Heterobifunctional compounds and methods for treating diseases

Abstract

The present invention provides heterobifunctional compounds capable of binding to both the androgen receptor and BRD4 (bromodomain-containing protein 4). Pharmaceutical compositions containing them and their use in the treatment of diseases such as cancer are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 494,364, filed April 5, 2023, U.S. Provisional Patent Application No. 63 / 444,828, filed February 10, 2023, and U.S. Provisional Patent Application No. 63 / 404,567, filed September 8, 2022, the contents of each of which are incorporated herein by reference.

[0002] The present invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in the treatment of diseases such as cancer. [Background technology]

[0003] Cancer remains a significant health problem despite significant research efforts and scientific advances reported in the literature to treat this disease. Solid tumors, including prostate, breast, and lung cancer, remain widely prevalent among the world's population. The incidence of prostate cancer increases with age, and as human lifespans increase, the number of patients suffering from prostate cancer continues to correspondingly increase. Breast cancer is one of the most common cancers among women and is the leading cause of death among women aged 50-55. Lung cancer is the leading cause of death among cancer patients, with more than 85% of lung cancers being non-small cell lung cancer (NSCLC). Many lung cancers are caused by tobacco smoking. Current treatment options for these cancers are not effective for all patients and / or may have significant adverse side effects.

[0004] New therapies are needed to address this unmet need in cancer therapy. In particular, new therapies that achieve anti-cancer effects through mechanisms different from those of commonly available therapies are needed. Exemplary mechanisms of common anti-cancer therapies include (a) DNA alkylation, which limits a cell's ability to reproduce; (b) topoisomerase inhibition, in which a therapeutic agent inhibits the activity of topoisomerase, thereby limiting DNA strand separation; and (c) mitotic inhibition, in which a therapeutic agent reduces a cell's ability to divide. New therapies that achieve anti-cancer effects through different mechanisms offer opportunities to treat cancer more effectively and / or to treat cancers that have become resistant to currently available drugs.

[0005] The present invention addresses the above-mentioned needs and provides other related advantages. Summary of the Invention

[0006] The present invention provides heterobifunctional compounds, pharmaceutical compositions, and their uses in the treatment of diseases such as cancer. In particular, one aspect of the present invention is a collection of heterobifunctional compounds, such as compounds represented by Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional sets of heterobifunctional compounds is provided in the detailed description. The compound can be part of a pharmaceutical composition that includes a pharmaceutically acceptable carrier.

[0007] Another aspect of the present invention is a collection of heterobifunctional compounds, such as compounds represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional sets of heterobifunctional compounds is provided in the detailed description. The compound can be part of a pharmaceutical composition that includes a pharmaceutically acceptable carrier.

[0008] Another aspect of the present invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or II, to treat the cancer.

[0009] Another aspect of the invention provides a method for inducing cancer cell death, comprising contacting the cancer cell with an effective amount of a compound described herein, e.g., a compound of Formula I or II, to induce cancer cell death. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a graph showing the dose-response curve of cell viability for compound I-49 in two cell lines, LnCap95 parental cells and LnCap95AR-FL KO cells.

[0011] [Figure 2] 1 is a graph showing the dose-response curve of cell viability for compound I-49 and compound I-50 in LnCap95 parental cells.

[0012] [Figure 3] 1 is a graph showing the dose-response curve of relative caspase 3 / 7 activity of compound I-49 in two cell lines, 22RV1 parental (FL-AR high) and 22RV1 parental (FL-AR low).

[0013] [Figure 4] 1 is a graph showing dose-response curves of relative caspase 3 / 7 activity for compound I-49 and compound I-50 in 22RV1 parental (FL-AR high) cells.

[0014] [Figure 5] 1 is a graph showing the dose-response curve of relative total gene X mRNA for compound I-49 in TReX293 cells in the presence and absence of doxycycline.

[0015] [Figure 6] 1 is a graph showing tumor growth curves for compound I-49-treated mice, enzalutimide-treated mice, and vehicle-treated mice in arm 1 of the Aramp, V7+castrated VcaP model.

[0016] [Figure 7] 1 is a graph showing tumor growth curves for compound I-49-treated mice, enzalutimide-treated mice, and vehicle-treated mice in arm 2 of the Aramp, V7+castrated VcaP model.

