more hetero atoms selected from among nitrogen, sulfur and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadi azole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazol oxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which may be optionally substituted.

[0034] The term “substituted aryl” refers to an aromatic carbocyclic group comprised of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic, wherein the ring(s) are substituted with one or more substituents. For example, an aryl group can comprise a substituent(s) selected from: -(CH2)nOH, -(CH2)n-O-(Ci-C6)alkyl, -(CH2)n-O- (CH2)n-(Ci-C6)alkyl, -(CH2)n-C(O)(C0-C6) alkyl, -(CH2)n-C(0)0(Co-C6)alkyl, -(CH2)n- OC(0)(Co-Ce)alkyl, amine, mono- or di-(Ci-Ce alkyl) amine wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, Ci-Ce alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted in ortho-, meta- and / or para- positions of the phenyl ring, preferably para-), an optionally substituted phenyl group (the phenyl group itself is preferably connected to a PTM group, including a ULM group, via a linker group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (in ortho-, meta- and / or parapositions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methyl substituted isoxazole, an optionally substituted oxazole including a methyl substituted oxazole, an optionally substituted thiazole including a methyl substituted thiazole, an optionally substituted isothiazole including a methyl substituted isothiazole, an optionally substituted pyrrole including a methyl substituted pyrrole, an optionally substituted imidazole including a methylimidazole, an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oximidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methyl substituted triazole group, an optionally substituted pyridine group, including a halo- (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (where the pyridine group is linked to the phenyl group by an oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2, 3, or 4- azaindolizine), an optionally substituted quinoline, and combinations thereof.15MEl\56615208.vl137508-05920

[0035] Unless otherwise indicated, a substituent connected by a bond drawn from the center of a ring means that the substituent can be bonded to any position in the ring. For example, piperidine shown with substituent R drawn from the center of the ring indicates that the R may be connected at the 1, 2, 3 or 4 positions as shown below:One of skill in the art will understand that multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[0036] The term “heteroaryl”, as used herein, refers to a mono- or poly-cyclic (e.g., bi-, or tricyclic or more) fused or non-fused, radical or ring system having at least one aromatic ring, having at least one ring atom (preferably 1 to 4 atoms) selected from S, O, P, and N. In other words, heteroaryl is aryl containing at least one heteroatom. Examples of heteroaryl include but are not limited to pyridinyl, furanyl, thiazolyl, imidazolyl, indolyl, benzofuranyl, and the like.

[0037] The term “5- to 12-membered heteroaryl”, is taken to mean a ring having five to twelve ring atoms of which at least one ring atom (preferably 1 to 4 atoms) is selected from S, O, P, and N. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.

[0038] The term “cycloalkyl” can mean but is in no way limited to univalent groups derived from monocyclic, bicyclic or polycyclic alkyl groups or cycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbon groups having from three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Bicyclic and polycyclic cycloalkyl groups contain more than one ring which can be fused (i.e., two adjacent rings are joined by two ring atoms), bridged (i.e., two adjacent rings are joined by three or more ring atoms), or spirocyclic (i.e., two adjacent rings are joined by one ring atom). The term “substituted cycloalkyl” can mean but is in no way limited to a monocyclic, bicyclic, or polycyclic alkyl group and being substituted by one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have16MEl\56615208.vl137508-05920 meanings which are identical with definitions of the corresponding groups as defined in this legend.

[0039] “Spirocycloalkyl” refers to a bicyclic or polycyclic cycloalkyl group with two adjacent rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another cycloalkyl or aryl group.

[0040] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom (preferably 1 to 4 atoms) of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S and P. “Substituted heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S and P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto and sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend. As with cycloalkyl groups, bicyclic and polycyclic heterocycloalkyl groups contain more than one ring which can be fused (i.e., two adjacent rings are joined by two ring atoms), bridged (i.e., two adjacent rings are joined by three or more ring atoms), or spirocyclic (i.e., two adjacent rings are joined by one ring atom).

[0041] “Spiroheterocycle” refers to a bicyclic or polycyclic heterocycloalkyl group with two adjacent rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include 2,7-diazaspiro[3.5]nonane, 2,6- diazaspiro[3.3]heptane, and 3,9-diazaspiro[5.5]undecane. One or both of the rings in a spiroheterocycle can be fused to one or more additional cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups.

[0042] The term “bridged cycloalkyl” or refers to a polycyclic alkyl group contining at least two rings, in which two rings share at least three ring atoms. The term “bridged heterocycle” refers to bridged cycloalkyl groups in which at least one ring carbon atom of its cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S and P. Bridged cycloalkyl and spiro-fused heterocycloalkyl groups may be further defined by their number of rings, e.g. bicyclic, tricyclic, tetracyclic, etc.

[0043] “Halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).17MEl\56615208.vl137508-05920

[0044] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, z.e., C=N.

[0045] The term “amino” as used herein means a substituent containing at least one nitrogen atom. Specifically, -NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”.

[0046] “Carboxyl” denotes the group — C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.

[0047] The term “thioalkyl” or “alkylthio” refers to an -S-alkyl radical. In some embodiments, thio group can be replaced by a sulfinyl (SO) or sulfonyl (SO2).

[0048] “Pharmaceutically acceptable salt”, as used herein with respect to a compound of the disclosure, means a salt form of the compound of the disclosure as well as hydrates of the salt form with one or more water molecules present. Such salt and hydrated forms retain the biological activity of the compound of the disclosure and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-m ethylglucamine ammonium salt, 3 -hydroxy -2 -naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3 -naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0049] The term “isomer” refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the salts of the compounds of18MEl\56615208.vl137508-05920 the disclosure may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0050] Solvate” means a solvent addition form that contains either a stoichiometric or non-stoichiometric amounts of solvent. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of salts of the compounds of the disclosure.

[0051] “Isotopic derivative”, as referred to herein, relates to a compound of the disclosure that is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in this application, the compounds of the disclosure include, for example, compounds that are isotopically enriched or labelled with one or more atoms such as deuterium

[0052] As used herein, “treating” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes decreasing or alleviating the symptoms or complications, or eliminating the disease, condition or disorder.

[0053] As used herein, “preventing” describes stopping the onset of the symptoms or complications of the disease, condition or disorder.

[0054] “Administration” refers to introducing an agent, such as a compound of the disclosure into a subject. The related terms “administering” and “administration of’ (and grammatical equivalents) refer both to direct administration, which may be administration to a subject by a medical professional or by self-administration by the subject, and / or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient.

[0055] “Therapeutically effective amount”, as used herein means an amount of the free base of a compound of the disclosure that is sufficient to treat, ameliorate, or prevent a specified19MEl\56615208.vl137508-05920 disease (e.g., prostate cancer), disease symptom, disorder or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount for a particular subject may depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and whether additional therapeutics are to be administered to the subject. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0056] Cmax , as used herein, refers to the observed maximum (peak) plasma concentration of a specified compound in the subject after administration of a dose of that compound to the subject.

[0057] “AUC”, as used herein, refers to the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest, and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng*H / mL (ng x H / mL), where “H” refers to hours.

[0058] “AUCtau”, as used herein, refers to the AUC from 0 hours to the end of a dosing interval.

[0059] “AUC0-24” means the AUC from 0 hours to 24 hours after administration of a single dose.

[0060] Dmax is the maximum concentration of the test compound relative to vehicle control.

[0061] DC50 is the test compound concentration at 50% of the maximum degradation achieved.

[0062] Therapeutic compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are described herein.

[0063] Compounds of the disclosure may be administered in single or divided doses by the oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, among other routes of administration. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient. Compounds of the disclosure may also be administered as sprays, mists, or aerosols for intra-nasal, intra-tracheal or pulmonary administration. The present disclosure therefore also is directed to pharmaceutical compositions comprising an effective amount of a compound of the disclosure20MEl\56615208.vl137508-05920 or a pharmaceutically acceptable salt thereof as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. Compounds of the disclosure may also be administered in immediate release, intermediate release or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of compound at an injection site.

[0064] The compositions as described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations.

[0065] The compositions as described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0066] Sterile inj ectable forms of the compositions as described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the 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 non-toxic parenterally-acceptable diluent or solvent.

[0067] The pharmaceutical compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.

[0068] Alternatively, the pharmaceutical compositions as described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.

[0069] The amount of compound in a pharmaceutical composition as described herein that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration. In some embodiments, the compositions should be formulated to contain between about 0.05 milligram to about 750 milligrams or more, about 1 milligram to about 600 milligrams, or about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one other compound according to the present disclosure.21MEl\56615208.vl137508-05920

[0070] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.

[0071] A compound of the disclosure be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or by aerosol form.

[0072] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient an effective amount for the desired indication, without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng / kg to about 300 mg / kg, about 0.1 to about 100 mg / kg per day, or about 0.5 to about 25 mg per kilogram body weight of the recipient / patient per day. A typical topical dosage will range from 0.01-5% wt. / wt. in a suitable carrier.

[0073] The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1 mg, 1 mg to 3000 mg, 5 to 500 mg of active ingredient per unit dosage form.

[0074] The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, or about 0.1-30 pM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.

[0075] The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once or may be divided into a number of smaller doses to be administered at varying intervals of time.22MEl\56615208.vl137508-05920

[0076] Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition.

[0077] The active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.

[0078] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0079] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Methods for preparation of such formulations will be apparent to those skilled in the art.

[0080] Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

[0081] The active compound or pharmaceutically acceptable salt thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as anti-cancer agents, as described herein among others. In certain preferred aspects of the disclosure, one or more compounds according to the present disclosure are coadministered with another bioactive agent, such as an anti-cancer agent or a wound-healing agent, including an antibiotic, as otherwise described herein.23MEl\56615208.vl137508-05920

[0082] Controlled release” or “CR” as used herein with respect to an oral dosage form refers to where a compound of the disclosure is released from the dosage form according to a pre-determined profile that may include when and where release occurs after oral administration and / or a specified rate of release over a specified time period.

[0083] Controlled release agent” as used herein with respect to an oral dosage form of the disclosure refers to one or more substances or materials that modulate release of a compound of the disclosure from the dosage form. Controlled release agents may be materials which are organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, and combinations thereof.

[0084] “Enteric coating” as used herein with respect to a dosage form of the disclosure refers to a pH-dependent material that surrounds a core comprising a compound of the disclosure and which remains substantially intact in the acid environment of the stomach, but which dissolves in the pH environment of the intestines.

[0085] Oral dosage form” as used herein refers to a pharmaceutical drug product that contains a specified amount (dose) of a compound of the disclosure as the active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and inactive components (excipients), formulated into a particular configuration that is suitable for oral administration, such as an oral tablet, liquid, or capsule. In one embodiment, the compositions are in the form of a tablet that can be scored.

[0086] The term “carrier”, as used in this disclosure, encompasses pharmaceutically acceptable excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0087] The term “about” is used herein to mean approximately, in the region of, roughly or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%, a variance of 10%, a variance of 5%, a variance of 3%, or a variance of 1%.

[0088] “Fasted condition” or “fasted state” as used to describe a subject means the subject has not eaten for at least 4 hours before a time point of interest, such as the time of administering24MEl\56615208.vl137508-05920 a compound of the disclosure. In an embodiment, a subject in the fasted state has not eaten for at least any of 6, 8, 10 or 12 hours prior to administration of a compound of the disclosure.

[0089] “Fed condition” or “fed state” as used to describe a subject herein means the subject has eaten less than 4 hours before a time point of interest, such as the time of administering a compound of the disclosure. In an embodiment, a subject in the fed state has eaten within at least any of 3, 2, 1 or 0.5 hours prior to administration of a compound of the disclosure.Compounds of the Present Disclosure

[0090] In an aspect, the present disclosure provides compound of Formula (I): PTM-L-CLM (I) or a pharmaceutically acceptable salt thereof, wherein:(a) PTM is (PTM-I):wherein:C-5- each Q1, Q2, Q3, and Q4is independently CRP™'2, ’ , or N, wherein exactly oneQ5 isNRPTM-3or CRPTM-7RPTM-8. each Q6, Q7, Q8, Q9, and Q10is independently CRP™-4RP™-5, NRP™'6, or O; each R™-1, RP™'2’ RP™-4,RPTM-5 ,RPTM-7 ,an(jRp™-8jsindependently H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; each Rp™'3andRp™'6is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; andthe connection to L;(b) L is (L-Ia) or (L-Ib):25MEl\56615208.vl137508-05920wherein:* is the connection to PTM and ** is the connection to CLM; each, is independently absent, C3-C10 cycloalkylene,4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, wherein each of, , is independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each Y1, Y2, Y3, Y4is independently absent, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene, -O-, -NR'-1-, -(CH2)h-SO2-, -(CH2)g-O-(CH2)p-, or Ci-C6alkoxy; each RL-1is independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each g, h, and p is independently 0, 1, 2, 3, 4 ,5, or 6;(c) CLM is (CLM-I):wherein:is C3-C10 cycloalkylene, Ce-Cio arylene, 4-12 membered heterocycloalkylene, or 5-10 membered heteroarylene;X is CH2or NH;A is a bond, Ci-Ce alkylene, or -C(O)-NH-; each RCLM-1isindependently H, halogen, CN, C=O, OH, oxo, Ci-Ce alkyl, Ci- Ce alkoxy, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;26MEl\56615208.vl137508-05920'< is the connection to L; and m is 0, 1, 2, 3, 4, 5, 6, or 7.

[0091] In some embodiments, PTM is (PTM-I):wherein:C-|- each Q1, Q2, Q3, and Q4is independently CRP™"2, * , or N, wherein exactly one Q1, Q2, Q3, and Q4isC;Q5 isNRPTM-3or CRPTM-7RPTM-8. each Q6, Q7, Q8, Q9, and Q10is independently CRPTM‘4RP™'5, NRP™"6, or O; each R™-1, Rp™'2,RP™-4,RPTM-5 ,RPTM-7 ,an(jRPTM-8 jnc[epenc[ent|y H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; each Rp™‘3and Rp™"6is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl; andthe connection to L.

[0092] In some embodiments, PTM is (PTM-II), (PTM-III), (PTM-IV), (PTM-V), (PTM-VI), or (PTM- VII):27MEl\56615208.vl137508-05920wherein: each Qla, Q2a, and Q4ais independently CRP™'2orN; andherein.28MEl\56615208.vl137508-05920

[0093] In some embodiments, PTM is (PTM-II). In some embodiments, PTM is (PTM-III). In some embodiments, PTM is (PTM-IV). In some embodiments, PTM is (PTM-V). In some embodiments, PTM is (PTM- VI). In some embodiments, PTM is (PTM- VII). c

[0094] In some embodiments, each Q1, Q2, Q3, and Q4is independently CRP™'2, ® , orN, wherein exactly oneC

[0095] In some embodiments, each Q1, Q2, Q3, and Q4is independently CRP™'2or « .

[0096] In some embodiments, exactly two of Q1, Q2, Q3, and Q4are CRP™'2, exactly oneQ1, Q2, Q3, and Q4is N, and exactly one

[0097] In some embodiments, exactly one of Q1, Q2, Q3, and Q4is CRP™'2, exactly two ofQ1, Q2, Q3, and Q4are N, and exactly onec

[0098] In some embodiments, each Q1, Q2, Q3, and Q4is independently ® or N. c

[0099] In some embodiments, Q2and Q4are both N. In some embodiments, Q3is * . In C-|- some embodiments, Q2and Q4are both N and Q3is ’ .

[0100] In some embodiments, Q5is NRP™'3or CRP™-7RP™-8

[0101] In some embodiments, Q5is NRP™'3. In some embodiments, Q5is N(CH3).

[0102] In some embodiments, Q5is CRPTM'7RP™'8.

[0103] In some embodiments, each Q6, Q7, Q8, Q9, and Q10is independently CRP™-4RP™-5, NRFTM-6,orQ

[0104] In some embodiments, each Q6, Q7, Q8, Q9, and Q10is independently CRP™-4RP™- 5

[0105] In some embodiments, each Q6, Q7, Q8, Q9, and Q10is independently NRP™'6.

[0106] In some embodiments, each Q6, Q7, Q8, Q9, and Q10is independently O.

[0107] In some embodiments, exactly one of Q6, Q7, Q8, Q9, and Q10is NRP™'3, exactly one of Q6, Q7, Q8, Q9, and Q10is O, and exactly three of Q6, Q7, Q8, Q9, and Q10are CRP™'4RPTM-5

[0108] In some embodiments, exactly two of Q6, Q7, Q8, Q9, and Q10is NRP™'3, exactly one of Q6, Q7, Q8, Q9, and Q10is O, and exactly two of Q6, Q7, Q8, Q9, and Q10are CRP™' 4RPTM-5

[0109] In some embodiments, exactly one of Q6, Q7, Q8, Q9, and Q10is NRP™'3, exactly two of Q6, Q7, Q8, Q9, and Q10is O, and exactly two of Q6, Q7, Q8, Q9, and Q10are CRP™' 4TJ PTM-529MEl\56615208.vl137508-05920

[0110] In some embodiments, exactly two of Q6, Q7, Q8, Q9, and Q10is NRP™'3, exactly two of Q6, Q7, Q8, Q9, and Q10is O, and exactly one of Q6, Q7, Q8, Q9, and Q10are CRP™' 4RPTM-5[OHl] In some embodiments, Rp™4is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0112] In some embodiments, RPTM-1is H.

[0113] In some embodiments, RPTM-1is halogen.

[0114] In some embodiments, Rp™-1is F. In some embodiments, Rp™-1is Cl. In some embodiments, RPTM-1is Br. In some embodiments, Rp™-1is I.

[0115] In some embodiments, Rp™4is Ci-Ce alkyl. In some embodiments, Rp™4is C2- Ce alkenyl. In some embodiments, Rp™-1is C2-C6 alkynyl. In some embodiments, Rp™4is Ci-Ce alkoxy. In some embodiments, Rp™-1is C3-C10 cycloalkyl. In some embodiments, Rp™'1is 4-12 membered heterocycloalkyl. In some embodiments, Rp™4is Ce-Cio aryl. In some embodiments, RPTM-1is 5- to 10-membered heteroaryl.

[0116] In some embodiments, Rp™'2is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0117] In some embodiments, Rp™'2is H. In some embodiments, Rp™'2is halogen.

[0118] In some embodiments, Rp™'2is Ci-Ce alkyl. In some embodiments, Rp™'2is C2- Ce alkenyl. In some embodiments, Rp™'2is C2-C6 alkynyl. In some embodiments, Rp™'2is Ci-Ce alkoxy. In some embodiments, RPTM'2is C3-C10 cycloalkyl. In some embodiments, Rp™'2is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'2is Ce-Cio aryl. In some embodiments, Rp™'2is 5- to 10-membered heteroaryl.

[0119] In some embodiments, Rp™'3is H.

[0120] In some embodiments, Rp™'3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl.

[0121] In some embodiments, Rp™'3is Ci-Ce alkyl. In some embodiments, Rp™'3is methyl. In some embodiments, Rp™'3is ethyl. In some embodiments, Rp™'3is propyl. In some embodiments, Rp™'3is n-propyl. In some embodiments, Rp™'3is isopropyl. In some embodiments, Rp™'3is butyl. In some embodiments, Rp™'3is n-butyl. In some embodiments, RP™-3 is isobutyl. In some embodiments, Rp™'3is sec-butyl. In some embodiments, Rp™'3is tert-butyl. In some embodiments, Rp™'3is pentyl. In some embodiments, Rp™'3is hexyl.30MEl\56615208.vl137508-05920

[0122] In some embodiments, Rp™'3is C2-C6 alkenyl. In some embodiments, Rp™'3 1SC2 alkenyl. In some embodiments, Rp™'3is C3 alkenyl. In some embodiments, Rp™'3is C4 alkenyl. In some embodiments, Rp™'3is C5 alkenyl. In some embodiments, Rp™'3is Ce alkenyl.

[0123] In some embodiments, Rp™'3is C2-C6 alkynyl. In some embodiments, Rp™'3is C2 alkynyl. In some embodiments, Rp™'3is C3 alkynyl. In some embodiments, RPTM'3is C4 alkynyl. In some embodiments, Rp™'3is C5 alkynyl. In some embodiments, Rp™'3is Ce alkynyl.

[0124] In some embodiments, Rp™'3is C3-C10 cycloalkyl. In some embodiments, Rp™'3is cyclopropyl. In some embodiments, RPTM'3is cyclobutyl. In some embodiments, Rp™'3is cyclopentyl. In some embodiments, Rp™'3is cyclohexyl. In some embodiments, Rp™'3is cycloheptyl. In some embodiments, RPTM'3is cyclooctyl. In some embodiments, RPTM'3is cyclononyl. In some embodiments, RPTM'3is cyclodecyl.

[0125] In some embodiments, Rp™'3is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'3is a monocyclic heterocycloalkyl. In some embodiments, Rp™'3is a polycyclic heterocycloalkyl.

[0126] In some embodiments, Rp™'3is 4-membered heterocycloalkyl. In some embodiments, RPTM'3is 4-membered heterocycloalkyl. In some embodiments, Rp™'3is 5- membered heterocycloalkyl. In some embodiments, Rp™'3is 6-membered heterocycloalkyl. In some embodiments, Rp™'3is 7-membered heterocycloalkyl. In some embodiments, Rp™'31is 8-membered heterocycloalkyl. In some embodiments, RPTM'3is 9-membered heterocycloalkyl. In some embodiments, RPTM'3is 10-membered heterocycloalkyl. In some embodiments, Rp™'3is 11-membered heterocycloalkyl. In some embodiments, Rp™'3is 12- membered heterocycloalkyl.

[0127] In some embodiments, Rp™'3is Ce-Cio aryl. In some embodiments, RPTM'3is Ce aryl (i.e., phenyl). In some embodiments, RPTM'3is C7 aryl. In some embodiments, RPTM'3is Cs aryl. In some embodiments, RPTM'3is C9 aryl. In some embodiments, Rp™'3is C10 aryl.

[0128] In some embodiments, Rp™'3is 5- to 10-membered heteroaryl. In some embodiments Rp™'3is 5- membered heteroaryl. In some embodiments, RPTM'3is 6- membered heteroaryl. In some embodiments, Rp™'3is 7- membered heteroaryl. In some embodiments, RP™-3 is 8- membered heteroaryl. In some embodiments, Rp™'3is 9- membered heteroaryl. In some embodiments, RPTM'3is 10- membered heteroaryl.

[0129] In some embodiments, Rp™'3is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms. In some embodiments, Rp™'3is 5- to 10-membered heteroaryl31MEl\56615208.vl137508-05920 comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments, Rp™'3is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O. In some embodiments, Rp™'3is 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'3is 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'3is 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'3is 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'3is 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'3is 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0130] In some embodiments, Rp™'4is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0131] In some embodiments, Rp™'4is H.

[0132] In some embodiments, Rp™'4is halogen.

[0133] In some embodiments, Rp™'4is halogen. In some embodiments, Rp™'4is F. In some embodiments, Rp™'4is Cl. In some embodiments, Rp™'4is Br. In some embodiments, Rp™’4is I.