[0017] [Figure 8] 1 is a graph showing the relative total gene X mRNA present in tumors harvested at the end of the PK / PD Aramp, V7+castrated VcaP model described above for various doses of compound I-49 treatment.

[0018] [Figure 9] FIG. 1 is a graph showing relative total gene X mRNA present in tumors harvested at the end of the PK / PD Aramp, V7+castrated VcaP model described above with compound I-49 and compound I-50 treatment.

[0019] [Figure 10] 1 is a graph showing plasma PSA concentrations at various compound I-49 doses for samples collected from arm 1 of the castrated VcaP tumor xenograft model described above.

[0020] [Figure 11] 1 is a graph showing plasma PSA concentrations at various compound I-49 doses for samples collected from arm 2 of the castrated VcaP tumor xenograft model described above.

[0021] [Figure 12] 1 is a graph showing the dose-response curves of the relative in vitro ternary complex formation of compound I-49 versus free AR and free EP ligands.

[0022] [Figure 13] 1 is a graph showing the dose-response curve of the relative in vitro ternary complex formation of compound I-49 versus compound I-50.

[0023] [Figure 14] FIG. 1 is a graph showing the relative ternary complex formation present with various doses of compound I-49 treatment in samples collected at the end of the PK / PD castrated VCaP tumor xenograft model.

[0024] [Figure 15] FIG. 1 is a graph showing the relative ternary complex formation present with compound I-49 treatment in samples collected from arm 2 of a castrated VCaP tumor xenograft model.

[0025] [Figure 16] FIG. 1 is a graph showing the relative ternary complex formation present with compound I-49 and compound I-50 treatment in samples collected at the end of the PK / PD castrated VCaP tumor xenograft model. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in the treatment of diseases such as cancer. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are described in such references as "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992), "Handbook of Experimental Immunology" (D.M. Weir & C.C. Blackwell, eds.), "Current Protocols in Molecular Biology" (F.M. Ausubel et al., eds., 1987, and periodically updated), and "Current Protocols in Immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0027] Various aspects of the present invention are described in the following sections, but aspects of the present invention described in a particular section are not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of the variable takes precedence.

[0028] definition The compounds of the present invention include those described generally herein and are further illustrated by the classes, subclasses, and genera disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" and "-O-alkyl," etc. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thAdditionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0029] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "alicyclic"), and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0030] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated, or having one or more unsaturated units, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junctions, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain or valence bond of atoms (or atoms) connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka]

[0031] Exemplary bridged bicyclic compounds include the following: [ka]

[0032] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0033] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0034] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0035] The term "unsaturated" as used herein means that a moiety has one or more units of unsaturation.

[0036] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched as defined herein.

[0037] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0038] The term "-(C alkylene)-" refers to a bond. 0-3 The term "alkylene)-" refers to a bond (i.e., C) and a -(C 1-3 alkylene)-groups.

[0039] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0040] The term "halogen" means F, Cl, Br, or I.

[0041] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused with one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, etc.). The term "haloaryl" refers to an aryl group substituted with at least one halogen. Exemplary haloaryl groups include chlorophenyl (e.g., 3-chlorophenyl, 4-chlorophenyl), fluorophenyl, and the like. The term "phenylene" refers to a divalent phenyl group.

[0042] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted.The term "haloheteroaryl" refers to a heteroaryl group substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, and the like. The term "heteroarylene" refers to a divalent heteroaryl group. Similarly, the terms "pyrazolylene," "imidazolylene," and "pyrrolylene" refer to divalent pyrazolyl, imidazolyl, and pyrrolyl groups, respectively. Similarly, the terms "pyridazinylene," "pyrimidinylene," "pyrazinylene," and "pyridinylene" refer to divalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl groups, respectively.

[0043] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may also be NR (as in N-substituted pyrrolidinyl).

[0044] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted. The term "heterocyclylene" refers to a divalent heterocyclyl group. The terms "piperidinylene," "piperazinylene," and "azetidinylene" refer to divalent piperidinyl, piperazinyl, and azetidinyl groups, respectively.

[0045] As used herein, the term "heterocycloalkyl" refers to a saturated heterocyclyl. The term "heterocycloalkylene" refers to a divalent heterocycloalkyl group.