[0134] In some embodiments, Rp™'4is Ci-Ce alkyl. In some embodiments, Rp™'4is methyl. In some embodiments, Rp™'4is ethyl. In some embodiments, Rp™'4is propyl. In some embodiments, Rp™'4is n-propyl. In some embodiments, Rp™'4is isopropyl. In some embodiments, RPTM'4is butyl. In some embodiments, Rp™'4is n-butyl. In some embodiments, RP™-4 is isobutyl. In some embodiments, Rp™'4is sec-butyl. In some embodiments, RPTM'4is tert-butyl. In some embodiments, Rp™'4is pentyl. In some embodiments, Rp™'4is hexyl.

[0135] In some embodiments, RPTM'4is C2-C6 alkenyl. In some embodiments, RPTM-41S2 alkenyl. In some embodiments, Rp™'4is C3 alkenyl. In some embodiments, Rp™'4is C4 alkenyl. In some embodiments, Rp™'4is C5 alkenyl. In some embodiments, Rp™'4is Ce alkenyl.

[0136] In some embodiments, RPTM'4is C2-C6 alkynyl. In some embodiments, Rp™'4is C2 alkynyl. In some embodiments, Rp™'4is C3 alkynyl. In some embodiments, RPTM'4is C4 alkynyl. In some embodiments, Rp™'4is C5 alkynyl. In some embodiments, Rp™'4is Ce alkynyl.

[0137] In some embodiments, Rp™'4is Ci-Ce alkoxy. In some embodiments, Rp™'4is methoxy. In some embodiments, RPTM'4is ethoxy. In some embodiments, RPTM'4is propoxy. In32MEl\56615208.vl137508-05920 some embodiments, RPTM'4is n-propoxy. In some embodiments, RPTM'4is isopropoxy. In some embodiments, Rp™'4is butoxy. In some embodiments, Rp™'4is n-butoxy. In some embodiments, Rp™'4is isobutoxy. In some embodiments, Rp™'4is sec-butoxy. In some embodiments, Rp™'4is tert-butoxy. In some embodiments, Rp™'4is pentoxy. In some embodiments, RPTM'4is hexoxy.

[0138] In some embodiments, RPTM'4is C3-C10 cycloalkyl. In some embodiments, RPTM'4is cyclopropyl. In some embodiments, RPTM'4is cyclobutyl. In some embodiments, RPTM'4is cyclopentyl. In some embodiments, RPTM'4is cyclohexyl. In some embodiments, RPTM'4is cycloheptyl. In some embodiments, RPTM'4is cyclooctyl. In some embodiments, RPTM'4is cyclononyl. In some embodiments, RPTM'4is cyclodecyl.

[0139] In some embodiments, Rp™'4is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'4is a monocyclic heterocycloalkyl. In some embodiments, Rp™'4is a polycyclic heterocycloalkyl.

[0140] In some embodiments, Rp™'4is 4-membered heterocycloalkyl. In some embodiments, RPTM'4is 4-membered heterocycloalkyl. In some embodiments, Rp™'4is 5- membered heterocycloalkyl. In some embodiments, Rp™'4is 6-membered heterocycloalkyl. In some embodiments, Rp™'4is 7-membered heterocycloalkyl. In some embodiments, Rp™'41is 8-membered heterocycloalkyl. In some embodiments, RPTM'4is 9-membered heterocycloalkyl. In some embodiments, RPTM'4is 10-membered heterocycloalkyl. In some embodiments, Rp™'4is 11-membered heterocycloalkyl. In some embodiments, Rp™'4is 12- membered heterocycloalkyl.

[0141] In some embodiments, Rp™'4is Ce-Cio aryl. In some embodiments, RPTM'4is Ce aryl (i.e., phenyl). In some embodiments, RPTM'4is C7 aryl. In some embodiments, RPTM'4is Cs aryl. In some embodiments, RPTM'4is C9 aryl. In some embodiments, Rp™'4is C10 aryl.

[0142] In some embodiments, Rp™'4is 5- to 10-membered heteroaryl. In some embodiments Rp™'4is 5- membered heteroaryl. In some embodiments, RPTM'4is 6- membered heteroaryl. In some embodiments, Rp™'4is 7- membered heteroaryl. In some embodiments, RP™-4 is 8- membered heteroaryl. In some embodiments, Rp™'4is 9- membered heteroaryl. In some embodiments, Rp™'4is 10- membered heteroaryl.

[0143] In some embodiments, Rp™'4is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms. In some embodiments, Rp™'4is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments, RP™-4 is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O.33MEl\56615208.vl137508-05920

[0144] In some embodiments, Rp™'4is 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'4is 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'4is 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'4is 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'4is 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'4is 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0145] In some embodiments, Rp™'5is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0146] In some embodiments, Rp™'5is H.

[0147] In some embodiments, Rp™'5is halogen.

[0148] In some embodiments, Rp™'5is halogen. In some embodiments, Rp™'5is F. In some embodiments, Rp™'5is Cl. In some embodiments, Rp™'5is Br. In some embodiments, Rp™’5is I.

[0149] In some embodiments, Rp™'5is Ci-Ce alkyl. In some embodiments, Rp™'5is methyl. In some embodiments, Rp™'5is ethyl. In some embodiments, Rp™'5is propyl. In some embodiments, Rp™'5is n-propyl. In some embodiments, Rp™'5is isopropyl. In some embodiments, Rp™'5is butyl. In some embodiments, Rp™'5is n-butyl. In some embodiments, RpTM-5 isobUtyi jnsome embodiments, Rp™'5is sec-butyl. In some embodiments, Rp™'5is tert-butyl. In some embodiments, Rp™'5is pentyl. In some embodiments, Rp™'5is hexyl.

[0150] In some embodiments, Rp™'5is C2-C6 alkenyl. In some embodiments, Rp™'5 1SC2 alkenyl. In some embodiments, Rp™'5is C3 alkenyl. In some embodiments, Rp™'5is C4 alkenyl. In some embodiments, Rp™'5is C5 alkenyl. In some embodiments, RPTM'5is Ce alkenyl.

[0151] In some embodiments, Rp™'5is C2-C6 alkynyl. In some embodiments, Rp™'5is C2 alkynyl. In some embodiments, Rp™'5is C3 alkynyl. In some embodiments, RPTM'5is C4 alkynyl. In some embodiments, Rp™'5is C5 alkynyl. In some embodiments, Rp™'5is Ce alkynyl.

[0152] In some embodiments, Rp™'5is Ci-Ce alkoxy. In some embodiments, Rp™'5is methoxy. In some embodiments, RPTM'5is ethoxy. In some embodiments, Rp™'5is propoxy. In some embodiments, Rp™'5is n-propoxy. In some embodiments, Rp™'5is isopropoxy. In some embodiments, Rp™'5is butoxy. In some embodiments, Rp™'5is n-butoxy. In some34MEl\56615208.vl137508-05920 embodiments, Rp™'5is isobutoxy. In some embodiments, Rp™'5is sec-butoxy. In some embodiments, Rp™'5is tert-butoxy. In some embodiments, Rp™'5is pentoxy. In some embodiments, Rp™'5is hexoxy.

[0153] In some embodiments, Rp™'5is C3-C10 cycloalkyl.

[0154] In some embodiments, RPTM'5is cyclopropyl. In some embodiments, RPTM'5is cyclobutyl. In some embodiments, Rp™'5is cyclopentyl. In some embodiments, Rp™'5is cyclohexyl. In some embodiments, Rp™'5is cycloheptyl. In some embodiments, Rp™'5is cyclooctyl. In some embodiments, RPTM'5is cyclononyl. In some embodiments, Rp™'5is cyclodecyl.

[0155] In some embodiments, Rp™'5is 4-12 membered heterocycloalkyl.

[0156] In some embodiments, Rp™'5is a monocyclic heterocycloalkyl. In some embodiments, Rp™'5is a polycyclic heterocycloalkyl.

[0157] In some embodiments, Rp™'5is 4-membered heterocycloalkyl. In some embodiments, RPTM'5is 4-membered heterocycloalkyl. In some embodiments, Rp™'5is 5- membered heterocycloalkyl. In some embodiments, Rp™'5is 6-membered heterocycloalkyl. In some embodiments, Rp™'5is 7-membered heterocycloalkyl. In some embodiments, Rp™'51is 8-membered heterocycloalkyl. In some embodiments, RPTM'5is 9-membered heterocycloalkyl. In some embodiments, RPTM'5is 10-membered heterocycloalkyl. In some embodiments, Rp™'5is 11-membered heterocycloalkyl. In some embodiments, Rp™'5is 12- membered heterocycloalkyl.

[0158] In some embodiments, Rp™'5is Ce-Cio aryl.

[0159] In some embodiments, RPTM'5is Ce aryl (i.e., phenyl). In some embodiments, Rp™'5is C7 aryl. In some embodiments, RPTM'5is Cs aryl. In some embodiments, RPTM'5is C9 aryl. In some embodiments, Rp™'5is C10 aryl.

[0160] In some embodiments, Rp™'5is 5- to 10-membered heteroaryl.

[0161] In some embodiments Rp™'5is 5- membered heteroaryl. In some embodiments, RPTM'5is 6- membered heteroaryl. In some embodiments, Rp™'5is 7- membered heteroaryl. In some embodiments, Rp™'5is 8- membered heteroaryl. In some embodiments, Rp™'5is 9- membered heteroaryl. In some embodiments, RPTM'5is 10- membered heteroaryl.

[0162] In some embodiments, Rp™'5is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms. In some embodiments, Rp™'5is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments, RFTM-5t010-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O.35MEl\56615208.vl137508-05920

[0163] In some embodiments, Rp™'5is 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'5is 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'5is 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'5is 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'5is 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'5is 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0164] In some embodiments, Rp™'6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl.

[0165] In some embodiments, Rp™'6is H.

[0166] In some embodiments, Rp™'6is Ci-Ce alkyl. In some embodiments, Rp™'6is methyl. In some embodiments, Rp™'6is ethyl. In some embodiments, Rp™'6is propyl. In some embodiments, Rp™'6is n-propyl. In some embodiments, Rp™'6is isopropyl. In some embodiments, Rp™'6is butyl. In some embodiments, Rp™'6is n-butyl. In some embodiments, RP™-6 is isobutyl. In some embodiments, Rp™'6is sec-butyl. In some embodiments, RPTM'6is tert-butyl. In some embodiments, Rp™'6is pentyl. In some embodiments, Rp™'6is hexyl.

[0167] In some embodiments, RPTM'6is C2-C6 alkenyl. In some embodiments, RPTM’6 1SC2 alkenyl. In some embodiments, Rp™'6is C3 alkenyl. In some embodiments, Rp™'6is C4 alkenyl. In some embodiments, Rp™'6is C5 alkenyl. In some embodiments, RPTM'6is Ce alkenyl.

[0168] In some embodiments, RPTM'6is C2-C6 alkynyl. In some embodiments, Rp™'6is C2 alkynyl. In some embodiments, Rp™'6is C3 alkynyl. In some embodiments, RPTM'6is C4 alkynyl. In some embodiments, Rp™'6is C5 alkynyl. In some embodiments, Rp™'6is Ce alkynyl.

[0169] In some embodiments, RPTM'6is C3-C10 cycloalkyl. In some embodiments, RPTM'6is cyclopropyl. In some embodiments, RPTM'6is cyclobutyl. In some embodiments, RPTM'6is cyclopentyl. In some embodiments, RPTM'6is cyclohexyl. In some embodiments, RPTM'6is cycloheptyl. In some embodiments, RPTM'6is cyclooctyl. In some embodiments, RPTM'6is cyclononyl. In some embodiments, RPTM'6is cyclodecyl.

[0170] In some embodiments, Rp™'6is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'6is a monocyclic heterocycloalkyl. In some embodiments, Rp™'6is a polycyclic heterocycloalkyl.36MEl\56615208.vl137508-05920

[0171] In some embodiments, Rp™'6is 4-membered heterocycloalkyl. In some embodiments, RPTM'6is 4-membered heterocycloalkyl. In some embodiments, Rp™'6is 5- membered heterocycloalkyl. In some embodiments, Rp™'6is 6-membered heterocycloalkyl. In some embodiments, Rp™'6is 7-membered heterocycloalkyl. In some embodiments, Rp™'61is 8-membered heterocycloalkyl. In some embodiments, RPTM'6is 9-membered heterocycloalkyl. In some embodiments, RPTM'6is 10-membered heterocycloalkyl. In some embodiments, Rp™'6is 11-membered heterocycloalkyl. In some embodiments, Rp™'6is 12- membered heterocycloalkyl.

[0172] In some embodiments, Rp™'6is Ce-Cio aryl. In some embodiments, RPTM'6is Ce aryl (i.e., phenyl). In some embodiments, RPTM'6is C7 aryl. In some embodiments, RPTM'6is Cs aryl. In some embodiments, RPTM'6is C9 aryl. In some embodiments, Rp™'6is C10 aryl.

[0173] In some embodiments, Rp™'6is 5- to 10-membered heteroaryl. In some embodiments Rp™'6is 5- membered heteroaryl. In some embodiments, RPTM'6is 6- membered heteroaryl. In some embodiments, Rp™'6is 7- membered heteroaryl. In some embodiments, RP™-6 is 8- membered heteroaryl. In some embodiments, Rp™'6is 9- membered heteroaryl. In some embodiments, RPTM'6is 10- membered heteroaryl.

[0174] In some embodiments, Rp™'6is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms. In some embodiments, Rp™'6is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments, RP™-6 is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O.

[0175] In some embodiments, Rp™'6is 5-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'6is 6-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'6is 7-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'6is 8-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'6is 9-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments, Rp™'6is 10-membered heteroaryl comprising 1-4 heteroatoms selected from O, N, and S.

[0176] In some embodiments, Rp™'7is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0177] In some embodiments, Rp™'7is H. In some embodiments, Rp™'7is halogen. In some embodiments, Rp™'7is Ci-Ce alkyl. In some embodiments, RPTM'7is C2-C6 alkenyl. In37MEl\56615208.vl137508-05920 some embodiments, RPTM'7is C2-C6 alkynyl. In some embodiments, Rp™'7is Ci-Ce alkoxy. In some embodiments, Rp™'7is C3-C10 cycloalkyl. In some embodiments, Rp™'7is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'7is Ce-Cio aryl. In some embodiments, Rp™'7is 5- to 10-membered heteroaryl.

[0178] In some embodiments Rp™'7is 5- membered heteroaryl. In some embodiments, RPTM'7is 6- membered heteroaryl. In some embodiments, Rp™'7is 7- membered heteroaryl. In some embodiments, Rp™'7is 8- membered heteroaryl. In some embodiments, Rp™'7is 9- membered heteroaryl. In some embodiments, RPTM'7is 10- membered heteroaryl.

[0179] In some embodiments, Rp™'7is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms. In some embodiments, Rp™'7is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments, Rp™'7is 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O.

[0180] In some embodiments, Rp™'8is H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5- 10 membered heteroaryl.

[0181] In some embodiments, Rp™'8is H. In some embodiments, Rp™'8is halogen.. In some embodiments, Rp™'8is Ci-Ce alkyl. In some embodiments, RPTM'8is C2-C6 alkenyl. In some embodiments, Rp™'8is C2-C6 alkynyl. In some embodiments, Rp™'8is Ci-Ce alkoxy. In some embodiments, Rp™'8is C3-C10 cycloalkyl. In some embodiments, Rp™'8is 4-12 membered heterocycloalkyl. In some embodiments, Rp™'8is a monocyclic heterocycloalkyl. In some embodiments, Rp™'8is a polycyclic heterocycloalkyl. In some embodiments, Rp™'8is Ce-Cio aryl. In some embodiments, Rp™'8is 5- to 10-membered heteroaryl.

[0182] In some embodiments, each Qla, Q2a, and Q4ais independently CRP™'2or N. In some embodiments, each Qla, Q2a, and Q4ais independently CRP™'2. In some embodiments, each Qla, Q2a, and Q4ais independently N. In some embodiments, exactly two of Qla, Q2a, and Q4aare N and exactly one of Qla, Q2a, and Q4ais CRP™'2. In some embodiments, exactly one of Qla, Q2a, and Q4ais N and exactly two of Qla, Q2a, and Q4aare CRP™'2. In some embodiments, Q2a, and Q4aare both N and Qlais CRP™'2. In some embodiments, Q2a, and Q4aare both N and Qlais CH.

[0183] In some embodiments, PTM is selected from:38MEl\56615208.vl137508-05920

[0184] In some embodiments, PTM is:

[0185] In some embodiments, L is (L-Ia) or (L-Ib):wherein:* is the connection to PTM and ** is the connection to CLM; each, is independently absent, C3-C10 cycloalkylene,4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio( D3arylene, wherein each ofand ' is independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each Y1, Y2, Y3, Y4is independently absent, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene, -O-, -NR'-1-, -(CH2)h-SO2-, -(CH2)g-O-(CH2)P-, or Ci-C6alkoxy; each RL-1is independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each g, h, and p is independently 0, 1, 2, 3, 4 ,5, or 6.

[0186] In some embodiments, L is (L-II) or (L-III):39MEl\56615208.vl137508-05920whereinis 4-12 membered heterocycloalkylene optionally substituted with one or more halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy;RL'lbis H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and40MEl\56615208.vl137508-05920 wherein each( D3h), and is independently absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, wherein each of, is independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each of Y2C, Yld, Y2d, Y2g, Y3g, and Y4gis independently absent, Ci-Ce alkylene, -O-, or-NR1'1andY2fis absent, Ci-Ce alkylene, C2-C6 alkynylene, -O-, or -NR1'1

[0189] In some embodiments, L is (L-IV). In some embodiments, L is (L-V). In some embodiments, L is (L-VI). In some embodiments, L is (L-VII). In some embodiments, L is (L- VIII). In some embodiments, L is (L-IX). In some embodiments, L is (L-X). f D3

[0190] In some embodiments, eachand is independently absent, C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-D2) 6 D3JCIO arylene, wherein each of, , and is independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.D2j ( D3)

[0191] In some embodiments, each■—J , and ' is independently absent, C3-Cio cycloalkylene, or 4-12 membered heterocycloalkylene, wherein each of, andis independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.( D3)

[0192] In some embodiments, each, , and is independently absent, C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, wherein each ofis unsubstituted.41MEl\56615208.vl137508-05920D1 e

[0193] In some embodiments, each ofis independently absent, C3-C10 cycloalkylene, or4-12 membered heterocycloalkylene, wherein each ofis independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0194] In some embodiments, each ofis independently absent, C3-C10 cycloalkylene, or4-12 membered heterocycloalkylene, wherein each ofunsubstituted.

[0195] In some embodiments,is absent, C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0196] In some embodiments,is absent.

[0197] In some embodiments,is C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0198] In some embodiments,is C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene whereinunsubstituted.42MEl\56615208.vl137508-05920

[0199] In some embodiments,C3-C10 cycloalkylene. In some embodiments,is monocyclic C3-C8 cycloalkylene. In some embodiments,fused bicyclic Ce-Cio cycloalkylene. In some embodiments,C7-C10 spirocycloalkylene.

[0200] In some embodiments,cyclopropylene. In some embodiments,is cyclobutylene. In some embodiments,cyclopentylene. In some embodimentsis cyclohexylene. In some embodiments,cycloheptylene. In some embodiments,is cyclooctylene. In some embodiments,cyclononylene. In some embodiments,is cyclodecylene.

[0201] In some embodiments,4-12 membered heterocycloalkylene.

[0202] In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0203] In some embodiments,a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,a 4-12 membered spiroheterocycloalkylene.

[0204] In some embodiments,4-membered heterocycloalkylene. In some embodiments,5-membered heterocycloalkylene. In some embodiments, 6-43MEl\56615208.vl137508-05920 membered heterocycloalkylene. In some embodiments,is 7-membered heterocycloalkylene. In some embodiments,8-membered heterocycloalkylene. In some embodiments,9-membered heterocycloalkylene. In some embodiments,10-membered heterocycloalkylene. In some embodiments,11 -membered heterocycloalkylene. In some embodiments,12-membered heterocycloalkylene.

[0205] In some embodiments,is azetidinylene. In some embodiments,azetidinylene optionally substituted with Ci-Ce alkoxy. In some embodiments,is azetidinylene substituted with Ci-Ce alkoxy. In some embodiments,is azetidinylene optionally substituted with methoxy. In some embodiments,is azetidinylene substituted with methoxy.

[0206] In some embodiments,is piperidinylene. In some embodiments,is piperidinylene optionally substituted with halogen. In some embodiments,is piperidinylene substituted with halogen. In some embodiments,is piperidinylene optionally substituted with F. In some embodiments,is piperidinylene substituted with F.

[0207] In some embodiments,is piperazinylene. In some embodiments,piperazinylene optionally substituted with Ci-Ce alkyl. In some embodiments,piperazinylene substituted with Ci-Ce alkyl. In some embodiments,is piperazinylene optionally substituted with methyl. In some embodiments,is piperazinylene substituted with methyl.44MEl\56615208.vl137508-05920

[0208] In some embodiments,5- to 10-membered heteroarylene.

[0209] In some embodiments5- membered heteroarylene. In some embodiments,is 6- membered heteroarylene. In some embodiments,7- membered heteroarylene. In some embodiments,8- membered heteroarylene. In some embodiments,9- membered heteroarylene. In some embodiments,membered heteroarylene.

[0210] In some embodimentsis Ce-Cio arylene.

[0211] In some embodiments,Ce arylene. In some embodiments,arylene. In some embodiments,Cs arylene. In some embodiments,C9 arylene.In some embodiments,Cio arylene.

[0212] In some embodiments,is absent, C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinoptionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0213] In some embodiments,is absent.

[0214] In some embodiments,is C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0215] In someis C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene whereinis unsubstituted.45MEl\56615208.vl137508-05920(

[0216] In some embodiments,D2) (D is C3-C10 cycloalkylene. In some embodiments,2is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene.( °2) (D2

[0217] In some embodiments, is cyclopropylene. In some embodiments, is cyclobutylene. In some embodiments,cyclopentylene. In some embodimentsis(D; (D cyclohexylene. In some embodiments, is cycloheptylene. In some embodiments,2( is cyclooctylene. In some embodiments,D2) (D ' is cyclononylene. In some embodiments,2- is cyclodecylene.

[0218] In some embodiments,4-12 membered heterocycloalkylene.( D2}

[0219] In some embodiments, is 4-12 membered heterocycloalkylene comprising( °2) one, two, or three heteroatoms. In some embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D2

[0220] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.( ID2}In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D2) embodiments, is a 4-12 membered spiroheterocycloalkylene.

[0221] In some embodiments,4-membered heterocycloalkylene. In some embodiments,5-membered heterocycloalkylene. In some embodiments, (D2') is 6-46MEl\56615208.vl137508-05920 membered heterocycloalkylene. In some embodiments,7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In some embodiments,9-membered heterocycloalkylene. In some embodiments,(D2) 10-membered heterocycloalkylene. In some embodiments, ^is 11-membered heterocycloalkylene. In some embodiments,12-membered heterocycloalkylene.

[0222] In some embodiments,is 6 membered heterocycloalkylene optionally substituted with OH. In some embodiments,is 6 membered heterocycloalkylene substituted with OH. In some embodiments,is 6 membered heterocycloalkylene optionally substituted with one or more halogen. In some embodiments,is 6 membered( D2j heterocycloalkylene substituted with one or more halogen. In some embodiments, is 6 membered heterocycloalkylene optionally substituted with one or more F. In some( D2} embodiments, is 6 membered heterocycloalkylene substituted with one or more F. In f D2some embodiments, is 6 membered heterocycloalkylene optionally substituted with one or more Ci-Ce alkyl. In some embodiments,is 6 membered heterocycloalkylene substituted with one or more Ci-Ce alkyl. In some embodiments,is 6 membered heterocycloalkylene optionally substituted with one or more methyl. In some embodiments,is 6 membered heterocycloalkylene substituted with one or more methyl.( °2)

[0223] In some embodiments, ' is 5- to 10-membered heteroarylene.47MEl\56615208.vl137508-05920

[0224] In some embodimentsis 5- membered heteroarylene. In some embodiments,D2) (D2)'-^ IS 6- membered heteroarylene. In some embodiments, •' is 7- membered(D2) heteroarylene. In some embodiments, is 8- membered heteroarylene. In some( °2) ( °2) embodiments, ' is 9- membered heteroarylene. In some embodiments, ' is 10- membered heteroarylene.

[0225] In someCio arylene.

[0226] In some embodiments,is Ce arylene. In some embodiments,is C7 arylene. In some embodiments, (D2') is Cs arylene. In some embodiments, (D2') is C9 arylene.In some embodiments,C10 arylene.

[0227] In some embodiments,is absent, C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0228] In some embodiments,is absent. f D3j

[0229] In some embodiments, is C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0230] In some embodiments,is C3-C10 cycloalkylene, 4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-Cio arylene whereinis unsubstituted.48MEl\56615208.vl137508-05920( D3) f D3

[0231] In some embodiments, is C3-C10 cycloalkylene. In some embodiments, 'K— ' is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene.( D3) ( D3)

[0232] In some embodiments, is cyclopropylene. In some embodiments, is( D3) ( D3) cyclobutylene. In some embodiments, ' — is cyclopentylene. In some embodiments is( D3) ( D3cyclohexylene. In some embodiments, is cycloheptylene. In some embodiments,1 D3) ( D3is cyclooctylene. In some embodiments, is cyclononylene. In some embodiments, ' is cyclodecylene. f D3}

[0233] In some embodiments, is 4-12 membered heterocycloalkylene.( D3)

[0234] In some embodiments, ' — ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.( D3)

[0235] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.( D3j 1 D3In some embodiments, J is a polycyclic heterocycloalkylene. In some embodiments, ' is a fused polycyclic heterocycloalkylene. In some embodiments,is a spiroheterocy cl oalky 1 ene .

[0236] In some embodiments,4-membered heterocycloalkylene. In some( D31 ( D3) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6-49MEl\56615208.vl137508-05920D3) membered heterocycloalkylene. In some embodiments, - / is 7-membered( D3) heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In( D31 ( D3) some embodiments, is 9-membered heterocycloalkylene. In some embodiments, ' is10-membered heterocycloalkylene. In some embodiments,is 11-membered( D3j heterocycloalkylene. In some embodiments, is 12-membered heterocycloalkylene.

[0237] In some embodiments,is 6 membered heterocycloalkylene.( D3)

[0238] In some embodiments, ' is 5- to 10-membered heteroarylene.

[0239] In some embodiments5- membered heteroarylene. In some embodiments,D3) '—^ is 6- membered heteroarylene. In some embodiments,membered( D3} heteroarylene. In some embodiments, ' — is 8- membered heteroarylene. In some( D3) ( D3) embodiments, is 9- membered heteroarylene. In some embodiments, ' is 10- membered heteroarylene.

[0240] In someCio arylene.( D3) ( D3)

[0241] In some embodiments, ' is Ce arylene. In some embodiments, is C7( D31 ( D3) arylene. In some embodiments, ' is Cs arylene. In some embodiments, ' is C9 arylene.In some embodiments,C10 arylene.

[0242] In some embodiments, Y1is absent.

[0243] In some embodiments, Y1is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, - O-, -NRL 1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0244] In some embodiments, Y1is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene.

[0245] In some embodiments, Y1is Ci-Ce alkylene. In some embodiments, Y1is methylene. In some embodiments, Y1is ethylene. In some embodiments, Y1is propylene. In50MEl\56615208.vl137508-05920 some embodiments, Y1is n-propylene. In some embodiments, Y1is isopropylene. In some embodiments, Y1is butylene. In some embodiments, Y1is n-butylene. In some embodiments, Y1is isobutylene. In some embodiments, Y1is sec-butylene. In some embodiments, Y1is tertbutylene. In some embodiments, Y1is pentylene. In some embodiments, Y1is hexylene.

[0246] In some embodiments, Y1is C2-C6 alkenylene. In some embodiments, Y1is C2 alkenylene. In some embodiments, Y1is C3 alkenylene. In some embodiments, Y1is C4 alkenylene. In some embodiments, Y1is C5 alkenylene. In some embodiments, Y1is Ce alkenylene.

[0247] In some embodiments, Y1is C2-C6 alkynylene. In some embodiments, Y1is C2 alkynylene. In some embodiments, Y1is C3 alkynylene. In some embodiments, Y1is C4 alkynylene. In some embodiments, Y1is C5 alkynylene. In some embodiments, Y1is Ce alkynylene. In some embodiments, Y1is -O-, -NR1'-1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0248] In some embodiments, Y1is -O-. In some embodiments, Y1is-NRL-1-. In some embodiments, Y1is -(CH2)h-SO2-. In some embodiments, Y1is -(CH2)g-O-(CH2)P-. In some embodiments, Y2is absent.

[0249] In some embodiments, Y2is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, - O-, -NR'-1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0250] In some embodiments, Y2is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene.

[0251] In some embodiments, Y2is Ci-Ce alkylene. In some embodiments, Y2is methylene. In some embodiments, Y2is ethylene. In some embodiments, Y2is propylene. In some embodiments, Y2is n-propylene. In some embodiments, Y2is isopropylene. In some embodiments, Y2is butylene. In some embodiments, Y2is n-butylene. In some embodiments, Y2is isobutylene. In some embodiments, Y2is sec-butylene. In some embodiments, Y2is tertbutylene. In some embodiments, Y2is pentylene. In some embodiments, Y2is hexylene.

[0252] In some embodiments, Y2is C2-C6 alkenylene. In some embodiments, Y2is C2 alkenylene. In some embodiments, Y2is C3 alkenylene. In some embodiments, Y2is C4 alkenylene. In some embodiments, Y2is C5 alkenylene. In some embodiments, Y2is Ce alkenylene.

[0253] In some embodiments, Y2is C2-C6 alkynylene. In some embodiments, Y2is C2 alkynylene. In some embodiments, Y2is C3 alkynylene. In some embodiments, Y2is C4 alkynylene. In some embodiments, Y2is C5 alkynylene. In some embodiments, Y2is Ce alkynylene.

[0254] In some embodiments, Y2is -O-, -NR'-1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.51MEl\56615208.vl137508-05920

[0255] In some embodiments, Y2is -O-. In some embodiments, Y2is-NRL-1In some embodiments, Y2is -(CH2)h-SO2-. In some embodiments, Y2is -(CH2)g-O-(CH2)P-. In some embodiments, Y3is absent.

[0256] In some embodiments, Y3is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, - O-, -NR'-1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0257] In some embodiments, Y3is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene.

[0258] In some embodiments, Y3is Ci-Ce alkylene. In some embodiments, Y3is methylene. In some embodiments, Y3is ethylene. In some embodiments, Y3is propylene. In some embodiments, Y3is n-propylene. In some embodiments, Y3is isopropylene. In some embodiments, Y3is butylene. In some embodiments, Y3is n-butylene. In some embodiments, Y3is isobutylene. In some embodiments, Y3is sec-butylene. In some embodiments, Y3is tertbutylene. In some embodiments, Y3is pentylene. In some embodiments, Y3is hexylene.

[0259] In some embodiments, Y3is C2-C6 alkenylene. In some embodiments, Y3is C2 alkenylene. In some embodiments, Y3is C3 alkenylene. In some embodiments, Y3is C4 alkenylene. In some embodiments, Y3is C5 alkenylene. In some embodiments, Y3is Ce alkenylene.

[0260] In some embodiments, Y3is C2-C6 alkynylene. In some embodiments, Y3is C2 alkynylene. In some embodiments, Y3is C3 alkynylene. In some embodiments, Y3is C4 alkynylene. In some embodiments, Y3is C5 alkynylene. In some embodiments, Y3is Ce alkynylene.

[0261] In some embodiments, Y3is -O-, -NR'-1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0262] In some embodiments, Y3is -O-. In some embodiments, Y3is-NRL-1-. In some embodiments, Y3is -(CH2)h-SO2-. In some embodiments, Y3is -(CH2)g-O-(CH2)P-. In some embodiments, Y4is absent.

[0263] In some embodiments, Y4is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene, - O-, -NR'-' -, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0264] In some embodiments, Y4is Ci-Ce alkylene, C2-C6 alkenylene, C2-C6 alkynylene.

[0265] In some embodiments, Y4is Ci-Ce alkylene. In some embodiments, Y4is methylene. In some embodiments, Y4is ethylene. In some embodiments, Y4is propylene. In some embodiments, Y4is n-propylene. In some embodiments, Y4is isopropylene. In some embodiments, Y4is butylene. In some embodiments, Y4is n-butylene. In some embodiments, Y4is isobutylene. In some embodiments, Y4is sec-butylene. In some embodiments, Y4is tertbutylene. In some embodiments, Y4is pentylene. In some embodiments, Y4is hexylene.52MEl\56615208.vl137508-05920

[0266] In some embodiments, Y4is C2-C6 alkenylene. In some embodiments, Y4is C2 alkenylene. In some embodiments, Y4is C3 alkenylene. In some embodiments, Y4is C4 alkenylene. In some embodiments, Y4is C5 alkenylene. In some embodiments, Y4is Ce alkenylene.

[0267] In some embodiments, Y4is C2-C6 alkynylene. In some embodiments, Y4is C2 alkynylene. In some embodiments, Y4is C3 alkynylene. In some embodiments, Y4is C4 alkynylene. In some embodiments, Y4is C5 alkynylene. In some embodiments, Y4is Ce alkynylene.

[0268] In some embodiments, Y4is -O-, -NRL 1-, -(CH2)h-SO2-, or -(CH2)g-O-(CH2)P-.

[0269] In some embodiments, Y4is -O-. In some embodiments, Y4is-NRL-1-. In some embodiments, Y4is -(QHfc -SCh-. In some embodiments, Y4is -(CH2)g-O-(CH2)P-.

[0270] In some embodiments,is 4-12 membered heterocycloalkylene.

[0271] In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0272] In some embodiments,a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,a 4-12 membered spiroheterocycloalkylene.

[0273] In some embodiments,is 4-membered heterocycloalkylene. In some embodiments,is 5-membered heterocycloalkylene. In some embodiments,is 6- membered heterocycloalkylene. In some embodiments,is 7-membered53MEl\56615208.vl137508-05920 heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In some embodiments,is 9-membered heterocycloalkylene. In some embodiments,is 10-membered heterocycloalkylene. In some embodiments,is 11 -membered heterocycloalkylene. In some embodiments,is 12-membered heterocycloalkylene.

[0274] In some embodiments,is azetidinylene.

[0275] In some embodiments,is azetidinylene optionally substituted with Ci-Ce alkoxy.

[0276] In some embodiments,is azetidinylene optionally substituted with methoxy.

[0277] In some embodiments,is piperidinylene.

[0278] In some embodiments,is piperidinylene optionally substituted with halogen.

[0279] In some embodiments,is piperidinylene optionally substituted with F.

[0280] In some embodiments,is piperazinylene.D1a)

[0281] In some embodiments, — ' is piperazinylene optionally substituted with Ci-Ce alkyl.

[0282] In some embodiments,is piperazinylene optionally substituted with methyl.

[0283] In some embodiments,is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinoptionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.54MEl\56615208.vl137508-05920

[0284] In some embodiments,is absent. In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinoptionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0285] In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinunsubstituted.

[0286] In some embodiments,C3-C10 cycloalkylene. In some embodiments,is monocyclic C3-C8 cycloalkylene. In some embodiments,fused bicyclic Ce-Cio cycloalkylene. In some embodiments,C7-C10 spirocycloalkylene.

[0287] In some embodiments,cyclopropylene. In some embodiments,is cyclobutylene. In some embodiments,cyclopentylene. In some embodimentsis cyclohexylene. In some embodiments,cycloheptylene. In some embodiments,cyclooctylene. In some embodiments,cyclononylene. In some embodiments,cyclodecylene.

[0288] In some embodiments,4-12 membered heterocycloalkylene. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0289] In some embodiments,a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,a polycyclic 4-12 membered heterocycloalkylene. In some55MEl\56615208.vl137508-05920 embodiments,a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,a 4-12 membered spiroheterocycloalkylene.

[0290] In some embodiments,4-membered heterocycloalkylene. In some embodiments,5-membered heterocycloalkylene. In some embodiments,6- membered heterocycloalkylene. In some embodiments,is 7-membered heterocycloalkylene. In some embodiments,8-membered heterocycloalkylene. In some embodiments,9-membered heterocycloalkylene. In some embodiments,10- membered heterocycloalkylene. In some embodiments,11 -membered heterocycloalkylene. In some embodiments,12-membered heterocycloalkylene.

[0291] In some embodiments,is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis unsubstituted.

[0292] In some embodiments,is piperidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, whereinis unsubstituted.56MEl\56615208.vl137508-05920

[0293] In some embodiments,is piperazinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene, whereinis unsubstituted.(D2b)

[0294] In some embodiments, is absent, C3-C10 cycloalkylene, or 4-12 membered(D2b) heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2b) (D2b)

[0295] In some embodiments, is absent. In some embodiments, is C3-C10(D2b) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2b)

[0296] In some embodiments, N- is C3-C10 cycloalkylene, or 4-12 membered fo2b) heterocycloalkylene, wherein ' is unsubstituted.(D2b) (D2b

[0297] In some embodiments, is C3-C10 cycloalkylene. In some embodiments,(D2b) is monocyclic C3-C8 cycloalkylene. In some embodiments, is fused bicyclic Ce-Cio(D2b) cycloalkylene. In some embodiments, ' is C7-C10 spirocycloalkylene.(D2b) (D2b)

[0298] In some embodiments, is cyclopropylene. In some embodiments, is(D2b) \D2b) cyclobutylene. In some embodiments, ' is cyclopentylene. In some embodiments is(D2b) (D2bcyclohexylene. In some embodiments, is cycloheptylene. In some embodiments,57MEl\56615208.vl137508-05920 is cyclooctylene. In some embodiments,is cyclononylene. In some embodiments,is cyclodecylene.(p2b)

[0299] In some embodiments, ' is 4-12 membered heterocycloalkylene. In some(p2b) embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three(p2b) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising(p2b) one, two, or three heteroatoms selected from N and O. In some embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D2b)

[0300] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.(D2b)In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some(D2b) embodiments, is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D2b) embodiments, is a 4-12 membered spiroheterocycloalkylene.(D2b)

[0301] In some embodiments, is 4-membered heterocycloalkylene. In some(D2b) (D2b) embodiments, ' is 5-membered heterocycloalkylene. In some embodiments, ' is 6-(D2b) membered heterocycloalkylene. In some embodiments, is 7-membered(D2b) heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In(D2b) (D2b) some embodiments, is 9-membered heterocycloalkylene. In some embodiments, is(D2b) 10-membered heterocycloalkylene. In some embodiments, ^-^ is 11-membered fD2b) heterocycloalkylene. In some embodiments, ' is 12-membered heterocycloalkylene.(D2b) (D2b)

[0302] In some embodiments, ' is azetidinylene, wherein ' is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some58MEl\56615208.vl137508-05920(D2b) (D2b) embodiments, is azetidinylene, wherein is substituted with one or more CN,(D2b) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is azetidinylene,(D2b) wherein is unsubstituted.(D2b) (D2b)

[0303] In some embodiments, is piperidinylene, wherein N— is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2b) (D2b) embodiments, is piperidinylene, wherein ' is substituted with one or more CN,D2bhalogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,D2bwherein is unsubstituted. (D2b)

[0304] In some embodiments,is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2b) (D2b) embodiments, is piperazinylene. In some embodiments, is piperazinylene, whereinD2b) is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2b) (D2b) embodiments, is piperazinylene, wherein ' is unsubstituted.(D1 c)

[0305] In some embodiments, ' is absent, C3-C10 cycloalkylene, or 4-12 membered(D1 c) heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 c) (D1C)

[0306] In some embodiments, ' is absent. In some embodiments, is C3-C10(D1 c) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.59MEl\56615208.vl137508-05920(D1 c)

[0307] In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered(D1C) heterocycloalkylene, wherein ' is unsubstituted.(D1 c) (D1C

[0308] In some embodiments, is C3-C10 cycloalkylene. In some embodiments,(D1 c) is monocyclic C3-C8 cycloalkylene. In some embodiments, is fused bicyclic Ce-Cio(D1 c) cycloalkylene. In some embodiments, is C7-C10 spirocycloalkylene.(D1 c) (D1C)

[0309] In some embodiments, is cyclopropylene. In some embodiments, is(D1 c) (D1Ccyclobutylene. In some embodiments, is cyclopentylene. In some embodiments(D1 c) is cyclohexylene. In some embodiments, is cycloheptylene. In some embodiments,D1 c) (D1 c)' is cyclooctylene. In some embodiments, ' is cyclononylene. In some(D1 c) embodiments, is cyclodecylene.(D1C)

[0310] In some embodiments, ' - / is 4-12 membered heterocycloalkylene. In some(D1 c) embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three(D1 c) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising(D1 c) one, two, or three heteroatoms selected from N and O. In some embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D1 c)

[0311] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.(D1 c)In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some(D1 c) embodiments, is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D1 c) embodiments, is a 4-12 membered spiroheterocycloalkylene.60MEl\56615208.vl137508-05920(D1 c)

[0312] In some embodiments, ' is 4-membered heterocycloalkylene. In some(D1 c) (D1C) embodiments, ' is 5-membered heterocycloalkylene. In some embodiments, is 6-(D1 c) membered heterocycloalkylene. In some embodiments, is 7-membered(D1 c) heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In(D1 c) (D1Csome embodiments, is 9-membered heterocycloalkylene. In some embodiments,(D1 c) is 10-membered heterocycloalkylene. In some embodiments, is 11-membered(D1 c) heterocycloalkylene. In some embodiments, ' is 12-membered heterocycloalkylene.(D1 c) (D1C)

[0313] In some embodiments, ' is azetidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 c) (D1C) embodiments, ' is azetidinylene, wherein is substituted with one or more CN,(D1 c) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is azetidinylene,(D1C) wherein is unsubstituted.(D1 c) (D1C)

[0314] In some embodiments, is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 c) (D1C) embodiments, is piperidinylene, wherein is substituted with one or more CN,(D1 c) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,(D1 c) wherein is unsubstituted.(D1 c) (D1C)

[0315] In some embodiments, is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 c) (D1C) embodiments, is piperazinylene. In some embodiments, is piperazinylene,61MEl\56615208.vl137508-05920(D1 c) wherein ' is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.@is piperazinylene, whereinis unsubstituted.(D2^

[0316] In some embodiments, is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0317] In some embodiments,is absent. In some embodiments,is C3-C10(D2C) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0318] In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.(D2C) (D2CJ

[0319] In some embodiments, is C3-C10 cycloalkylene. In some embodiments, is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio( D2<4 cycloalkylene. In some embodiments, is C7-C10 spirocycloalkylene.

[0320] In some embodiments,is cyclopropylene. In some embodiments,is(2cJ cyclobutylene. In some embodiments,is cyclopentylene. In some embodiments is cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments,is cyclooctylene. In some embodiments,is cyclononylene. In some embodiments,is cyclodecylene.62MEl\56615208.vl137508-05920(D2<4

[0321] In some embodiments, ' is 4-12 membered heterocycloalkylene. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising(D2^ one, two, or three heteroatoms selected from N and O. In some embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0322] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D2C) embodiments, is a 4-12 membered spiroheterocycloalkylene.

[0323] In some embodiments,is 4-membered heterocycloalkylene. In some(D2C) (D2C) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6-(D2C) membered heterocycloalkylene. In some embodiments, is 7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In(D2<4 (D2<5 some embodiments, ' is 9-membered heterocycloalkylene. In some embodiments, ' is 10-membered heterocycloalkylene. In some embodiments,is 11 -membered(D2C) heterocycloalkylene. In some embodiments, is 12-membered heterocycloalkylene.

[0324] In some embodiments,is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis substituted with one or more CN,63MEl\56615208.vl137508-05920 halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene,(D2CJ wherein is unsubstituted.

[0325] In some embodiments,is piperidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, wherein is unsubstituted. (D^

[0326] In some embodiments,is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene, wherein is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2^ (D2^In some embodiments, is piperazinylene, wherein is unsubstituted.

[0327] In some embodiments,is absent, C3-C10 cycloalkylene, or 4-12 membered(Dz heterocycloalkylene, wherein ' is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0328] In some embodiments,is absent. In some embodiments,is C3-C10(Dz cycloalkylene, or 4-12 membered heterocycloalkylene, wherein ' is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2CJ

[0329] In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.64MEl\56615208.vl137508-05920(D2<4 (D2<5

[0330] In some embodiments, is C3-C10 cycloalkylene. In some embodiments, is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio(D2C) cycloalkylene. In some embodiments, is C7-C10 spirocycloalkylene.

[0331] In some embodiments,is cyclopropylene. In some embodiments,is(D2CJ cyclobutylene. In some embodiments,is cyclopentylene. In some embodiments ' is cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments,is cyclooctylene. In some embodiments,is cyclononylene. In some(D / embodiments, is cyclodecylene.

[0332] In some embodiments,is 4-12 membered heterocycloalkylene. In some( D2<4 embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0333] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D2C) embodiments, is a 4-12 membered spiroheterocycloalkylene.

[0334] In some embodiments,is 4-membered heterocycloalkylene. In some(D2C) (D2C) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6-65MEl\56615208.vl137508-05920( D2<d membered heterocycloalkylene. In some embodiments, is 7-membered heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In(D2C) (D2CJ some embodiments, is 9-membered heterocycloalkylene. In some embodiments, is 10-membered heterocycloalkylene. In some embodiments,is 11 -membered(Dz heterocycloalkylene. In some embodiments, is 12-membered heterocycloalkylene.

[0335] In some embodiments,is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene,(D2C) wherein is unsubstituted.

[0336] In some embodiments,is piperidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some( D2<d (D2<7 embodiments, is piperidinylene, wherein is substituted with one or more CN,( D2<d halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,D2CJ wherein is unsubstituted.(D2C)

[0337] In some embodiments,is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2CJIn some embodiments,is piperazinylene, wherein ' — is unsubstituted.66MEl\56615208.vl137508-05920

[0338] In some embodiments, is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0339] In some embodiments,is absent. In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0340] In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered ) heterocycloalkylene, wherein is unsubstituted.

[0341] In some embodiments,is C3-C10 cycloalkylene. In some embodiments,is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene.

[0342] In some embodiments,is cyclopropylene. In some embodiments,is cyclobutylene. In some embodiments,is cyclopentylene. In some embodimentsis cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments,is cyclooctylene. In some embodiments,is cyclononylene. In some ) embodiments, is cyclodecylene.

[0343] In some embodiments,is 4-12 membered heterocycloalkylene. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three( ) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising67MEl\56615208.vl137508-05920 one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0344] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene.( )In some embodiments, N- ' is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a 4-12 membered spiroheterocycloalkylene.( )

[0345] In some embodiments, is 4-membered heterocycloalkylene. In some embodiments,is 5-membered heterocycloalkylene. In some embodiments,is 6- membered heterocycloalkylene. In some embodiments,is 7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In some embodiments,is 9-membered heterocycloalkylene. In some embodiments,) is 10-membered heterocycloalkylene. In some embodiments, ' is 11-membered heterocycloalkylene. In some embodiments, ( 'P —^ ') is 12-membered heterocycloalkylene.

[0346] In some embodiments,is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis unsubstituted.

[0347] In some embodiments, H is piperidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some68MEl\56615208.vl137508-05920 embodiments,is piperidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, whereinis unsubstituted.

[0348] In some embodiments,is piperazinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.In some embodiments,is piperazinylene, whereinis unsubstituted.(D1 e)

[0349] In some embodiments, ' is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 e) (D1 e)

[0350] In some embodiments, is absent. In some embodiments, is C3-C10(D1 e) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 e)

[0351] In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered(D1 e) heterocycloalkylene, wherein is unsubstituted.(D1 e) (D1 e

[0352] In some embodiments, ' is C3-C10 cycloalkylene. In some embodiments,z(D1 e) is monocyclic C3-C8 cycloalkylene. In some embodiments, is fused bicyclic Ce-Cio(D1 e) cycloalkylene. In some embodiments, ' is C7-C10 spirocycloalkylene.69MEl\56615208.vl137508-05920(D1 e) (D1 e)

[0353] In some embodiments, is cyclopropylene. In some embodiments, ' — ' is(D1 e) (D1 ecyclobutylene. In some embodiments, ' — ' is cyclopentylene. In some embodiments(D1 e) is cyclohexylene. In some embodiments, is cycloheptylene. In some embodiments,D1 e) (D1 e) is cyclooctylene. In some embodiments, is cyclononylene. In some(D1 e) embodiments, is cyclodecylene.(D1 e)

[0354] In some embodiments, ' is 4-12 membered heterocycloalkylene. In some(D1 e) embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three(D1 e) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising(D1 e) one, two, or three heteroatoms selected from N and O. In some embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D1 e)

[0355] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.(D1 e)In some embodiments, ' is a polycyclic 4-12 membered heterocycloalkylene. In some(D1 e) embodiments, ' — ' is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D1 e) embodiments, is a 4-12 membered spiroheterocycloalkylene.(D1 e)

[0356] In some embodiments, ' is 4-membered heterocycloalkylene. In some(D1 e) (D1 e) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6-(D1 e) membered heterocycloalkylene. In some embodiments, is 7-membered(D1 e) heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In(D1 e) (D1 esome embodiments, is 9-membered heterocycloalkylene. In some embodiments,70MEl\56615208.vl137508-05920(D1 e) is 10-membered heterocycloalkylene. In some embodiments, is 11-membered(Dl e) heterocycloalkylene. In some embodiments, ' — is 12-membered heterocycloalkylene.(D1 e) (D1 e)

[0357] In some embodiments, is azetidinylene, wherein N— is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 e) (D1 e) embodiments, ' is azetidinylene, wherein ' is substituted with one or more CN,(D1 e) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, ' is azetidinylene,(D1 e) wherein is unsubstituted.(D1 e) (D1 e)

[0358] In some embodiments, ' is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 e) (D1 e) embodiments, is piperidinylene, wherein is substituted with one or more CN,(D1 e) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,(D1 e) wherein ' is unsubstituted.(D1 e) (D1 e)

[0359] In some embodiments, is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 e) (D1 e) embodiments, is piperazinylene. In some embodiments, ' is piperazinylene,(D1 e) wherein is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 e) (D1 e)In some embodiments, is piperazinylene, wherein ' is unsubstituted.(D1 f)

[0360] In some embodiments, is absent, C3-C10 cycloalkylene, or 4-12 membered(D1 f) heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.71MEl\56615208.vl137508-05920(D1 f) (D1 f)

[0361] In some embodiments, is absent. In some embodiments, ' is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1f)

[0362] In some embodiments, ' is C3-C10 cycloalkylene, or 4-12 membered(D1 f) heterocycloalkylene, wherein s is unsubstituted.

[0363] In some embodiments,is C3-C10 cycloalkylene. In some embodiments, R is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene. (Jf)

[0364] In some embodiments,is cyclopropylene. In some embodiments, ' is cyclobutylene. In some embodiments,is cyclopentylene. In some embodiments(D1 f) is cyclohexylene. In some embodiments, is cycloheptylene. In some embodiments, is cyclooctylene. In some embodiments,is cyclononylene. In some embodiments,is cyclodecylene.(pif)

[0365] In some embodiments, is 4-12 membered heterocycloalkylene. In some(i?f) embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising(pif) one, two, or three heteroatoms selected from N and O. In some embodiments, ' is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0366] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene.(D1 f)In some embodiments, ' is a polycyclic 4-12 membered heterocycloalkylene. In some72MEl\56615208.vl137508-05920(D1 f) embodiments, is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D1 f) embodiments, ' is a 4-12 membered spiroheterocycloalkylene.(D1 f)

[0367] In some embodiments, is 4-membered heterocycloalkylene. In some(D1 f) (D1f) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6-(D1 f) membered heterocycloalkylene. In some embodiments, N-^7is 7-membered(D1 f) heterocycloalkylene. In some embodiments, N_ ' is 8-membered heterocycloalkylene. In(D1 f) (D1 fsome embodiments, is 9-membered heterocycloalkylene. In some embodiments,(D1 f) is 10-membered heterocycloalkylene. In some embodiments, N-'7is 11-membered heterocycloalkylene. In some embodiments,is 12-membered heterocycloalkylene.(D1f) (D1 f)

[0368] In some embodiments, is azetidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 f) (D1 f) embodiments, is azetidinylene, wherein is substituted with one or more CN,(D1f) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is azetidinylene,(D1 f) wherein is unsubstituted.(D1 f) (D1f)

[0369] In some embodiments, is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 f) (D1 f) embodiments, ' is piperidinylene, wherein N- s is substituted with one or more CN,(D1 f) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, ' is piperidinylene,(D1 f) wherein isunsubstituted.73MEl\56615208.vl137508-05920(D1 f) (D1 f)

[0370] In some embodiments, ' — ' is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 f) (D1 f) embodiments, is piperazinylene. In some embodiments, is piperazinylene,(D1f) wherein N_ ' is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 f)In some embodiments, is piperazinylene, whereinis unsubstituted.

[0371] In some embodiments,is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0372] In some embodiments,is absent. In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

[0373] In some embodiments,is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.

[0374] In some embodiments,is C3-C10 cycloalkylene. In some embodiments,is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene.

[0375] In some embodiments,is cyclopropylene. In some embodiments,is cyclobutylene. In some embodiments,is cyclopentylene. In some embodimentsis cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments,74MEl\56615208.vl137508-05920is cyclooctylene. In some embodiments,is cyclononylene. In some embodiments,is cyclodecylene.

[0376] In some embodiments,is 4-12 membered heterocycloalkylene. In someD19 embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0377] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a 4-12 membered spiroheterocycloalkylene.

[0378] In some embodiments,is 4-membered heterocycloalkylene. In some(D19) (D19) embodiments, ' — ' is 5-membered heterocycloalkylene. In some embodiments, ' — ' is 6- membered heterocycloalkylene. In some embodiments,is 7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In some embodiments,is 9-membered heterocycloalkylene. In some embodiments,is 10-membered heterocycloalkylene. In some embodiments,is 11 -membered heterocycloalkylene. In some embodiments,is 12-membered heterocycloalkylene.75MEl\56615208.vl137508-05920

[0379] In some embodiments, is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene, whereinis substituted with one or more CN,D19 halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is azetidinylene, whereinis unsubstituted.

[0380] In some embodiments,is piperidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene, wherein is unsubstituted.

[0381] In some embodiments,is piperazinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene, whereinis substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.In some embodiments,is piperazinylene, whereinis unsubstituted.

[0382] In some embodiments,is absent, C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D39) (D39j

[0383] In some embodiments, is absent. In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.76MEl\56615208.vl137508-05920[D39)

[0384] In some embodiments, ' is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.(D39) (D3g

[0385] In some embodiments, is C3-C10 cycloalkylene. In some embodiments,(D3g) is monocyclic C3-C8 cycloalkylene. In some embodiments, ' — ' is fused bicyclic Ce-Cio(D3g) cycloalkylene. In some embodiments, ' — ' is C7-C10 spirocycloalkylene.

[0386] In some embodiments,is cyclopropylene. In some embodiments,is(D39J (b3S cyclobutylene. In some embodiments, is cyclopentylene. In some embodiments is cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments, (D39)is cyclooctylene. In some embodiments, is cyclononylene. In some embodiments,is cyclodecylene.

[0387] In some embodiments,is 4-12 membered heterocycloalkylene. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D3g)

[0388] In some embodiments, ' — ' is a monocyclic 4-12 membered heterocycloalkylene.In some embodiments,is a polycyclic 4-12 membered heterocycloalkylene. In some(D3g) embodiments, ' — ' is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D3S) embodiments, is a 4-12 membered spiroheterocycloalkylene.77MEl\56615208.vl137508-05920

[0389] In some embodiments, is 4-membered heterocycloalkylene. In some(D39) (D39j embodiments, ' is 5-membered heterocycloalkylene. In some embodiments, ' is 6-(D3g) membered heterocycloalkylene. In some embodiments, ' — ' is 7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In some embodiments,is 9-membered heterocycloalkylene. In some embodiments,is 10-membered heterocycloalkylene. In some embodiments,is 11-membered heterocycloalkylene. In some embodiments,is 12-membered heterocycloalkylene.(W

[0390] In some embodiments, is azetidinylene, whereinis optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(b3s) (b39) embodiments, is azetidinylene, wherein is substituted with one or more CN,D3S halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is azetidinylene,D39 wherein is unsubstituted.<D3g) (b39j

[0391] In some embodiments, is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some<D39) (D39) embodiments, ' is piperidinylene, wherein ' is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperidinylene,(b3s) wherein is unsubstituted.(D3S) (b3a)

[0392] In some embodiments, is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is piperazinylene. In some embodiments,is piperazinylene,78MEl\56615208.vl137508-05920(D3S) wherein ' — ' is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.D3S)In some embodiments, ' — ' is piperazinylene, whereinis unsubstituted. m1h)

[0393] In some embodiments, ' is absent, C3-C10 cycloalkylene, or 4-12 membered(b1h) heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 h) (D1 h)

[0394] In some embodiments, is absent. In some embodiments, is C3-C10 m1h) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein s is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 h)

[0395] In some embodiments, ' is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.(D1h) (D1h

[0396] In some embodiments, ' is C3-C10 cycloalkylene. In some embodiments,(D1 h) is monocyclic C3-C8 cycloalkylene. In some embodiments, is fused bicyclic Ce-Cio(b1h) cycloalkylene. In some embodiments, ' is C7-C10 spirocycloalkylene.(D1 h) (D1 h)

[0397] In some embodiments, is cyclopropylene. In some embodiments, ' is(D1 h) (D1 hcyclobutylene. In some embodiments, ' is cyclopentylene. In some embodiments m1h) is cyclohexylene. In some embodiments, ' is cycloheptylene. In some embodiments,D1 h) (D1 h)' is cyclooctylene. In some embodiments, ' is cyclononylene. In some(b1h) embodiments, is cyclodecylene.79MEl\56615208.vl137508-05920

[0398] In some embodiments,is 4-12 membered heterocycloalkylene. In some(°1 h) embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three(D1 h) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising(D1 h) one, two, or three heteroatoms selected from N and O. In some embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.HD1 h)

[0399] In some embodiments, ' is a monocyclic 4-12 membered heterocycloalkylene.(°1 h)In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some(°1 h) embodiments, is a fused polycyclic 4-12 membered heterocycloalkylene. In some(°1 h) embodiments, is a 4-12 membered spiroheterocycloalkylene.(°1 h)

[0400] In some embodiments, is 4-membered heterocycloalkylene. In some(D1 h) (D1 h) embodiments, ' is 5-membered heterocycloalkylene. In some embodiments, ' is 6- m1 h) membered heterocycloalkylene. In some embodiments, ' is 7-membered m1 h) heterocycloalkylene. In some embodiments, ' is 8-membered heterocycloalkylene. In(D1 h) (D1 hsome embodiments, is 9-membered heterocycloalkylene. In some embodiments,(°1 h) is 10-membered heterocycloalkylene. In some embodiments, ' is 11-membered heterocycloalkylene. In some embodiments,is 12-membered heterocycloalkylene.(D1 h) (D1 h)

[0401] In some embodiments, is azetidinylene, wherein ' is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 h) (D1 h) embodiments, ' is azetidinylene, wherein ' is substituted with one or more CN,80MEl\56615208.vl137508-05920 halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene,(°1 h) wherein is unsubstituted.(D1 h) (D1 h)

[0402] In some embodiments, —2is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 h) (D1 h) embodiments, ' is piperidinylene, wherein is substituted with one or more CN,(°1 h) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,(Dl h) wherein is unsubstituted.(D1 h) (D1 h)

[0403] In some embodiments, is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D1 h) (D1 h) embodiments, is piperazinylene. In some embodiments, is piperazinylene,(D1 h) wherein is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D1 h) (D1 h)In some embodiments, is piperazinylene, wherein ' is unsubstituted.( D2h)

[0404] In some embodiments, is absent, C3-C10 cycloalkylene, or 4-12 membered(D25 heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2h) (D2h)

[0405] In some embodiments, is absent. In some embodiments, is C3-C10(p2h) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein ' is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(p2h)

[0406] In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered heterocycloalkylene, whereinis unsubstituted.81MEl\56615208.vl137508-05920 m2h) (p2h;

[0407] In some embodiments, is C3-C10 cycloalkylene. In some embodiments, is monocyclic C3-C8 cycloalkylene. In some embodiments,is fused bicyclic Ce-Cio cycloalkylene. In some embodiments,is C7-C10 spirocycloalkylene.(D2h) (D2h)

[0408] In some embodiments, is cyclopropylene. In some embodiments, is(D2h) (D21; cyclobutylene. In some embodiments, ' is cyclopentylene. In some embodiments '(p2h) is cyclohexylene. In some embodiments, ' is cycloheptylene. In some embodiments,D2h) (D2h)"—J is cyclooctylene. In some embodiments, is cyclononylene. In some embodiments,is cyclodecylene.(p2h)

[0409] In some embodiments, ' is 4-12 membered heterocycloalkylene. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three(p2h) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.

[0410] In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene. m2h)In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a fused polycyclic 4-12 membered heterocycloalkylene. In some embodiments,is a 4-12 membered spiroheterocycloalkylene.(D2h)

[0411] In some embodiments, ' is 4-membered heterocycloalkylene. In some(D2h) embodiments, is 5-membered heterocycloalkylene. In some embodiments,is 6-82MEl\56615208.vl137508-05920(p2h) membered heterocycloalkylene. In some embodiments, is 7-membered(p2h) heterocycloalkylene. In some embodiments, is 8-membered heterocycloalkylene. In(D2h) (D2hJ some embodiments, is 9-membered heterocycloalkylene. In some embodiments,(D2h) is 10-membered heterocycloalkylene. In some embodiments, is 11-membered( D2h) heterocycloalkylene. In some embodiments, ' is 12-membered heterocycloalkylene.( D2h) (D2h)

[0412] In some embodiments, ' is azetidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2h) (D2I7 embodiments, —2is azetidinylene, wherein —2is substituted with one or more CN,(p2h) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, ' is azetidinylene,(D25 wherein is unsubstituted. \.D2I7

[0413] In some embodiments,is piperidinylene, wherein N-^2is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2h) (D2h) embodiments, is piperidinylene, wherein is substituted with one or more CN,(D25 halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, is piperidinylene,(D2h) wherein is unsubstituted.(D2h) (D2h)

[0414] In some embodiments, is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D2h) (D2h) embodiments, '^-^2is piperazinylene. In some embodiments,x^-^2is piperazinylene,(p2h) wherein N-^2is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D2h) (D2h)In some embodiments, is piperazinylene, wherein —2is unsubstituted.83MEl\56615208.vl137508-05920

[0415] In some embodiments,is absent, C3-C10 cycloalkylene, or 4-12 memberedD3H1 heterocycloalkylene, wherein is optionally substituted with one or more CN, halogen,OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D3h) (D3h)

[0416] In some embodiments, is absent. In some embodiments, is C3-C10(D3h) cycloalkylene, or 4-12 membered heterocycloalkylene, wherein ' is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D3h)

[0417] In some embodiments, is C3-C10 cycloalkylene, or 4-12 membered(D3h) heterocycloalkylene, wherein is unsubstituted. (D3hJ

[0418] In some embodiments,is C3-C10 cycloalkylene. In some embodiments, '(D3h) is monocyclic C3-C8 cycloalkylene. In some embodiments, is fused bicyclic Ce-Cio(D3h) cycloalkylene. In some embodiments, is C7-C10 spirocycloalkylene.(D3h) (D3h)

[0419] In some embodiments, ' is cyclopropylene. In some embodiments, is 3h) m3hcyclobutylene. In some embodiments, ' — is cyclopentylene. In some embodiments is cyclohexylene. In some embodiments,is cycloheptylene. In some embodiments,D3h) (D3h) is cyclooctylene. In some embodiments, is cyclononylene. In some(D3h) embodiments, is cyclodecylene.

[0420] In some embodiments,is 4-12 membered heterocycloalkylene. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three(D3h) heteroatoms. In some embodiments, is 4-12 membered heterocycloalkylene comprising84MEl\56615208.vl137508-05920 one, two, or three heteroatoms selected from N and O. In some embodiments,is 4-12 membered heterocycloalkylene comprising one, two, or three heteroatoms that are each N.(D3h)

[0421] In some embodiments, is a monocyclic 4-12 membered heterocycloalkylene.(D3h)In some embodiments, is a polycyclic 4-12 membered heterocycloalkylene. In some( D3h) embodiments, is a fused polycyclic 4-12 membered heterocycloalkylene. In some(D3h) embodiments, is a 4-12 membered spiroheterocycloalkylene.(D3h)

[0422] In some embodiments, is 4-membered heterocycloalkylene. In some(D3h) (D3h) embodiments, is 5-membered heterocycloalkylene. In some embodiments, is 6- membered heterocycloalkylene. In some embodiments,is 7-membered heterocycloalkylene. In some embodiments,is 8-membered heterocycloalkylene. In(D3h) (D3hJ some embodiments, is 9-membered heterocycloalkylene. In some embodiments,(D3h) is 10-membered heterocycloalkylene. In some embodiments, is 11-membered(D3h) heterocycloalkylene. In some embodiments, ' is 12-membered heterocycloalkylene. 3h) (D3h)

[0423] In some embodiments, ' is azetidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D3h) (D3h) embodiments, is azetidinylene, wherein is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments,is azetidinylene,(D3h) wherein is unsubstituted.(D3h) (D3h)

[0424] In some embodiments, is piperidinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some85MEl\56615208.vl137508-05920( D3h) ( D3h) embodiments, ' is piperidinylene, wherein ' is substituted with one or more CN,( D3h) halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, ' is piperidinylene,(D3h) wherein is unsubstituted.(D3h) (D3h)

[0425] In some embodiments, ' is piperazinylene, wherein is optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy. In some(D3h) (D3h) embodiments, is piperazinylene. In some embodiments, is piperazinylene,(D3h) wherein is substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.(D3h) (D3h)In some embodiments, is piperazinylene, wherein is unsubstituted.

[0426] In some embodiments, Y2cis absent, Ci-Ce alkylene, -O-, or -NR1"1-.

[0427] In some embodiments, Y2cis absent. In some embodiments, Y2cis Ci-Ce alkylene,-O-, or -NRL 1-.

[0428] In some embodiments, Y2cis Ci-Ce alkylene. In some embodiments, Y2cis methylene. In some embodiments, Y2cis ethylene. In some embodiments, Y2cis propylene. In some embodiments, Y2cis n-propylene. In some embodiments, Y2cis isopropylene. In some embodiments, Y2cis butylene. In some embodiments, Y2cis n-butylene. In some embodiments, Y2Cis isobutylene. In some embodiments, Y2cis sec-butylene. In some embodiments, Y2cis tert-butylene. In some embodiments, Y2cis pentylene. In some embodiments, Y2cis hexylene.

[0429] In some embodiments, Y2cis -O- or -NR1"1-. In some embodiments, Y2cis -O-.In some embodiments, Y2cis-NR.L-1-.

[0430] In some embodiments, Yldis absent, Ci-Ce alkylene, -O-, or -NR1"1-.

[0431] In some embodiments, Yldis absent. In some embodiments, Yldis Ci-Ce alkylene,-O-, or -NR1"1-.

[0432] In some embodiments, Yldis Ci-Ce alkylene. In some embodiments, Yldis methylene. In some embodiments, Yldis ethylene. In some embodiments, Yldis propylene. In some embodiments, Yldis n-propylene. In some embodiments, Yldis isopropylene. In some embodiments, Yldis butylene. In some embodiments, Yldis n-butylene. In some embodiments, Yldis isobutylene. In some embodiments, Yldis sec-butylene. In some embodiments, Yldis tert-butylene. In some embodiments, Yldis pentylene. In some embodiments, Yldis hexylene.86MEl\56615208.vl137508-05920

[0433] In some embodiments, Yldis -O- or -NRL-1-. In some embodiments, Yldis -O-. In some embodiments, Yldis-NRL-1

[0434] In some embodiments, Y2dis absent, Ci-Ce alkylene, -O-, or -NR1"1

[0435] In some embodiments, Y2dis absent. In some embodiments, Y2dis Ci-Ce alkylene,-O-, or -NRL 1

[0436] In some embodiments, Y2dis Ci-Ce alkylene. In some embodiments, Y2dis methylene. In some embodiments, Y2dis ethylene. In some embodiments, Y2dis propylene. In some embodiments, Y2dis n-propylene. In some embodiments, Y2dis isopropylene. In some embodiments, Y2dis butylene. In some embodiments, Y2dis n-butylene. In some embodiments, Y2dis isobutylene. In some embodiments, Y2dis sec-butylene. In some embodiments, Y2dis tert-butylene. In some embodiments, Y2dis pentylene. In some embodiments, Y2dis hexylene.

[0437] In some embodiments, Y2dis -O- or -NR1"1-. In some embodiments, Y2dis -O-. In some embodiments, Y2dis-NRL-1-.

[0438] In some embodiments, Y2gis absent, Ci-Ce alkylene, -O-, or -NR1"1-.

[0439] In some embodiments, Y2gis absent. In some embodiments, Y2gis Ci-Ce alkylene,-O-, or -NRL 1-.

[0440] In some embodiments, Y2gis Ci-Ce alkylene. In some embodiments, Y2gis methylene. In some embodiments, Y2gis ethylene. In some embodiments, Y2gis propylene. In some embodiments, Y2gis n-propylene. In some embodiments, Y2gis isopropylene. In some embodiments, Y2gis butylene. In some embodiments, Y2gis n-butylene. In some embodiments, Y2gis isobutylene. In some embodiments, Y2gis sec-butylene. In some embodiments, Y2gis tert-butylene. In some embodiments, Y2gis pentylene. In some embodiments, Y2gis hexylene.

[0441] In some embodiments, Y2gis -O- or -NR1"1-. In some embodiments, Y2gis -O-. In some embodiments, Y2gis-NRL-1-.

[0442] In some embodiments, Y3gis absent, Ci-Ce alkylene, -O-, or -NR1"1-.

[0443] In some embodiments, Y3gis absent. In some embodiments, Y3gis Ci-Ce alkylene,-O-, or -NRL 1-.

[0444] In some embodiments, Y3gis Ci-Ce alkylene. In some embodiments, Y3gis methylene. In some embodiments, Y3gis ethylene. In some embodiments, Y3gis propylene. In some embodiments, Y3gis n-propylene. In some embodiments, Y3gis isopropylene. In some embodiments, Y3gis butylene. In some embodiments, Y3gis n-butylene. In some embodiments, Y3gis isobutylene. In some embodiments, Y3gis sec-butylene. In some embodiments, Y3gis tert-butylene. In some embodiments, Y3gis pentylene. In some embodiments, Y3gis hexylene.87MEl\56615208.vl137508-05920

[0445] In some embodiments, Y3gis -O- or -NRL-1-. In some embodiments, Y3gis -O-. In some embodiments, Y3gis-NRL-1

[0446] In some embodiments, Y4gis absent, Ci-Ce alkylene, -O-, or -NR1"1

[0447] In some embodiments, Y4gis absent. In some embodiments, Y4gis Ci-Ce alkylene,-O-, or -NRL 1

[0448] In some embodiments, Y4gis Ci-Ce alkylene. In some embodiments, Y4gis methylene. In some embodiments, Y4gis ethylene. In some embodiments, Y4gis propylene. In some embodiments, Y4gis n-propylene. In some embodiments, Y4gis isopropylene. In some embodiments, Y4gis butylene. In some embodiments, Y4gis n-butylene. In some embodiments, Y4gis isobutylene. In some embodiments, Y4gis sec-butylene. In some embodiments, Y4gis tert-butylene. In some embodiments, Y4gis pentylene. In some embodiments, Y4gis hexylene.

[0449] In some embodiments, Y4gis -O- or -NR1"1-. In some embodiments, Y4gis -O-. In some embodiments, Y4gis-NRL-1-.

[0450] In some embodiments, Y2fis absent, Ci-Ce alkylene, C2-C6 alkynylene, -O-, or - NR1"1-.

[0451] In some embodiments, Y2fis absent. In some embodiments, Y2fis Ci-Ce alkylene, C2-C6 alkynylene, -O-, or -NR1"1-. In some embodiments, Y2fis Ci-Ce alkylene or C2-C6 alkynylene.

[0452] In some embodiments, Y2fis Ci-Ce alkylene. In some embodiments, Y2fis methylene. In some embodiments, Y2fis ethylene. In some embodiments, Y2fis propylene. In some embodiments, Y2fis n-propylene. In some embodiments, Y2fis isopropylene. In some embodiments, Y2fis butylene. In some embodiments, Y2fis n-butylene. In some embodiments, Y2fis isobutylene. In some embodiments, Y2fis sec-butylene. In some embodiments, Y2fis tert-butylene. In some embodiments, Y2fis pentylene. In some embodiments, Y2fis hexylene.

[0453] In some embodiments, Y2fis C2-C6 alkynylene. In some embodiments, Y2fis C2 alkynylene. In some embodiments, Y2fis C3 alkynylene. In some embodiments, Y2fis C4 alkynylene. In some embodiments, Y2fis C5 alkynylene. In some embodiments, Y2fis Ce alkynylene.

[0454] In some embodiments, Y2fis -O- or -NR1"1-. In some embodiments, Y2fis -O-. In some embodiments, Y2fis-NRL-1-.

[0455] In some embodiments, R1"1is H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0456] In some embodiments, R1"1is H.

[0457] In some embodiments, R1"1is Ci-Ce alkyl. In some embodiments, R1"1is methyl. In some embodiments, R1"1is ethyl. In some embodiments, R1"1is propyl. In some embodiments,88MEl\56615208.vl137508-05920RL-1is n-propyl. In some embodiments, R1'1is isopropyl. In some embodiments, R1'1is butyl. In some embodiments, R1'1is n-butyl. In some embodiments, R1'1is isobutyl. In some embodiments, R1'1is sec-butyl. In some embodiments, R1'1is tert-butyl. In some embodiments, R, _|is pentyl. In some embodiments, R1'1is hexyl.

[0458] In some embodiments, R1'1is C2-C6 alkenyl. In some embodiments, R1'1is C2 alkenyl. In some embodiments, R1'1is C3 alkenyl. In some embodiments, R1'1is C4 alkenyl. In some embodiments, R1'1is C5 alkenyl. In some embodiments, R1'1is Ce alkenyl.

[0459] In some embodiments, R1'1is C2-C6 alkynyl. In some embodiments, R1'1is C2 alkynyl. In some embodiments, R1'1is C3 alkynyl. In some embodiments, R1'1is C4 alkynyl. In some embodiments, R1'1is C5 alkynyl. In some embodiments, R1'1is Ce alkynyl.

[0460] In some embodiments, RL'lbis H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0461] In some embodiments, RL'lbis H.

[0462] In some embodiments, RL'lbis Ci-Ce alkyl. In some embodiments, RL'lbis methyl. In some embodiments, RL'lbis ethyl. In some embodiments, RL'lbis propyl. In some embodiments, RL'lbis n-propyl. In some embodiments, RL'lbis isopropyl. In some embodiments, RL'lbis butyl. In some embodiments, RL'lbis n-butyl. In some embodiments, RL'lbis isobutyl. In some embodiments, RL'lbis sec-butyl. In some embodiments, RL'lbis tertbutyl. In some embodiments, RL'lbis pentyl. In some embodiments, RL'lbis hexyl.

[0463] In some embodiments, RL'lbis C2-C6 alkenyl. In some embodiments, RL'lbis C2 alkenyl. In some embodiments, RL'lbis C3 alkenyl. In some embodiments, RL'lbis C4 alkenyl. In some embodiments, RL'lbis C5 alkenyl. In some embodiments, RL'lbis Ce alkenyl.

[0464] In some embodiments, RL'lbis C2-C6 alkynyl. In some embodiments, RL'lbis C2 alkynyl. In some embodiments, RL'lbis C3 alkynyl. In some embodiments, RL'lbis C4 alkynyl. In some embodiments, RL'lbis C5 alkynyl. In some embodiments, RL'lbis Ce alkynyl.

[0465] In some embodiments, g is 0, 1, 2, 3, 4 ,5, or 6. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5. In some embodiments, g is 6.

[0466] In some embodiments, h is 0, 1, 2, 3, 4 ,5, or 6. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4. In some embodiments, h is 5. In some embodiments, h is 6.

[0467] In some embodiments, p is 0, 1, 2, 3, 4 ,5, or 6. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, L is selected from:89MEl\56615208.vl137508-0592090MEl\56615208.vl137508-0592091MEl\56615208.vl137508-0592092MEl\56615208.vl137508-0592093MEl\56615208.vl137508-05920wherein:is C3-C10 cycloalkylene, Ce-Cio arylene, 4-12 membered heterocycloalkylene, or 5-10 membered heteroarylene;XisCH2orNH;94MEl\56615208.vl137508-05920A is a bond, Ci-Ce alkylene, or -C(O)-NH-;Each RC[AMisindependently H, halogen, CN, C=O, OH, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl; the connection to L; and m is 0, 1, 2, 3, 4, 5, 6, or 7.

[0469] In some embodiments, CLM is (CLM-II), (CLM-III), (CLM-IV), (CLM-V), (CLM- VI), or (CLM- VII):95MEl\56615208.vl137508-05920wherein:W is CRCLM'la’ RCLM-la” or C=O;is Ce arylene, 6-membered heterocycloalkylene, or 6 membered heteroarylene;X’ is CH or N;A’ is a bond or Ci-Ce alkylene;Each of RCLM'laRCLM'lbj^cLM-ic J^CLM-U j^cLM-ieand RCLM'lfis independently halogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;Each RCLM-la’, RCLM-ia” j^cLM-ie’and RCLM-IF jsinc[ependently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; each mame, and mfis independently 0, 1, 2, or 3; each mb, mc, and mdis independently 0, 1, 2, 3, or 4; and whereinis as described herein.96MEl\56615208.vl137508-05920

[0470] In some embodiments, CLM is (CLM-II). In some embodiments, CLM is (CLM-III). In some embodiments, CLM is (CLM-IV). In some embodiments, CLM is (CLM-V). In some embodiments, CLM is (CLM- VI). In some embodiments, CLM is (CLM- VII).

[0471] In some embodiments,C3-C10 cycloalkylene, Ce-Cio arylene, 4-12 membered heterocycloalkylene, or 5-10 membered heteroarylene.

[0472] In some embodiments,C3-C10 cycloalkylene. In some embodiments,is cyclopropylene. In some embodiments,is cyclobutylene. In some embodiments,is cyclopentylene. In some embodimentsis cyclohexyl. In some embodiments,is cycloheptylene. In some embodiments,cyclooctylene. In some embodiments,cyclononylene. In some embodiments,is cyclodecylene.

[0473] In some embodiments,Ce-Cio arylene. In some embodiments,arylene. In some embodiments,C7 arylene. In some embodiments,Cs arylene. In some embodiments,C9 arylene. In some embodiments,C10 arylene.

[0474]

[0475] In some embodiments,4-12 membered heterocycloalkylene. In some embodiments,is a monocyclic 4-12 membered heterocycloalkylene. In some embodiments,a polycyclic 4-12 membered heterocycloalkylene.97MEl\56615208.vl137508-05920

[0476] In some embodiments,4-membered heterocycloalkylene. In some embodiments,is 5-membered heterocycloalkylene. In some embodiments,membered heterocycloalkylene. In some embodiments,7-membered heterocycloalkylene. In some embodiments,8-membered heterocycloalkylene. In some embodiments,is 9-membered heterocycloalkylene. In some embodiments,is 10-membered heterocycloalkylene. In some embodiments,11 -membered heterocycloalkylene. In some embodiments,12-membered heterocycloalkylene.

[0477] In some embodiments,5-10 membered heteroarylene. In some embodiments5- membered heteroarylene. In some embodiments,membered heteroarylene. In some embodiments,7- membered heteroarylene. In some embodiments,8- membered heteroarylene. In some embodiments,9- membered heteroarylene. In some embodiments,10- membered heteroarylene.

[0478] In some embodiments,is 5-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments,is 6-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments,is 7-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S. In98MEl\56615208.vl137508-05920 some embodiments,8-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments,is 9-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S. In some embodiments,is 10-membered heteroarylene comprising 1-4 heteroatoms selected from O, N, and S.

[0479] In some embodiments,is 6-membered heteroarylene comprising 1 heteroatom that is N.

[0480] In some embodiments,9-membered heteroarylene comprising 1-2 heteroatoms that are each N.

[0481] In some embodiments,10-membered heteroarylene comprising 2 heteroatoms that are each N.

[0482] In some embodiments, X’ is CH or N. In some embodiments, X’ is CH. In some embodiments, X’ is N.

[0483] In some embodiments, X is CH2 or NH. In some embodiments, X is CH2. In some embodiments, X is NH.

[0484] In some embodiments, A is a bond, Ci-Ce alkylene, or -C(O)-NH-.

[0485] In some embodiments, A is a bond.

[0486] In some embodiments, A is Ci-Ce alkylene. In some embodiments, A is methylene.In some embodiments, A is ethylene. In some embodiments, A is propylene. In some embodiments, A is n-propylene. In some embodiments, A is isopropylene. In some embodiments, A is butylene. In some embodiments, A is n-butylene. In some embodiments, A is isobutylene. In some embodiments, A is sec-butylene. In some embodiments, A is tertbutylene. In some embodiments, A is pentylene. In some embodiments, A is hexylene.

[0487] In some embodiments, A is -C(O)-NH-.

[0488] In some embodiments, RCLM-1is H, halogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0489] In some embodiments, RCLM-1is H.99MEl\56615208.vl137508-05920

[0490] In some embodiments, RC,AI-1is halogen. In some embodiments, RCLM-1is F. In some embodiments, RC,AMis Cl. In some embodiments, RC,AMis Br. In some embodiments, RC[AMis I.

[0491] In some embodiments, RC,AI-1is CN.

[0492] In some embodiments, RC,AI-1is C=O.

[0493] In some embodiments, RC,AI-1is OH.

[0494] In some embodiments, RC[AMis Ci-Ce alkyl.

[0495] In some embodiments, RC,AI-1is methyl. In some embodiments, RC,AMis ethyl. In some embodiments, RC,AMis propyl. In some embodiments, RC,AI-1is n-propyl. In some embodiments, RC,AI-1is isopropyl. In some embodiments, RC,AMis butyl. In some embodiments, RC,AI-1is n-butyl. In some embodiments, RC,AMis isobutyl. In some embodiments, RC[AMis sec-butyl. In some embodiments, RC[AMis tert-butyl. In some embodiments, RC,AI-1is pentyl. In some embodiments, RC,AMis hexyl.

[0496] In some embodiments, RC[AMis Ci-Ce alkoxy.

[0497] In some embodiments, RC,AI-1is methoxy. In some embodiments, RC,AMis ethoxy. In some embodiments, RCLM-1is propoxy. In some embodiments, RC,AI-1is n-propoxy. In some embodiments, RC,AI-1is isopropoxy. In some embodiments, RC,AMis butoxy. In some embodiments, RC,AMis n-butoxy. In some embodiments, RC,AI-1is isobutoxy. In some embodiments, RC,AMis sec-butoxy. In some embodiments, RC,AMis tert-butoxy. In some embodiments, RC,AI-1is pentoxy. In some embodiments, RC,AMis hexoxy.

[0498] In some embodiments, RC[AMis Ci-Ce haloalkyl.

[0499] In some embodiments, RC,AI-1is Ci haloalkyl. In some embodiments, RC,AMis C2 haloalkyl. In some embodiments, RC,AMis C3 haloalkyl. In some embodiments, RC,AMis C4 haloalkyl. In some embodiments, RC,AMis C5 haloalkyl. In some embodiments, RC,AMis Ce haloalkyl.

[0500] In some embodiments, RC[AMis C3-C10 cycloalkyl.

[0501] In some embodiments, RC,AI-1is cyclopropyl. In some embodiments, RC,AI-1is cyclobutyl. In some embodiments, RC,AMis cyclopentyl. In some embodiments, RC,AMis cyclohexyl. In some embodiments, RC,AMis cycloheptyl. In some embodiments, RC,AMis cyclooctyl. In some embodiments, RC,AMis cyclononyl. In some embodiments, RC,AMis cyclodecyl.

[0502] In some embodiments, RC,AI-1is 4-12 membered heterocycloalkyl.

[0503] In some embodiments, RC,AMis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RC,AI-1is a polycyclic 4-12 membered heterocycloalkyl.100MEl\56615208.vl137508-05920

[0504] In some embodiments, RCLM’lcis 4-membered heterocycloalkyl. In some embodiments, RCLM’lcis 4-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 5- membered heterocycloalkyl. In some embodiments, RCLM’1Cis 6-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 7-membered heterocycloalkyl. In some embodiments, RCLM'lcis 8-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 9-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 10-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 11-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 12- membered heterocycloalkyl.

[0505] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7.

[0506] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7.

[0507]

[0508] In some embodiments, W is CRCLM'laRCLM-la”orC=O. In some embodiments, W is CRCLM'laRCLM'la. In some embodiments, W is C=O.

[0509] In some embodiments,is Ce arylene, 6-membered heterocycloalkylene, or 6 membered heteroarylene;

[0510] In some embodiments,is Ce arylene. In some embodiments,membered heterocycloalkylene. In some embodiments,is 6 membered heteroarylene.In some embodiments,is pyridinylene.

[0511] In some embodiments, A’ is a bond or Ci-Ce alkylene.

[0512] In some embodiments, A’ is a bond.

[0513] In some embodiments, A’ is Ci-Ce alkylene. In some embodiments, A’ is methylene. In some embodiments, A’ is ethylene. In some embodiments, A’ is propylene. In some embodiments, A’ is n-propylene. In some embodiments, A’ is isopropylene. In some embodiments, A’ is butylene. In some embodiments, A’ is n-butylene. In some embodiments, A’ is isobutylene. In some embodiments, A’ is sec-butylene. In some embodiments, A’ is tertbutylene. In some embodiments, A’ is pentylene. In some embodiments, A' is hexylene.101MEl\56615208.vl137508-05920

[0514] In some embodiments, RCLM’laishalogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0515] In some embodiments, RCLM’lais halogen. In some embodiments, RCLM’lais F. In some embodiments, RCLM’lais Cl. In some embodiments, RCLM-laisBr. In some embodiments,RCLM-laisj

[0516] In some embodiments, RCLM-laisCN.

[0517] In some embodiments, RCLM-laisC=O.

[0518] In some embodiments, RCLM-laisOH.

[0519] In some embodiments, RCLM-laisCi-Ce alkyl.

[0520] In some embodiments, RCLM’lais methyl. In some embodiments, RCLM’lais ethyl. In some embodiments, RCLM’lais propyl. In some embodiments, RCLM’lais n-propyl. In some embodiments, RCLM’lais isopropyl. In some embodiments, RCLM’lais butyl. In some embodiments, RCLM4ais n-butyl. In some embodiments, RCLM’lais isobutyl. In some embodiments, RCLM’lais sec-butyl. In some embodiments, RCLM’lais tert-butyl. In some embodiments, RCLM’lais pentyl. In some embodiments, RCLM’lais hexyl.

[0521] In some embodiments, RCLM-laisCi-Ce alkoxy.

[0522] In some embodiments, RCLM-laismethoxy. In some embodiments, RCLM’lais ethoxy. In some embodiments, RCLM-laispropoxy. In some embodiments, RCLM-laisn-propoxy. In some embodiments, RCLM’lais isopropoxy. In some embodiments, RCLM’lais butoxy. In some embodiments, RCLM’lais n-butoxy. In some embodiments, RCLM’lais isobutoxy. In some embodiments, RCLM’lais sec-butoxy. In some embodiments, RCLM4ais tert-butoxy. In some embodiments, RCLM-laispentoxy. In some embodiments, RCLM-laishexoxy.

[0523] In some embodiments, RCLM-1AaisCi-Ce haloalkyl.

[0524] In some embodiments, RCLM-laisCi haloalkyl. In some embodiments, RCLM-laisC2 haloalkyl. In some embodiments, RCLM-laisC3 haloalkyl. In some embodiments, RCLM-laisC4 haloalkyl. In some embodiments, RCLM’lais C5 haloalkyl. In some embodiments, RCLM-laisCe haloalkyl.

[0525] In some embodiments, RCLM’lais C3-C10 cycloalkyl. In some embodiments, RCLM-laiscyclopropyl. In some embodiments, RCLM-laiscyclobutyl. In some embodiments, RCLM-laiscyclopentyl. In some embodiments, RCLM-laiscyclohexyl. In some embodiments, RCLM-laiscycloheptyl. In some embodiments, RCLM-laiscyclooctyl. In some embodiments, RCLM-laiscyclononyl. In some embodiments, RCLM-laiscyclodecyl.102MEl\56615208.vl137508-05920

[0526] In some embodiments, RCLM’lais 4-12 membered heterocycloalkyl. In some embodiments, RCLM’lais a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM’lais a polycyclic 4-12 membered heterocycloalkyl.

[0527] In some embodiments, RCLM’lais 4-membered heterocycloalkyl. In some embodiments, RCLM’lais 4-membered heterocycloalkyl. In some embodiments, RCLM’lais 5- membered heterocycloalkyl. In some embodiments, RCLM’lais 6-membered heterocycloalkyl. In some embodiments, RCLM’lais 7-membered heterocycloalkyl. In some embodiments, RCLM'lais 8-membered heterocycloalkyl. In some embodiments, RCLM’lais 9-membered heterocycloalkyl. In some embodiments, RCLM’lais 10-membered heterocycloalkyl. In some embodiments, RCLM’lais 11-membered heterocycloalkyl. In some embodiments, RCLM’lais 12- membered heterocycloalkyl.

[0528] In some embodiments, RCLM’lbishalogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0529] In some embodiments, RCLM’lbis halogen. In some embodiments, RCLM’lbis F. In some embodiments, RCLM’lbis Cl. In some embodiments, RCLM'lbis Br. In some embodiments, RCLM’lbis I.

[0530] In some embodiments, RCLM’lbis CN. In some embodiments, RCLM’lbis C=O. In some embodiments, RCLM’lbis OH.

[0531] In some embodiments, RCLM’lbis Ci-Ce alkyl. In some embodiments, RCLM’lbis methyl. In some embodiments, RCLM’lbis ethyl. In some embodiments, RCLM’lbis propyl. In some embodiments, RCLM’lbis n-propyl. In some embodiments, RCLM’lbis isopropyl. In some embodiments, RCLM’lbis butyl. In some embodiments, RCLM’lbis n-butyl. In some embodiments, RCLM’lbis isobutyl. In some embodiments, RCLM’lbis sec-butyl. In some embodiments, RCLM’lbis tert-butyl. In some embodiments, RCLM’lbis pentyl. In some embodiments, RCLM’lbis hexyl.

[0532] In some embodiments, RCLM’lbis Ci-Ce alkoxy. In some embodiments, RCLM’lbis methoxy. In some embodiments, RCLM’lbis ethoxy. In some embodiments, RCLM’lbis propoxy. In some embodiments, RCLM’lbis n-propoxy. In some embodiments, RCLM’lbis isopropoxy. In some embodiments, RCLM’lbis butoxy. In some embodiments, RCLM’lbis n-butoxy. In some embodiments, RCLM’lbis isobutoxy. In some embodiments, RCLM’lbis sec-butoxy. In some embodiments, RCLM’lbis tert-butoxy. In some embodiments, RCLM’lbis pentoxy. In some embodiments, RCLM'lbis hexoxy.103MEl\56615208.vl137508-05920

[0533] In some embodiments, RCLM-1BaisCi-Ce haloalkyl. In some embodiments, RCLM’lbis Ci haloalkyl. In some embodiments, RCLM’lbis C2 haloalkyl. In some embodiments, RCLM’lbis C3 haloalkyl. In some embodiments, RCLM’lbis C4 haloalkyl. In some embodiments, RCLM’lbis C5 haloalkyl. In some embodiments, RCLM’lbisCe haloalkyl.

[0534] In some embodiments, RCLM’lbis C3-C10 cycloalkyl, n some embodiments, RCLM'lbis cyclopropyl. In some embodiments, RCLM'lbis cyclobutyl. In some embodiments, RCLM'lbis cyclopentyl. In some embodiments, RCLM'lbis cyclohexyl. In some embodiments, RCLM'lbis cycloheptyl. In some embodiments, RCLM'lbis cyclooctyl. In some embodiments, RCLM'lbis cyclononyl. In some embodiments, RCLM'lbis cyclodecyl.

[0535] In some embodiments, RCLM’lbis 4-12 membered heterocycloalkyl. In some embodiments, RCLM’lbis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM’lbis a polycyclic 4-12 membered heterocycloalkyl.

[0536] In some embodiments, RCLM’lbis 4-membered heterocycloalkyl. In some embodiments, RCLM’lbis 4-membered heterocycloalkyl. In some embodiments, RCLM’lbis 5- membered heterocycloalkyl. In some embodiments, RCLM’lbis 6-membered heterocycloalkyl. In some embodiments, RCLM’lbis 7-membered heterocycloalkyl. In some embodiments, RCLM'lbis 8-membered heterocycloalkyl. In some embodiments, RCLM’lbis 9-membered heterocycloalkyl. In some embodiments, RCLM’lbis 10-membered heterocycloalkyl. In some embodiments, RCLM’lbis 11-membered heterocycloalkyl. In some embodiments, RCLM’lbis 12- membered heterocycloalkyl.

[0537] In some embodiments, RCLM'lcishalogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0538] In some embodiments, RCLM’1Cis halogen. In some embodiments, RCLM’1Cis F. In some embodiments, RCLM’lcis Cl. In some embodiments, RCLM'lcis Br. In some embodiments, RCLM-ic is l

[0539] In some embodiments, RCLM’1Cis CN. In some embodiments, RCLM’1Cis C=O. In some embodiments, RCLM’1Cis OH.

[0540] In some embodiments, RCLM’1Cis Ci-Ce alkyl. In some embodiments, RCLM’1Cis methyl. In some embodiments, RCLM’1Cis ethyl. In some embodiments, RCLM’1Cis propyl. In some embodiments, RCLM’lcis n-propyl. In some embodiments, RCLM’1Cis isopropyl. In some embodiments, RCLM’1Cis butyl. In some embodiments, RCLM’1Cis n-butyl. In some embodiments, RCLM’1Cis isobutyl. In some embodiments, RCLM’1Cis sec-butyl. In some104MEl\56615208.vl137508-05920 embodiments, RCLM’lcis tert-butyl. In some embodiments, RCLM’lcis pentyl. In some embodiments, RCLM’1Cis hexyl.

[0541] In some embodiments, RCLM’1Cis Ci-Ce alkoxy. In some embodiments, RCLM’1Cis methoxy. In some embodiments, RCLM’1Cis ethoxy. In some embodiments, RCLM’1Cis propoxy. In some embodiments, RCLM’1Cis n-propoxy. In some embodiments, RCLM’1Cis isopropoxy. In some embodiments, RCLM’lcis butoxy. In some embodiments, RCLM’1Cis n-butoxy. In some embodiments, RCLM’1Cis isobutoxy. In some embodiments, RCLM’1Cis sec-butoxy. In some embodiments, RCLM’1Cis tert-butoxy. In some embodiments, RCLM’1Cis pentoxy. In some embodiments, RCLM’1Cis hexoxy.

[0542] In some embodiments, RCLM-1CaisCi-Ce haloalkyl. In some embodiments, RCLM’1Cis Ci haloalkyl. In some embodiments, RCLM'lcis C2 haloalkyl. In some embodiments, RCLM’1Cis C3 haloalkyl. In some embodiments, RCLM'lcis C4 haloalkyl. In some embodiments, RCLM’1Cis C5 haloalkyl. In some embodiments, RCLM'lcisCe haloalkyl.

[0543] In some embodiments, RCLM’1Cis C3-C10 cycloalkyl. In some embodiments, RCLM'lcis cyclopropyl. In some embodiments, RCLM'lcis cyclobutyl. In some embodiments, RCLM'lcis cyclopentyl. In some embodiments, RCLM'lcis cyclohexyl. In some embodiments, RCLM'lcis cycloheptyl. In some embodiments, RCLM'lcis cyclooctyl. In some embodiments, RCLM'lcis cyclononyl. In some embodiments, RCLM'lcis cyclodecyl.

[0544] In some embodiments, RCLM’1Cis 4-12 membered heterocycloalkyl. In some embodiments, RCLM’1Cis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM’1Cis a polycyclic 4-12 membered heterocycloalkyl.

[0545] In some embodiments, RCLM’1Cis 4-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 4-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 5- membered heterocycloalkyl. In some embodiments, RCLM’1Cis 6-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 7-membered heterocycloalkyl. In some embodiments, RCLM'lcis 8-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 9-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 10-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 11-membered heterocycloalkyl. In some embodiments, RCLM’1Cis 12- membered heterocycloalkyl.

[0546] In some embodiments, RCLM’ldishalogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.105MEl\56615208.vl137508-05920

[0547] In some embodiments, RCLM’ldis halogen. In some embodiments, RCLM’ldis F. In some embodiments, RCLM’ldis Cl. In some embodiments, RCLM'ldis Br. In some embodiments, RCLM-ldis I.

[0548] In some embodiments, RCLM'ldis CN.

[0549] In some embodiments, RCLM’ldis C=O.

[0550] In some embodiments, RCLM'ldis OH.

[0551] In some embodiments, RCLM'ldis Ci-Ce alkyl.

[0552] In some embodiments, RCLM’ldis methyl. In some embodiments, RCLM’ldis ethyl. In some embodiments, RCLM’ldis propyl. In some embodiments, RCLM’ldis n-propyl. In some embodiments, RCLM’ldis isopropyl. In some embodiments, RCLM’ldis butyl. In some embodiments, RCLM’ldis n-butyl. In some embodiments, RCLM’ldis isobutyl. In some embodiments, RCLM’ldis sec-butyl. In some embodiments, RCLM’ldis tert-butyl. In some embodiments, RCLM’ldis pentyl. In some embodiments, RCLM’ldis hexyl.

[0553] In some embodiments, RCLM'ldis Ci-Ce alkoxy.

[0554] In some embodiments, RCLM'ldis methoxy. In some embodiments, RCLM’ldis ethoxy. In some embodiments, RCLM'ldis propoxy. In some embodiments, RCLM'ldis n-propoxy. In some embodiments, RCLM’ldis isopropoxy. In some embodiments, RCLM’ldis butoxy. In some embodiments, RCLM’ldis n-butoxy. In some embodiments, RCLM’ldis isobutoxy. In some embodiments, RCLM’ldis sec-butoxy. In some embodiments, RCLM’ldis tert-butoxy. In some embodiments, RCLM'ldis pentoxy. In some embodiments, RCLM'ldis hexoxy.

[0555] In some embodiments, RCLM-1DaisCi-Ce haloalkyl.

[0556] In some embodiments, RCLM'ldis Ci haloalkyl. In some embodiments, RCLM'ldis C2 haloalkyl. In some embodiments, RCLM'ldis C3 haloalkyl. In some embodiments, RCLM'ldis C4 haloalkyl. In some embodiments, RCLM dis C5 haloalkyl. In some embodiments, RCLM'ldis Ce haloalkyl.

[0557] In some embodiments, RCLM’ldisC3-C10 cycloalkyl.

[0558] In some embodiments, RCLM'ldis cyclopropyl. In some embodiments, RCLM'ldis cyclobutyl. In some embodiments, RCLM'ldis cyclopentyl. In some embodiments, RCLM'ldis cyclohexyl. In some embodiments, RCLM'ldis cycloheptyl. In some embodiments, RCLM'ldis cyclooctyl. In some embodiments, RCLM'ldis cyclononyl. In some embodiments, RCLM'ldis cyclodecyl.

[0559] In some embodiments, RCLM’ldis 4-12 membered heterocycloalkyl. In some embodiments, RCLM’ldis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM’ldis a polycyclic 4-12 membered heterocycloalkyl.106MEl\56615208.vl137508-05920

[0560] In some embodiments, RCLM4dis 4-membered heterocycloalkyl. In some embodiments, RCLM’ldis 4-membered heterocycloalkyl. In some embodiments, RCLM’ldis 5- membered heterocycloalkyl. In some embodiments, RCLM’ldis 6-membered heterocycloalkyl. In some embodiments, RCLM’ldis 7-membered heterocycloalkyl. In some embodiments, RCLM'ldis 8-membered heterocycloalkyl. In some embodiments, RCLM’ldis 9-membered heterocycloalkyl. In some embodiments, RCLM’ldis 10-membered heterocycloalkyl. In some embodiments, RCLM’ldis 11-membered heterocycloalkyl. In some embodiments, RCLM4dis 12- membered heterocycloalkyl.

[0561] In some embodiments, RCLM’leis halogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0562] In some embodiments, RCLM’leis halogen. In some embodiments, RCLM’leis F. In some embodiments, RCLM’leis Cl. In some embodiments, RCLM'leis Br. In some embodiments, RCLM-ie is l

[0563] In some embodiments, RCLM’leis CN.

[0564] In some embodiments, RCLM’leis C=O.

[0565] In some embodiments, RCLM’leis OH.

[0566] In some embodiments, RCLM'leisCi-Ce alkyl.

[0567] In some embodiments, RCLM’leis methyl. In some embodiments, RCLM’leis ethyl. In some embodiments, RCLM’leis propyl. In some embodiments, RCLM’leis n-propyl. In some embodiments, RCLM’leis isopropyl. In some embodiments, RCLM’leis butyl. In some embodiments, RCLM4eis n-butyl. In some embodiments, RCLM’leis isobutyl. In some embodiments, RCLM’leis sec-butyl. In some embodiments, RCLM’leis tert-butyl. In some embodiments, RCLM’leis pentyl. In some embodiments, RCLM’leis hexyl.

[0568] In some embodiments, RCLM’leis Ci-Ce alkoxy.

[0569] In some embodiments, RCLM'leis methoxy. In some embodiments, RCLM’leis ethoxy. In some embodiments, RCLM’leis propoxy. In some embodiments, RCLM’leis n-propoxy. In some embodiments, RCLM’leis isopropoxy. In some embodiments, RCLM’leis butoxy. In some embodiments, RCLM’leis n-butoxy. In some embodiments, RCLM’leis isobutoxy. In some embodiments, RCLM’leis sec-butoxy. In some embodiments, RCLM4eis tert-butoxy. In some embodiments, RCLM’leis pentoxy. In some embodiments, RCLM’leis hexoxy.

[0570] In some embodiments, RCLM-1EaisCi-Ce haloalkyl.

[0571] In some embodiments, RCLM'leis Ci haloalkyl. In some embodiments, RCLM'leis C2 haloalkyl. In some embodiments, RCLM'leis C3 haloalkyl. In some embodiments, RCLM'leis C4107MEl\56615208.vl137508-05920 haloalkyl. In some embodiments, RCLM’leis C5 haloalkyl. In some embodiments, RCLM'leis Ce haloalkyl.

[0572] In some embodiments, RCLM'leisC3-C10 cycloalkyl.

[0573] In some embodiments, RCLM'leis cyclopropyl. In some embodiments, RCLM'leis cyclobutyl. In some embodiments, RCLM'leis cyclopentyl. In some embodiments, RCLM'leis cyclohexyl. In some embodiments, RCLM'leis cycloheptyl. In some embodiments, RCLM'leis cyclooctyl. In some embodiments, RCLM'leis cyclononyl. In some embodiments, RCLM'leis cyclodecyl.

[0574] In some embodiments, RCLM’leis 4-12 membered heterocycloalkyl. In some embodiments, RCLM’leis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM’leis a polycyclic 4-12 membered heterocycloalkyl.

[0575] In some embodiments, RCLM’leis 4-membered heterocycloalkyl. In some embodiments, RCLM’leis 4-membered heterocycloalkyl. In some embodiments, RCLM’leis 5- membered heterocycloalkyl. In some embodiments, RCLM’leis 6-membered heterocycloalkyl. In some embodiments, RCLM’leis 7-membered heterocycloalkyl. In some embodiments, RCLM'leis 8-membered heterocycloalkyl. In some embodiments, RCLM’leis 9-membered heterocycloalkyl. In some embodiments, RCLM’leis 10-membered heterocycloalkyl. In some embodiments, RCLM’leis 11-membered heterocycloalkyl. In some embodiments, RCLM’leis 12- membered heterocycloalkyl.

[0576] In some embodiments, RCLM’lfishalogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl.

[0577] In some embodiments, RCLM'lfis halogen. In some embodiments, RCLM'lfis F. In some embodiments, RCLM'lfis Cl. In some embodiments, RCLM'lfis Br. In some embodiments, RCLM-lfis I.

[0578] In some embodiments, RCLM'lfis CN. In some embodiments, RCLM'lfis C=O. In some embodiments, RCLM'lfis OH.

[0579] In some embodiments, RCLM'lfis Ci-Ce alkyl. In some embodiments, RCLM’lfis methyl. In some embodiments, RCLM fis ethyl. In some embodiments, RCLM’lfis propyl. In some embodiments, RCLM'lfis n-propyl. In some embodiments, RCLM'lfis isopropyl. In some embodiments, RCLM'lfis butyl. In some embodiments, RCLM'lfis n-butyl. In some embodiments, RCLM-if isisobutyl. In some embodiments, RCLM'lfis sec-butyl. In some embodiments, RCLM’lfis tert-butyl. In some embodiments, RCLM'lfis pentyl. In some embodiments, RCLM'lfis hexyl.108MEl\56615208.vl137508-05920

[0580] In some embodiments, RCLM’lfis Ci-Ce alkoxy. In some embodiments, RCLM’lfis methoxy. In some embodiments, RCLM'lfis ethoxy. In some embodiments, RCLM'lfis propoxy. In some embodiments, RCLM'lfis n-propoxy. In some embodiments, RCLM'lfis isopropoxy. In some embodiments, RCLM'lfis butoxy. In some embodiments, RCLM'lfis n-butoxy. In some embodiments, RCLM’lfis isobutoxy. In some embodiments, RCLM’lfis sec-butoxy. In some embodiments, RCLM’lfis tert-butoxy. In some embodiments, RCLM’lfis pentoxy. In some embodiments, RCLM'lfis hexoxy.

[0581] In some embodiments, RCLM-1FaisCi-Ce haloalkyl. In some embodiments, RCLM’lfis Ci haloalkyl. In some embodiments, RCLM'lfis C2 haloalkyl. In some embodiments, RCLM’lfis C3 haloalkyl. In some embodiments, RCLM'lfis C4 haloalkyl. In some embodiments, RCLM’lfis C5 haloalkyl. In some embodiments, RCLM'lfis Ce haloalkyl.

[0582] In some embodiments, RCLM'lfis C3-C10 cycloalkyl. In some embodiments, RCLM'lfis cyclopropyl. In some embodiments, RCLM'lfis cyclobutyl. In some embodiments, RCLM'lfis cyclopentyl. In some embodiments, RCLM'lfis cyclohexyl. In some embodiments, RCLM'lfis cycloheptyl. In some embodiments, RCLM'lfis cyclooctyl. In some embodiments, RCLM'lfis cyclononyl. In some embodiments, RCLM'lfis cyclodecyl.

[0583] In some embodiments, RCLM’lfis 4-12 membered heterocycloalkyl. In some embodiments, RCLM’lfis a monocyclic 4-12 membered heterocycloalkyl. In some embodiments, RCLM'lfis a polycyclic 4-12 membered heterocycloalkyl.

[0584] In some embodiments, RCLM fis 4-membered heterocycloalkyl. In some embodiments, RCLM’lfis 4-membered heterocycloalkyl. In some embodiments, RCLM’lfis 5- membered heterocycloalkyl. In some embodiments, RCLM'lfis 6-membered heterocycloalkyl. In some embodiments, RCLM'lfis 7-membered heterocycloalkyl. In some embodiments, RCLM'lfis 8-membered heterocycloalkyl. In some embodiments, RCLM fis 9-membered heterocycloalkyl. In some embodiments, RCLM’lfis 10-membered heterocycloalkyl. In some embodiments, RCLM'lfis 11-membered heterocycloalkyl. In some embodiments, RCLM'lfis 12- membered heterocycloalkyl.

[0585] In some embodiments, RCLM'la’ isH, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0586] In some embodiments, RCLM'la’ is H.

[0587] In some embodiments, RCLM'la’ is Ci-Ce alkyl. In some embodiments, RCLM'la’ is methyl. In some embodiments, RCLM'la’ is ethyl. In some embodiments, RCLM'la’ is propyl. In some embodiments, RCLM'la’ is n-propyl. In some embodiments, RCLM'la’ is isopropyl. In some embodiments, RCLM a’ is butyl. In some embodiments, RCLM'la’ is n-butyl. In some embodiments, RCLM'la’ is isobutyl. In some embodiments, RCLM'la’ is sec-butyl. In some109MEl\56615208.vl137508-05920 embodiments, RCLM4ais tert-butyl. In some embodiments, RCLM'la’ is pentyl. In some embodiments, RCLM'la’ is hexyl.

[0588] In some embodiments, RCLM'la’ isC2-C6 alkenyl. In some embodiments, RCLM'la’ isC2 alkenyl. In some embodiments, RCLM'la’ is C3 alkenyl. In some embodiments, RCLM'la’ is C4 alkenyl. In some embodiments, RCLM-la’ isC5 alkenyl. In some embodiments, RCLM'la’ is Ce alkenyl.

[0589] In some embodiments, RCLM'la’ is C2-C6 alkynyl. In some embodiments, RCLM'la’ isC2 alkynyl. In some embodiments, RCLM'la’ is C3 alkynyl. In some embodiments, RCLM-la’isC4 alkynyl. In some embodiments, RCLM-la’ isC5 alkynyl. In some embodiments, RCLM'la’ is Ce alkynyl.

[0590] In some embodiments, RCLM’la” isH, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0591] In some embodiments, RCLM-la” isH.

[0592] In some embodiments, RCLM-la” isCi-Ce alkyl. In some embodiments, RCLM-la” ismethyl. In some embodiments, RCLM-la” isethyl. In some embodiments, RCLM-la” ispropyl. In some embodiments, RCLM’lais n-propyl. In some embodiments, RCLM-la” isisopropyl. In some embodiments, RCLM’lais butyl. In some embodiments, RCLM-la” isn-butyl. In some embodiments, RCLM’lais isobutyl. In some embodiments, RCLM-la” issec-butyl. In some embodiments, RCLM4ais tert-butyl. In some embodiments, RCLM-la” ispentyl. In some embodiments, RCLM-la” ishexyl.

[0593] In some embodiments, RCLM-la” isC2-C6 alkenyl. In some embodiments, RCLM’la” is C2 alkenyl. In some embodiments, RCLM-la” isC3 alkenyl. In some embodiments, RCLM-la” isC4 alkenyl. In some embodiments, RCLM-la” isC5 alkenyl. In some embodiments, RCLM-la” isCe alkenyl.

[0594] In some embodiments, RCLM-la” isC2-C6 alkynyl. In some embodiments, RCLM’la” is C2 alkynyl. In some embodiments, RCLM-la” isC3 alkynyl. In some embodiments, RCLM'lais C4 alkynyl. In some embodiments, RCLM-la” isC5 alkynyl. In some embodiments, RCLM-la” isCe alkynyl.

[0595] In some embodiments, RCLM-lfisH or Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0596] In some embodiments, RCLM’lfis H.

[0597] In some embodiments, RCLM’lfis Ci-Ce alkyl. In some embodiments, RCLM’lfismethyl. In some embodiments, RCLM-lfisethyl. In some embodiments, RCLM’lfis propyl. In some embodiments, RCLM’lfis n-propyl. In some embodiments, RCLM’lfis isopropyl. In some embodiments, RCLM’lfis butyl. In some embodiments, RCLM-lfisn-butyl. In some embodiments, RCLM’lfis isobutyl. In some embodiments, RCLM-lfissec-butyl. In some110MEl\56615208.vl137508-05920 embodiments, RCLM’lfis tert-butyl. In some embodiments, RCLM’lfis pentyl. In some embodiments, RCLM’lfis hexyl.

[0598] In some embodiments, RCLM-lfisC2-C6 alkenyl. In some embodiments, RCLM-lfisC2 alkenyl. In some embodiments, RCLM’lfis C3 alkenyl. In some embodiments, RCLM’lfis C4 alkenyl. In some embodiments, RCLM-lfisC5 alkenyl. In some embodiments, RCLM’lfis C6alkenyl.

[0599] In some embodiments, RCLM-lfisC2-C6 alkynyl. In some embodiments, RCLM'le’ isC2 alkynyl. In some embodiments, RCLM'le’ is C3 alkynyl. In some embodiments, RCLM'leis C4 alkynyl. In some embodiments, RCLM-le’ isC5 alkynyl. In some embodiments, RCLM'le’ is C6alkynyl.

[0600] In some embodiments, RCLM-lfisH or Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0601] In some embodiments, RCLM’lfis H.

[0602] In some embodiments, RCLM’lfis Ci-Ce alkyl. In some embodiments, RCLM’lfismethyl. In some embodiments, RCLM-lfisethyl. In some embodiments, RCLM’lfis propyl. In some embodiments, RCLM’lfis n-propyl. In some embodiments, RCLM’lfis isopropyl. In some embodiments, RCLM’lfis butyl. In some embodiments, RCLM-lfisn-butyl. In some embodiments, RCLM’lfis isobutyl. In some embodiments, RCLM-lfissec-butyl. In some embodiments, RCLM’lfis tert-butyl. In some embodiments, RCLM’lfis pentyl. In some embodiments, RCLM’lfis hexyl.

[0603] In some embodiments, RCLM-lfisC2-C6 alkenyl. In some embodiments, RCLM-lfisC2 alkenyl. In some embodiments, RCLM’lfis C3 alkenyl. In some embodiments, RCLM’lfis C4 alkenyl. In some embodiments, RCLM-lfisC5 alkenyl. In some embodiments, RCLM’lfis C6alkenyl.

[0604] In some embodiments, RCLM’lfis C2-C6 alkynyl. In some embodiments, RCLM’lfisC2 alkynyl. In some embodiments, RCLM’lfis C3 alkynyl. In some embodiments, RCLM'lfis C4 alkynyl. In some embodiments, RCLM-lfisC5 alkynyl. In some embodiments, RCLM’lfis C6alkynyl.

[0605] In some embodiments, mais 0, 1, 2, or 3. In some embodiments, mais 0. In some embodiments, mais 1. In some embodiments, mais 2. In some embodiments, mais 3.

[0606] In some embodiments, mbis 0, 1, 2, 3, or 4. In some embodiments, mbis 0. In some embodiments, mbis 1. In some embodiments, mbis 2. In some embodiments, mbis 3. In some embodiments, mbis 4.111MEl\56615208.vl137508-05920

[0607] In some embodiments, mcis 0, 1, 2, 3, or 4. In some embodiments, mcis 0. In some embodiments, mcis 1. In some embodiments, mcis 2. In some embodiments, mcis 3. In some embodiments, mcis 4.

[0608] In some embodiments, mdis 0, 1, 2, 3, or 4. In some embodiments, mdis 0. In some embodiments, mdis 1. In some embodiments, mdis 2. In some embodiments, mdis 3. In some embodiments, mdis 4.

[0609] In some embodiments, meis 0, 1, 2, or 3. In some embodiments, meis 0. In some embodiments, meis 1. In some embodiments, meis 2. In some embodiments, meis 3.

[0610] In some embodiments, mfis 0, 1, 2, or 3. In some embodiments, mfis 0. In some embodiments, mfis 1. In some embodiments, mfis 2. In some embodiments, mfis 3.

[0611] In some embodiments, L is selected from:112MEl\56615208.vl137508-05920

[0612] In some embodiments, the compound is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the compounds described in Table 1.Table 1113MEl\56615208.vl137508-05920114MEl\56615208.vl137508-05920115MEl\56615208.vl137508-05920116MEl\56615208.vl137508-05920117MEl\56615208.vl137508-05920118MEl\56615208.vl137508-05920119MEl\56615208.vl137508-05920120MEl\56615208.vl137508-05920121MEl\56615208.vl137508-05920122MEl\56615208.vl137508-05920123MEl\56615208.vl137508-05920124MEl\56615208.vl137508-05920125MEl\56615208.vl137508-05920126MEl\56615208.vl137508-05920127MEl\56615208.vl137508-05920128MEl\56615208.vl137508-05920129MEl\56615208.vl137508-05920130MEl\56615208.vl137508-05920131MEl\56615208.vl137508-05920132MEl\56615208.vl137508-05920133MEl\56615208.vl137508-05920134MEl\56615208.vl137508-05920135MEl\56615208.vl137508-05920136MEl\56615208.vl137508-05920

[0613] In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof).

[0614] The terms “treat”, “treating”, and “treatment”, etc., as used herein, refer to any action providing a benefit to a patient for which the present compounds may be administered, including the treatment of any disease state or condition which is modulated through the protein to which the present compounds bind. Disease states or conditions, including cancer, which may be treated using compounds according to the present disclosure are set forth hereinabove.

[0615] In some embodiments, the disease or disorder is associated with aberrant BCL6 expression and / or activity. In some embodiments, the disease or disorder is a cancer associated with aberrant BCL6 expression and / or activity. In some embodiments, the disease or disorder is associated with BCL6 accumulation and aggregation. In some embodiments, the disease or disorder is a cancer associated with BCL6 accumulation and aggregation.

[0616] In some embodiments, the disease or disorder is cancer.

[0617] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mature B-cell neoplasm, transformed follicular lymphoma,137MEl\56615208.vl137508-05920 high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin lymphoma not otherwise specified, or solid tumors.

[0618] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, and nonHodgkin lymphoma not otherwise specified, or solid tumors.

[0619] In some embodiments, the cancer is advanced cancer, relapsed / refractory (R / R) cancer, advanced lymphoma, relapsed / refractory (R / R) lymphoma, advanced non-Hodgkin lymphoma (NHL), relapsed / refractory (R / R) non-Hodgkin lymphoma (NHL), advanced B-Cell non- Hodgkin lymphoma (NHL), relapsed / refractory (R / R) B-Cell non-Hodgkin lymphoma (NHL), advanced angioimmunoblastic T-cell lymphoma (AITL), or relapsed / refractory (R / R) angioimmunoblastic T-cell lymphoma (AITL).

[0620] In some embodiments, the cancer is advanced non-Hodgkin lymphoma (NHL), relapsed / refractory (R / R) non-Hodgkin lymphoma (NHL), advanced angioimmunoblastic T- cell lymphoma (AITL), or relapsed / refractory (R / R) angioimmunoblastic T-cell lymphoma (AITL).

[0621] As used herein, “angioimmunoblastic T-cell lymphoma” is also known as “AITL” or “Nodal T-follicular helper (TFH) cell lymphoma, angioimmunoblastic-type.”

[0622] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin lymphoma not otherwise specified, or solid tumors.

[0623] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high grade B-cell lymphoma, non-Hodgkin lymphoma not otherwise specified, or solid tumors.

[0624] The term “neoplasia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant138MEl\56615208.vl137508-05920 hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present include non-Hodgkin lymphoma (NHL) including advanced NHL and relapsed / refractory (R / R) NHL, B-cell non-Hodgkin lymphoma (NHL) including advanced B- cell NHL and relapsed / refractory B-cell (R / R) NHL, angioimmunoblastic T-cell lymphoma (AITL) including advanced AITL and relapsed / refractory AITL, diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, mature B-cell neoplasm, transformed follicular lymphoma, high grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin lymphoma not otherwise specified, or solid tumors, including, but not limited to, breast, lung and ovarian cancers, and neuroblastoma and glioblastoma.

[0625] In some embodiments, the cancer is solid tumors, wherein the solid tumors are selected from breast cancer, lung cancer, ovarian cancer, blastoma, neuroblastoma, and glioblastoma.EXAMPLES(Scheme 1)

[0626] Example 1. Compounds of the invention can be prepared e.g., according to the strategy described in Scheme 1. The 2-chloro- or 2-fluoropyrimidine compounds of Formula I (wherein E is Cl or F respectively), may be prepared according to standard methods known in the art, e.g., as described in Davis et. al. J. Med. Chem. (2022) 65 (12) 8169-8190 & 8191 - 8207). Compounds of Formula I can be heated with an L-CLM such as a compound ofFormula II (wherein L*, N*, and R*, together with any intervening atoms indicated by •' optionally form a ring, and wherein L*, N*, R*, and ■' together comprise L) in a solvent, e.g., DMSO, in the presence of a base, e.g., diisopropylethylamine, to form a compound of139MEl\56615208.vl137508-05920Formula III. The amines of the form shown in Scheme 1 can be prepared by methods known in the art.

[0627] Example 2: Synthesis of (3S)-3-(4-fhroro-7-methyl-l-oxo-5-{l-[(lr,3r)-3-{[l-(5- chloro-4-{[(2S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-lH,2H,3H,4H,6H,7H- [l,4]oxazepino[2,3-c]quinolin-10-yl]amino}pyrimidin-2-yl)piperidin-4- yl]oxy}cyclobutyl]piperidin-4-yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (Compound No. 10)140MEl\56615208.vl137508-05920

[0628] Step 1 : Preparation of methyl 4-bromo-5-fluoro-2-methylbenzoate

[0629] A solution of 4-bromo-5-fluoro-2-methylbenzoic acid (2 g, 9 mmol) and sulfuric acid(2.0 mL, 37 mmol) in methanol (25 mL) was stirred for 12 h at 60141MEl\56615208.vl137508-05920°C under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to afford the title compound (2.1 g, crude) as a oil, which was used in the next step directly.

[0630] Step 2: Preparation of tert-butyl 4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]- 3,6-dihydro-2H-pyridine-l-carboxylate

[0631] To a stirred solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (2.1 g, 8.5 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate (3.15 g, 10 mmol) in 1,4-dioxane / water (5: 1, 24 mL) were added cesium fluoride (3.87 g, 25 mmol) and [l,l’-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (554 mg, 0.9 mmol), the mixture was stirred at 90 °C under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7: 1) to afford the title compound (2.2 g, 74%) as a yellow solid.

[0632] Step 3: Preparation of tert-butyl 4-[2-fluoro-4-(methoxycarbonyl)-5- methylphenyl]piperidine- 1 -carboxylate

[0633] To a solution of tert-butyl 4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]-3,6- dihydro-2H-pyridine-l -carboxylate (2.2 g, 6.3 mmol) in methanol(20 mL) was added 10% palladium over carbon (0.3 g) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen several times. The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure to afford the title compound (1.9 g, 86%) as a yellow solid. LC / MS (ESI): m / z 335.10 [M+H]+.

[0634] Step 4: Preparation of 4-[l-(tert-butoxycarbonyl)piperidin-4-yl]-5-fluoro-2- methylbenzoic acid142MEl\56615208.vl137508-05920

[0635] A solution of tert-butyl 4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]piperidine- 1-carboxylate (1.9 g, 5.4 mmol) and sodium hydroxide (0.87 g, 22 mmol) in tetrahydrofuran / water (1 : 1, 20 mL was stirred overnight at 40°C under nitrogen atmosphere. The reaction mixture was diluted with concentrated hydrochloric acid until pH 5, and the resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.6 g, 88%) as a yellow solid.

[0636] Step 5: Preparation of tert-butyl 4-(4-fluoro-3-hydroxy-7-methyl-l-oxo-3H-2- benzofuran-5-yl)piperidine-l -carboxylate

[0637] To a solution of 4-[l-(tert-butoxycarbonyl)piperidin-4-yl]-5-fluoro-2 -methylbenzoic acid (1.6 g, 4.7 mmol) in tetrahydrofuran (10 mL) was dropwise added n-butyllithium solution (2.5 M in hexane, 4.7 mL, 2.5 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h, followed by the dropwise addition of dimethylformamide (1.8 mL) and tetrahydrofuran (5 mL). The reaction mixture was stirred for 40 min, then diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1 g, 58%) as a yellow oil.

[0638] Step 6: Preparation of tert-butyl 4-[2-fluoro-3-formyl-4-(methoxycarbonyl)-5- methylphenyl]piperidine- 1 -carboxylate

[0639] To a stirred solution of tert-butyl 4-(4-fluoro-3-hydroxy-7-methyl-l-oxo-3H-2- benzofuran-5-yl)piperidine-l -carboxylate (1 g, 3 mmol) and potassium carbonate (1.13 g, 8.2 mmol) in N, N-dimethylformamide (10 mL) was dropwise added iodomethane (389 mg, 2.7143MEl\56615208.vl137508-05920 mmol) under nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 : 1) to afford the title compound (680 mg, 65%) as a yellow oil.

[0640] Step 7: Preparation of tert-butyl 4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]- 4-fluoro-7-methyl-l-oxo-3H-isoindol-5-yl (piperidine- 1 -carboxylate

[0641] A solution of tert-butyl 4-[2-fluoro-3-formyl-4-(methoxycarbonyl)-5- methylphenyl]piperidine-l -carboxylate (680 mg, 1.8 mmol) and tert-butyl (4S)-4-amino-4- carbamoylbutanoate (399 mg, 2 mmol) in di chloroethane (30 mL) was stirred overnight at 40 °C under nitrogen atmosphere, followed by the addition of sodium triacetoxyborohydride (3 mg, 0.05 mmol). The reaction mixture was stirred for 1 h at 40 °C under nitrogen, then diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane = 1 :3) to afford the title compound (380 mg, 40%) as a yellow solid.

[0642] Step 8: Preparation of tert-butyl (4S)-4-carbamoyl-4-[4-fluoro-7-methyl-l-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]butanoate

[0643] To a stirred solution of tert-butyl 4-(2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]- 4-fluoro-7-methyl-l-oxo-3H-isoindol-5-ylpiperidine-l -carboxylate (1 g, 2 mmol) in isopropanol (30 mL) was dropwise added trimethyl silyl chloride (1.2 mL, 9 mmol) at 0 °C. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was diluted with saturated sodium carbonate solution until pH 8, the resulting mixture was extracted with dichloromethane (100 mL). The organic layer was washed with brine (100 mL),144MEl\56615208.vl137508-05920 dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (610 mg, 75%) as a white solid. LC / MS (ESI): m / z 434.35 [M+H]+.

[0644] Step 9: Preparation of (ls,3s)-3-(benzyloxy)cyclobutan-l-ol

[0645] To a solution of 3-(benzyloxy)cyclobutan-l-one (100 g, 567 mmol)) in methanol was added sodium borohydride (13.5 g, 357 mmol) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature, then filtered and concentrated under reduced pressure. The residue was diluted with water (400 mL) at 0 °C and extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (99 g, 98%) as a colorless oil.

[0646] Step 10: Preparation of trimethyl[(ls,3s)-3-(benzyloxy)cyclobutoxy]silaneBnO— <^>-OTMS

[0647] To a solution of (ls,3s)-3-(benzyloxy)cyclobutan-l-ol (79.0 g, 443 mmol) in dichloromethane (400 mL) were slowly added triethylamine (134.0 g, 1.3 mol) and trimethyl silyl chloride (53.0 g, 488 mmol) at 0 °C. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (110 g, 99%) as a oil.

[0648] Step 11 : Preparation of benzyl 4-[(ls,3s)-3-(benzyloxy)cyclobutoxy]piperidine-l- carb oxy late

[0649] To a solution of trimethyl[(ls,3s)-3-(benzyloxy)cyclobutoxy]silane (67.6 g, 270 mmol) and benzyl 4-oxopiperidine-l -carboxylate (69.3 g, 297 mmol) in dichloromethane (600 mL) was dropwise added tri ethylsilane (34.5 g, 297 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 5 min, followed by the dropwise addition of trimethyl silyl trifluoromethanesulfonate (30.0 g, 135 mmol) in dichloromethane (50 mL). The mixture was stirred for 10 min at -78 °C, then slowly warmed to 0 °C and stirred for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by145MEl\56615208.vl137508-05920 silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford the title compound (81 g, 76%) as a oil.

[0650] Step 12: Preparation of tert-butyl 4-[(ls,3s)-3-hyroxycyclobutoxy]piperidine-l- carb oxy late

[0651] To a solution of benzyl 4-[(ls,3s)-3-(benzyloxy)cyclobutoxy]piperidine-l-carboxylate (20 g, 51 mmol) and di -tert-butyl dicarbonate (16.6 g, 76 mmol) in ethanol (200 mL) and tetrahydrofuran (150 mL) were added 10% palladium over carbon (10 g) and 10% palladium hydroxide over carbon (10 g) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen several times. The resulting mixture was stirred at 55 °C under hydrogen atmosphere (15 psi) for 48 h. The reaction mixture was cooled to room temperature and filtered. The filtrate solution was concentrated, and the residue was purified by reverse flash chromatography (5% to 40% acetonitrile in water (10 mmol / L ammonium bicarbonate) over 30 min) to afford the title compound (28 g, 82%) as an off-white solid.

[0652] Step 13: Preparation of tert-butyl 4-[(ls,3s)-3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-l-carboxylateBoc

[0653] To a solution of tert-butyl 4-[(ls,3s)-3-hydroxycyclobutoxy]piperidine-l-carboxylate (10.0 g, 37 mmol) in dichloromethane (150 mL) were slowly added tri ethylamine (11.2 g, 111 mmol) and triflic anhydride (16.6 g, 59 mmol) at -40 °C under nitrogen atmosphere. The mixture was stirred at -40 °C for 2 h under nitrogen. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9: 1) to afford the title compound (9.6 g, 65%) as a yellow solid.

[0654] Step 14: Preparation of tert-butyl 4-[(lr,3r)-3-(4-(2-[(lS)-4-(tert-butoxy)-l-carbamoyl- 4-oxobutyl]-4-fluoro-7-methyl-l-oxo-3H-isoindol-5-ylpiperidin-l-yl)cyclobutoxy]piperidine- 1 -carboxylate146MEl\56615208.vl137508-05920

[0655] To a stirred mixture of tert-butyl (4S)-4-carbamoyl-4-[4-fluoro-7-methyl-l-oxo-5- (piperidin-4-yl)-3H-isoindol-2-yl]butanoate (580 mg, 1.3 mmol) and tert-butyl 4-[(ls,3s)-3- (trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-l-carboxylate (809.6 mg, 2 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (519 mg, 4 mmol). The mixture was stirred for 2 h at 35 °C under nitrogen atmosphere, then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (10% to 80% acetonitrile in water (10 mmol / L ammonium bicarbonate) over 30 min) to afford the title compound (352 mg, 39% as a white solid. LC / MS (ESI): m / z 687.55 [M+H]+.

[0656] Step 15: Preparation of (3S)-3-(4-fluoro-7-methyl-l-oxo-5-(l-[(lr,3r)-3-(piperidin-4- yloxy)cyclobutyl]piperidin-4-yl-3H-isoindol-2-yl)piperidine-2, 6-dione

[0657] To a solution of tert-butyl 4-[(lr,3r)-3-(4-(2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4- oxobutyl]-4-fluoro-7 -methyl- 1 -oxo-3H-isoindol-5-ylpiperidin- 1 -yl)cyclobutoxy]piperidine- 1 - carboxylate (332 mg, 0.5 mmol) in acetonitrile (15 mL) was added [(lR,4S)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (15 mL). The reaction solution was stirred overnight at 85 °C under nitrogen atmosphere, then concentrated under reduced pressure to afford the title compound (247 mg, crude) as an oil. LC / MS (ESI): m / z 513.25 [M+H]+.

[0658] Step 16: Preparation of l-methyl-6-nitro-3,l-benzoxazine-2, 4-dione147MEl\56615208.vl137508-05920

[0659] A mixture of 6-nitro-lH-3,l-benzoxazine-2, 4-dione (22.0 g, 106 mmol) and sodium hydride (3.8 g, 0.16 mol, 60% in mineral oil) in N, N-dimethylformamide was stirred for 15 min at room temperature under nitrogen atmosphere, followed by the dropwise addition of iodomethane (200 mL, 3.2 mol). The resulting mixture was stirred for 4 h at room temperature, then poured into ice-water. The suspension was filtered and washed with water (500 mL). The filter cake was dried under vacuum overnight to afford the title compound (17.4 g, 74%) as an orange powder.

[0660] Step 17: Preparation of ethyl 4-hydroxy-l-methyl-6-nitro-2-oxoquinoline-3- carb oxy late

[0661] To a stirred solution of l-methyl-6-nitro-3,l-benzoxazine-2, 4-dione (17.4 g, 78 mmol) in N, N-dimethylformamide (200 mL) was added diethyl malonate (37.6 g, 235 mmol). The solution was cooled to 0 °C, and sodium hydride (3.80 g, 156 mmol, 60% in mineral oil) was added. The reaction was stirred at room temperature. The reaction was diluted with 10% aqueous hydrochloric acid solution until pH 5. The suspension was filtered, the filter cake was dried under vacuum to afford the title compound (28.5 g) as a pale yellow solid.

[0662] Step 18: Preparation of ethyl 4-chloro-l-methyl-6-nitro-2-oxoquinoline-3 -carboxylate

[0663] A mixture of phosphorus oxychloride (250 mL) and ethyl 4-hydroxy-l-methyl-6-nitro- 2-oxoquinoline-3 -carboxylate (28.5 g, 98 mmol) was stirred at 80 °C for 2.5 h under argon atmosphere. The mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford the title compound (21 g, 69%) as a yellow solid. LC / MS (ESI): m / z 310.85 [M+H]+.

[0664] Step 19: Preparation of ethyl 4-{[(lS)-l-cyclopropyl-2,2-difluoro-3- hydroxypropyl]amino}-l-methyl-6-nitro-2-oxoquinoline-3-carboxylate148MEl\56615208.vl137508-05920

[0665] To a stirred mixture of (3S)-3-amino-3-cyclopropyl-2,2-difluoropropan-l-ol (5.3 g, 35 mmol) and ethyl 4-chloro-l-methyl-6-nitro-2-oxoquinoline-3 -carboxylate (9.0 g, 29 mmol) in n-butanol (100 mL) was added N,N-diisopropylethylamine (18.7 g, 145 mmol). The resulting mixture was stirred for 16 h at 120 °C under nitrogen atmosphere, then concentrated under reduced pressure. The residue was suspended in water, filtered and washed with water. The filter cake was dried to afford the title compound (8.5 g, 69%) as a light yellow solid. LC / MS (ESI): m / z 426.15 [M+H]+.

[0666] Step 20: Preparation of 4-{[(lS)-l-cyclopropyl-2,2-difluoro-3-hydroxypropyl]amino}- 1 -methyl-6-nitroquinolin-2-one

[0667] A mixture of ethyl 4-{[(lS)-l-cyclopropyl-2,2-difhioro-3-hydroxypropyl]amino}-l- methyl-6-nitro-2-oxoquinoline-3-carboxylate (11.5 g, 27 mmol) and 2 M aqueous sodium hydroxide solution (66 mL) in 1,4-dioxane (80 mL) was stirred for 2 h at 85 °C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 3 M aqueous hydrochloric acid solution until pH 5-6, and the resulting mixture was filtered, washed with water (100 mL) and dried to afford the title compound (8.2 g, 85%) as a beige solid.

[0668] Step 21 : Preparation of 3-bromo-4-{[(lS)-l-cyclopropyl-2,2-difluoro-3- hydroxypropyl]amino}-l-methyl-6-nitroquinolin-2-one

[0669] To a stirred mixture of 4-{[(lS)-l-cyclopropyl-2,2-difluoro-3-hydroxypropyl]amino}- l-methyl-6-nitroquinolin-2-one (8.2 g, 23 mmol) and freshly recrystallized N- bromosuccinimide (4.1 g, 23 mmol) in anhydrous dichloromethane (150 mL) was added149MEl\56615208.vl137508-05920 trifluoroacetic acid (13.2 g, 116 mmol) at 0 °C under argon atmosphere, the mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with di chloromethane (100 mL) and washed with saturated sodium bicarbonate solution (3 x 100 mL). The combined aqueous layers were further extracted with dichloromethane (100 mL). The combined organic layers were washed with brine (100 mL) and concentrated to afford the title compound (9.4 g, 94%) as a yellow solid. LC / MS (ESI): m / z 432.15 [M+H]+.

[0670] Step 22: Preparation of (2S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-lH,2H,4H- [ 1 ,4]oxazepino[2,3 -c]quinolin-6-one

[0671] To a solution of 3-bromo-4-{[(lS)-l-cyclopropyl-2,2-difluoro-3- hydroxypropyl]amino}-l-methyl-6-nitroquinolin-2-one (9.4 g, 22 mmol) in tetrahydrofuran (150 mL) was added lithium / c / 7-butoxide (2.6 g, 33 mmol), and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:7) to afford the title compound (5.2 g, 68%) as a light yellow solid. LC / MS (ESI): m / z 351.95 [M+H]+.

[0672] Step 23: Preparation of (2S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl- lH,2H,4H-[l,4]oxazepino[2,3-c]quinolin-6-one

[0673] To a solution of (2S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-lH,2H,4H- [l,4]oxazepino[2,3-c]quinolin-6-one (5.2 g, 15 mmol) in ethanol (80 mL) was added 10% palladium over carbon (3.0 g) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen several times. The reaction mixture was stirred at room temperature for 2 h under hydrogen atmosphere, then filtered through a celite pad and concentrated under150MEl\56615208.vl137508-05920 reduced pressure to afford the title compound (4.8 g, crude) as a light yellow solid. LC / MS (ESI): m / z 322.15 [M+H]+.

[0674] Step 24: Preparation of (2S)-10-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-2- cyclopropyl-3,3-difluoro-7-methyl-lH,2H,4H-[l,4]oxazepino[2,3-c]quinolin-6-one

[0675] A mixture of (2S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-lH,2H,4H- [l,4]oxazepino[2,3-c]quinolin-6-one (4.8 g, 15 mmol) and 5-chloro-2,4-difluoropyrimidine (2.3 g, 15 mmol) inN, N-dimethylformamide (70 mL) was stirred for 2 h at 50 °C. The reaction mixture was suspended in water (1500 mL), filtered and washed with water (3 x 200 mL). The filter cake was purified by trituration with petroleum ether / ethyl acetate (1 : 1, 200 mL) to afford the title compound (5.1 g, 75%) as a white solid. LC / MS (ESI): m / z 452.10 [M+H]+.

[0676] Step 25: Preparation of (3S)-3-(4-fluoro-7-methyl-l-oxo-5-(l-[(lr,3r)-3-([l-(5-chloro- 4-([(2S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-lH,2H,4H-[l,4]oxazepino[2,3- c]quinolin-10-yl]aminopyrimidin-2-yl)piperidin-4-yl]oxycyclobutyl]piperidin-4-yl-3H- isoindol-2-yl)piperidine-2, 6-dione

[0677] To a stirred mixture of (3S)-3-(4-fluoro-7-methyl-l-oxo-5-(l-[(lr,3r)-3-(piperidin-4- yloxy)cy cl obutyl]piperidin-4-yl-3H-isoindol-2-yl)piperidine-2, 6-dione (90.8 mg, 0.18 mmol) and (2S)-10-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-2-cyclopropyl-3,3-difluoro-7-methyl- lH,2H,4H-[l,4]oxazepino[2,3-c]quinolin-6-one (80 mg, 0.18 mmol) in DMSO (10 mL) was added N,N-diisopropylethylamine (68.7 mg, 0.5 mmol). The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The reaction mixture was directly purified by reversed-151MEl\56615208.vl137508-05920 phase flash chromatography (10% to 80% acetonitrile in water (10 mmol / L ammonium bicarbonate) over 30 min) to afford the title compound (50 mg, 29%) as a white solid.1H NMR (300 MHz, DMSO) 5 10.98 (s, 1H), 8.80 (s, 1H), 8.19 (m, 1H), 8.03 (s, 1H), 7.71 (m, 1H), 7.43 (m, 1H), 7.26 (m, 1H), 6.20 (s, 1H), 5.06 (m, 1H), 4.52-4.28 (m, 4H), 4.14-4.06 (m, 3H), 3.56 (s, 4H), 3.16 (s, 3H), 3.00 (s, 2H), 2.85 (s, 2H), 2.57 (s, 4H), 2.48-2.33 (m, 1H), 2.15 (s, 6H), 1.98-1.76 (s, 8H), 1.34 (m, 3H), 0.76-0.65 (m, 1H), 0.52 (m, 2H), 0.35 (m, 1H); LC / MS (ESI): m / z 944.50 [M+H]+.

[0678] Example 3: Synthesis of (3S)-3-(4-fluoro-l-oxo-5-{ l-[(lr,3r)-3-{[l-(5-chloro-4- {[(2S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-lH,2H,3H,4H,6H,7H-[l,4]oxazepino[2,3- c]quinolin-10-yl]amino}pyrimidin-2-yl)piperidin-4-yl]oxy}cyclobutyl]piperidin-4-yl}-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (Compound No. 11)

[0679] Step 1 : Preparation of methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate

[0680] A mixture of methyl 4-bromo-3-fluoro-2 -methylbenzoate (2.9 g, 12 mmol), azobisisobutyronitrile (385 mg, 2.3 mmol) and N-bromosuccinimide (2.5 g, 14 mmol) in carbon tetrachloride (50 mL) was stirred overnight at 70 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, the residue was diluted with water (200 mL) and extracted with di chloromethane (2 x 100 mL). The combined organic layers were152MEl\56615208.vl137508-05920 washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (3.8 g, crude) as a solid. LC / MS (ESI): m / z 323.05 [M+H]+.

[0681] Step 2: Preparation of tert-butyl (4S)-4-(5-bromo-4-fluoro-l-oxo-3H-isoindol-2-yl)-4- carbamoylbutanoate

[0682] To a mixture of methyl 4-bromo-2-(bromomethyl)- 3 -fluorobenzoate (3.8 g, 12 mmol) and tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (4.2 g, 17 mmol) in acetonitrile (80 mL) was added N,N-diisopropylethylamine (9.0 g, 70 mmol). The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere, then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (4.8 g, 99%) as a yellow solid. LC / MS (ESI): m / z 415.05 [M+H]+.

[0683] Step 3: Preparation of tert-butyl 4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]- 4-fluoro- 1-OXO-3EI- isoindol-5-yl }-3,6-dihydro-2H-pyri dine- 1 -carboxylate

[0684] A mixture of tert-butyl (4S)-4-(5-bromo-4-fluoro-l-oxo-3H-isoindol-2-yl)-4- carbamoylbutanoate (4.8 g, 11 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-l -carboxylate (5.4 g, 17 mmol), Pd^ppfJChCEECh (942 mg, 1.2 mmol) and cesium fluoride (5.3 g, 35 mmol) in dioxane (90 mL) and water (18 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 80% ethyl acetate / petroleum ether) to afford the title compound (5.1 g, 85%) as a yellow solid. LC / MS (ESI): m / z 518.25 [M+H]+.

[0685] Step 4: Preparation of tert-butyl 4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]- 4-fluoro-l-oxo-3H- isoindol-5-yl}piperidine-l-carboxylate153MEl\56615208.vl137508-05920

[0686] To a solution of tert-butyl 4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]-4- fluoro-l-oxo-3H-isoindol-5-yl}-3,6-dihydro-2H-pyridine-l-carboxylate (5.0 g, 9.7 mmol) in tetrahydrofuran (50 mL) was added 10% palladium hydroxide (2.0 g). The mixture was degassed and purged with hydrogen several times. The reaction mixture was stirred overnight at room temperature, filtered and washed with tetrahydrofuran (2 x 100 mL). The filtrate solution was concentrated under reduced pressure to afford the title compound (5.0 g, crude) as a solid. LC / MS (ESI): m / z 520.35 [M+H]+.

[0687] Step 5: Preparation of tert-butyl (4S)-4-carbamoyl-4-[4-fluoro-l-oxo-5-(piperidin-4- yl)-3H-isoindol-2-yl]butanoate

[0688] To a stirred solution of tert-butyl 4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4-oxobutyl]- 4-fluoro-l-oxo-3H-isoindol-5-yl}piperidine-l-carboxylate (954 mg, 1.8 mmol) in isopropanol (10 mL) was dropwise added trimethyl silyl chloride (1.99 g, 18 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature, then diluted with saturated sodium carbonate solution until pH 8. The mixture was extracted with di chloromethane (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (627 mg, 81%) as a yellow solid. LC / MS (ESI): m / z . l [M+H]+.

[0689] Step 6: Preparation of tert-butyl 4-[(lr,3r)-3-(4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl- 4-oxobutyl]-4-fluoro-l-oxo-3H-isoindol-5-yl}piperidin-l-yl)cyclobutoxy]piperidine-l- carb oxy late154MEl\56615208.vl137508-05920

[0690] To a solution of tert-butyl (4S)-4-carbamoyl-4-[4-fluoro-l-oxo-5-(piperidin-4-yl)-3H- isoindol-2-yl]butanoate (600 mg, 1.4 mmol) in acetonitrile (10 mL) were slowly added N,N- diisopropylethylamine (0.75 mL, 4.3 mmol) and tert-butyl 4-[(lr,3r)-3- (trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-l-carboxylate (692 mg, 1.7 mmol) in acetonitrile (5 mL). The resulting mixture was stirred for 2 h at 30 °C under nitrogen atmosphere, then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (5% to 45% acetonitrile in water (10 mmol / L ammonium bicarbonate) over 20 min) to afford the title compound (420 mg, 44%) as a white solid. LC / MS (ESI): m / z 672.39 [M+H]+.

[0691] Step 7: Preparation of (3S)-3-(4-fluoro-l-oxo-5-{ l-[(lr,3r)-3-(piperidin-4- yloxy)cyclobutyl]piperidin-4-yl}-3H-isoindol-2-yl)piperidine-2, 6-dione

[0692] To a solution of tert-butyl 4-[(lr,3r)-3-(4-{2-[(lS)-4-(tert-butoxy)-l-carbamoyl-4- oxobutyl]-4-fluoro-l-oxo-3H-isoindol-5-yl}piperidin-l-yl)cyclobutoxy]piperidine-l- carboxylate (200 mg, 0.3 mmol) in acetonitrile (3 mL) was added [(lR,4S)-7,7-dimethyl-2- oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (207 mg, 0.9 mmol). The resulting mixture was stirred overnight at 85 °C, then concentrated under reduced pressure to afford the title compound (148 mg, crude) as an off- white solid. LC / MS (ESI): m / z 498.26 [M+H]+.

[0693] Step 8: Preparation of 4-fluoro-2-[(3S)-2-methylidene-6-oxopiperidin-3-yl]-5-{ l- [(lr,3r)-3-{[l-(5-chloro-4-{[(2S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-lH,2H,4H- [l,4]oxazepino[2,3-c]quinolin-10-yl]amino}pyrimidin-2-yl)piperidin-4- yl]oxy}cyclobutyl]piperidin-4-yl}-3H-isoindol-l-one155MEl\56615208.vl137508-05920

[0694] To a solution of (3S)-3-(4-fluoro-l-oxo-5-{ l-[(lr,3r)-3-(piperidin-4- yloxy)cyclobutyl]piperidin-4-yl}-3H-isoindol-2-yl)piperidine-2, 6-dione (141 mg, 0.3 mmol) in DMSO (5 mL) was added (2S)-10-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-2- cyclopropyl-3,3-difluoro-7-methyl-lH,2H,4H-[l,4]oxazepino[2,3-c]quinolin-6-one (80 mg, 0.2 mmol), followed by the dropwise addition of N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred for 3 h at 50 °C. The reaction solution was directly purified by reversed-phase flash chromatography (5% to 50% acetonitrile in water (10 mmol / L ammonium bicarbonate) over 10 min) to afford the title compound (59.1 mg, 35%) as a white solid. LC / MS (ESI): m / z 929.36 [M+H]+; 'H NMR (300 MHz, DMSO-d6) 5 11.00 (s, 1H), 8.81 (s, 1H), 8.19 (m, 1H), 8.04 (s, 1H), 7.71 (m, 1H), 7.53 (m, 2H), 7.44 (m, 1H), 6.20 (s, 1H), 5.11 (m, 1H), 4.61 - 4.31 (m, 4H), 4.06 (m, 3H), 3.57 (m, 5H), 3.16 (m, 3H), 3.06 - 2.73 (m, 5H), 2.63 (s, 2H), 2.33 (m, 3H), 2.12 (m, 2H), 2.06 - 1.89 (m, 3H), 1.77 (s, 8H), 1.35 (m, 3H), 0.72 (m, 1H), 0.53 (m, 2H), 0.37 (s, 1H).

[0695] Example 4. Biological AssaysHigh Content IF Protocol for BCL6 Supplies / Reagents :• T47D adherent breast cancer cell line (ATCC), subculture 1 :4 to 1 :8 when 80% confluent• Media: ATCC RPMI-1640 (ATCC 30-2001) + 10% Gibco FBS (Thermo Fisher 16000044)• DPBS• Trypsin• 96-well black / clear bottom plates (Corning 3904)• 96-well polypropylene plates (VWR 82050-678)156MEl\56615208.vl137508-05920• 96-well deep well polypropylene plates (VWR 76183-226)• 16% paraformaldehyde (VWR #100504-782)• 10% Triton X-100 (Sigma Aldrich 93443)• lOx Blocking Buffer (Abeam abl26587): Spin down prior to use.• Rabbit anti-BCL6 Ab (Cell Signaling CST-14895)• Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody Alexa Fluor 488 (Thermo Fisher A32731)• AlexaFluor-647-Phalloidin (Thermo Fisher A22287)• Hoechst (Thermo Fisher 62249)• Wash buffer: 10X PBS (Thomas Scientific C837K73), 100 mL 10X PBS + 1 mL Calcium Chloride (Sigma Aldrich 21115-100ML) + ImL Magnesium Chloride (Sigma Aldrich M1028-100ML) + 898 mL diH2ODay 1: SEED T47D breast cancer epithelial cells into 96-well black, clear bottom plates.Duplicate plates were seeded. 2 plates are required for each 8 PROTACs tested.• The media was aspirated and the cells were washed with 10 mL DPBS.• The DPBS was aspirated and the cells were trypsinized with 5 mL trypsin for 5 min.• The cells were resuspended in 10 mL media and counted on the Countess cell counter using 4% trypan blue.• The cells were diluted to 5,000 cells / 100 pL media (50,000 cells / mL).• 100 pL cells were added to each well of a 96-well plate (Corning 3904).• The plates were left in a 37°C incubator for 24 hours.Expected seeding density is -70-90% confluence on day immunofluorescence is performed.Day 2: TREATMENTPrepare 2X PROTAC 9-point dose response prepared in mediaFinal concentrations in assay plate will start at 1 pM with 3-fold sequential dilutions, plus DMSO only.DMSO Dilution PlatePROTACS157MEl\56615208.vl137508-05920Using a 96-well polypropylene compound titration plate, dose response titrations in DMSO were prepared.• 245 pL DMSO was added to each well in column 2 and well A12.• 40 pL DMSO was added to each well in columns 1 and 3-12 (except A12).• 5 pL 10 mM PROTAC stock was added to A2, B2, C2, D2, E2, F2, G2, H2 and mixed well after each addition. Each PROTAC was 200 pM in DMSO. o 20 pL was transferred sequentially from column 2 through columns 10. and mixed well.Control PROTAC• 5 pL 10 mM control was added to Al 2 and mixed well. o 20 pL from A12 was transferred sequentially, vertically through G12, and mixed after each addition (control A64265-4).Intermediate Dilution PlateDMSO dose response curves were diluted 1 : 1000 into media .• 1 pL from each well of the DMSO dilution plates were added into 96-well deep well plates.• 999 pL media was added to each well of the deep well plates.• 750 pL was mixed lOx per well.Treat T47D plates• The plates containing T47D cells were removed from the incubator.• 100 pL from each well of the Intermediate dilution plates were added to the respective wells containing T47D cells.• The plates were tapped gently to mix.• The plates were returned to the incubator for 72 hours.Day 5: IMMUNOFLUORESCENCEA “wash ” consists of adding ~200 ul Wash Buffer (room temperature) to each well using a combi dispenser (low speed), then flicking liquid from the plate.158MEl\56615208.vl137508-05920• The plates were removed from the incubator.• The media was flicked into a bleach container in cell culture room sink.• The cells were washed once with 200 ul Wash Buffer and flicked to remove the liquid.FIX• 16% paraformaldehyde (PF A) was diluted with Wash Buffer to make 4% PFA to fix the cells. o 50 pL 4% PFA was added to each well. o The plates were left to incubate for 15 minutes at room temperature. o The PFA was aspirated in the fume hood.• The plates were washed x 2 with Wash Buffer.PERMEABILIZE• 10% triton X-100 was diluted with Wash Buffer to make 0.1% Triton X-100 to permeabilize the cells. o 100 pL 0.1% Triton X-100 was added to each well. o The plates were left to incubate at room temperature for 15 minutes. o The plates were flicked to remove the liquid.• The plates were washed x 2 with Wash Buffer.BLOCK• lOx Blocking Buffer was diluted with Wash Buffer to make 3x Blocking Buffer. o 100 pL 3x Blocking Buffer was added to each well. o The plates were left to incubate for at least 1 hour at room temperature. o The plates were flicked to remove the liquid.PRIMARY ANTIBODY• lOx Blocking Buffer was diluted with Wash Buffer to make lx Blocking Buffer. o 50 pL lx Blocking Buffer was added to Column 1 (on each assay plate) for no primary antibody control. o Anti-BCL6 (CST-14895) primary antibody 1 :300 in lx Blocking Buffer was prepared.■ 50 pL primary antibody was added to Columns 2-12 on each assay plate.159MEl\56615208.vl137508-05920■ The plates were left to incubate for 24 hours at 4°C with slow orbital movement.Day 6: SECONDARY ANTIBODY with Phalloidin and Hoechst• The plates were flicked to remove liquid.• The plates were washed 4x with 200 pL fresh Wash Buffer with gentle agitation for 5 minutes.• lOx Blocking Buffer was diluted with Wash Buffer to make lx Blocking Buffer. o Goat anti -Rabbit IgG Alexa-488 1 : 1000 + 1 : 1000 AlexaFluor-647-Phalloidin + Hoechst 1 : 1000 was added to lx Blocking Buffer to make secondary.■ 50 pL secondary was added to each well.■ The plates were left to incubate at room temperature for 1 hour in the dark.• The plates were washed 4x with 200 pL fresh Wash Buffer with gentle agitation for 5 minutes.• 100 pL Wash Buffer was added to each well and the plates were covered with a plastic opaque cover. o Plates were stored at 4°C and covered in aluminum foil until imaged.IMAGING• Plates were equilibrated to room temperature before reading.• Each plate bottom was wiped gently with 70% ethanol immediately prior to imaging.• The images were acquired using Molecular Devices IXM instrumentation and MetaXpress software. o Data acquisition: 10X, 4 fields / wellANALYSIS• Analysis was performed through Custom Module Editor and Scilligence software.• Dmax is the maximum concentration of the test compound relative to vehicle control.• DCso is the test compound concentration at 50% of the maximum degradation achieved.

[0696] The results are shown below in Table 3Table 3.160MEl\56615208.vl137508-05920161MEl\56615208.vl137508-05920162MEl\56615208.vl137508-05920NT = Not Tested, NA = Not Applicable163MEl\56615208.vl

Claims

137508-05920CLAIMSWhat is claimed is:

1. A compound of formula (I):PTM-L-CLM (I) or a pharmaceutically acceptable salt thereof, wherein:(a) PTM is (PTM-I):wherein:C-5- each Q1, Q2, Q3, and Q4is independently CRP™'2, ’ , or N, wherein exactly oneQ5 isNRPTM-3or CRPTM-7RPTM-8. each Q6, Q7, Q8, Q9, and Q10is independently CRP™-4RP™-5, NRP™'6, or O; each R™-1, RP™-2, Rp™-4,RPTM-5 ,RPTM-7 ,an(jRp™-8jsindependently H, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; each Rp™'3andRp™'6is independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 4-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; andthe connection to L;(b) L is (L-Ia) or (L-Ib):164MEl\56615208.vl137508-05920 wherein:* is the connection to PTM and ** is the connection to CLM;D2) (D3), and ' is independently absent, C3-C10 cycloalkylene,4-12 membered heterocycloalkylene, 5-10 membered heteroarylene, or Ce-CioD2} ( D3arylene, wherein each of, and ' is independently optionally substituted with one or more CN, halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy; each Y1, Y2, Y3, Y4is independently absent, Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene, -O-, -NR'-1-, -(CH2)h-SO2-, -(CH2)g-O-(CH2)P-, or Ci-C6alkoxy; each RL-1is independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each g, h, and p is independently 0, 1, 2, 3, 4 ,5, or 6;(c) CLM is (CLM-I):wherein:is C3-C10 cycloalkylene, Ce-Cio arylene, 4-12 membered heterocycloalkylene, or 5-10 membered heteroarylene;X is CH2or NH;A is a bond, Ci-Ce alkylene, or -C(O)-NH-;Each RC[isindependently H, halogen, CN, C=O, OH, oxo, Ci-Ce alkyl, Ci- Ce alkoxy, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;the connection to L; and m is 0, 1, 2, 3, 4, 5, 6, or 7.165MEl\56615208.vl137508-059202. The compound of claim 1, wherein PTM is (PTM-II), (PTM-III), (PTM-IV),166MEl\56615208.vl137508-05920wherein each Qla, Q2a, and Q4ais independently CRP™'2or N.

3. The compound of any one of the preceding claims, wherein L is (L-II) or (L-III):Whereinis 4-12 membered heterocycloalkylene optionally substituted with one or more halogen, OH, Ci-Ce alkyl, or Ci-Ce alkoxy.

4. The compound of any one of the preceding claims, wherein CLM is (CLM-II), (CLM-III), (CLM-IV), (CLM-V), (CLM- VI), or (CLM- VII):167MEl\56615208.vl137508-05920wherein:W is CRCLM'la’ RCLM'la” or C=O;is Ce arylene, 6-membered heterocycloalkylene, or 6 membered heteroarylene;168MEl\56615208.vl137508-05920X’ is CH or N;A’ is a bond or Ci-Ce alkylene;Each of RCLM'laRCLM'lbRCLM-ic J^CLM-U j^cLM-ieand RCLM'lfis independently halogen, CN, C=O, OH, Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl;Each RCLM-la’ and RCLM’la” isindependently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;Each of RCLM'leand RCLM-lfisindependently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each mame, and mfis independently 0, 1, 2, or 3; each mb, mc, and mdis independently 0, 1, 2, 3, or 4.

5. The compound of any one of the preceding claims, wherein the compound is selected from selected from the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound of any one of the preceding claims and one or more pharmaceutically acceptable excipients.

7. A method of treating a disease or disorder in a subject comprising administering to the subject a therapeutically effective amount the compound or pharmaceutical composition of any one of the preceding claims.

8. The method of claim 7, wherein the disease or disorder is associated with aberrant BCL6 expression and / or activity.

9. The method of any one of claims 7-8, wherein the disease or disorder is cancer.

10. The method of claim 9, wherein the cancer is malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, advanced non-Hodgkin Lymphoma, B-cell advanced non-Hodgkin Lymphoma, Large B-cell Lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, transformed follicular lymphoma, angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, germinal center B-169MEl\56615208.vl137508-05920 cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin’s lymphoma not otherwise specified, solid tumors, Kaposi advanced non-Hodgkin’s lymphoma (NHL), relapsed / refractory (R / R) non-Hodgkin’s lymphoma (NHL), relapsed / refractory (R / R) B cell non-Hodgkin’s Lymphoma, advanced relapsed / refractory (R / R) non-Hodgkin’s lymphoma (NHL), advanced nodal T-follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI), relapsed / refractory (R / R) nodal T-follicular helper cell lymphoma, angioimmunoblastic type, T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, or Pre-B-cell Lymphoma.

11. The method of claim 10, wherein the solid tumors are selected from breast cancer, lung cancer, ovarian cancer, neuroblastoma, and glioblastoma.170MEl\56615208.vl

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