[0046] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0047] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at each and every position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0048] Each optional substitution on a substitutable carbon is independently selected from halogen, -(CH) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, R° may be substituted -(CH2) 0-4 Ph, R° may be substituted -(CH2) 0-4 O(CH2) 0-1 Ph, may be substituted with R° -CH=CHPh, may be substituted with R° -(CH 0-4O(CH2) 0-1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR-, SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -S(O)(NR°)R°, -S(O)2N=C(NR°2)2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1-4 linear or branched alkylene)ON(R°)2, or -(C 1-4 A monovalent substituent selected from the group consisting of straight-chain or branched alkylene)C(O)ON(R°)2.

[0049] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted on a saturated carbon atom of R° by a divalent substituent selected from =O and =S; or each R° is selected from halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent independently selected from

[0050] Each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, is substituted with one or more halogens only, or the optional substituents on the saturated carbon are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 or the divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of represents hydrogen, C 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] R * C 1-6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, substituted only with one or more halogens.

[0052] The optional substituents on the substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R † two independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † C 1-6 If aliphatic, R † is optionally a halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● independently, C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by halo, substituted with one or more halogens only.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Acid salts include, for example, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0054] Additionally, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33-201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on its website). The disclosures of these publications are incorporated herein by reference.

[0055] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0056] Unless otherwise specified, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. The compounds of the invention include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the structures of the present invention that include the replacement of a carbon with a C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0057] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Still further, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereoisomers so formed by fractional crystallization or chromatographic means known in the art, and then recovery of the pure enantiomers.

[0058] Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate or with all or selected other stereoisomers. The chiral center(s) in the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered to be part of the present invention.

[0059] Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. When a chemical compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure takes precedence. Also, note that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have a sufficient number of hydrogen atoms (or atoms) to satisfy the valences.

[0060] As used herein, the words "a" and "an" mean "one or more" and include plurals unless the context is inappropriate.

[0061] The term "alkyl" as used herein refers to C-C 12 Alkyl, C1-C 10Alkyl refers to saturated straight or branched hydrocarbons, such as straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, referred to as C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0062] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, e.g., derived from cycloalkane, designated "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0063] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, and the like. The term "chloroalkyl" refers to an alkyl group substituted with at least one chloro. The term "bromoalkyl" refers to an alkyl group substituted with at least one bromo. The term "haloalkylene" refers to a divalent haloalkyl group.

[0064] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CHCHOH, -C(H)(OH)CH, -CHC(H)(OH)CHCHOH, and the like.

[0065] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH, -CHOCH, -CHCHN(CH), and -CHCHOH. A heteroalkyl group can contain, for example, 2 to 4, 2 to 6, or 2 to 8 atoms selected from the group consisting of carbon and heteroatoms (e.g., N, O, or S). The phrase 3- to 8-membered heteroalkyl refers to a heteroalkyl group having 3 to 8 atoms selected from the group consisting of carbon and heteroatoms. The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0066] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond, respectively. The term "haloalkenyl" refers to an alkenyl group substituted with at least one halogen. The term "fluoroalkenyl" refers to an alkenyl group substituted with at least one fluoro. The term "nitroalkenyl" refers to an alkenyl group substituted with at least one nitro.

[0067] The term "carbocyclylene" refers to a divalent alicyclic radical.

[0068] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCHF, -OCHF, -OCF, -OCHCF, -OCFCF, and the like.

[0069] The term "oxo" is art-recognized and refers to an "=O" substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0070] The term "amino" is art-recognized and refers to both unsubstituted and substituted amines, for example, amines of the general formula: [ka] where R 50 , R 51 , R 52 and R 53 are each independently hydrogen, alkyl, alkenyl, -(CH2) m -R 61 or R 50 and R 51 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, and R 61 represents a 3- to 7-membered cycloalkyl, a 4- to 7-membered cycloalkenyl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered heterocyclyl; and m is zero or an integer ranging from 1 to 8.

[0071] The term "amide" is art-recognized and includes both unsubstituted and substituted amides, for example, amides of the general formula: [ka] where R 50 and R 51 are each independently hydrogen, alkyl, alkenyl, -(CH2) m -R 61 or R 50 and R 51 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, and R 61 represents a 3- to 7-membered cycloalkyl, a 4- to 7-membered cycloalkenyl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered heterocyclyl; m is zero or an integer ranging from 1 to 8; R 52 is alkyl, alkenyl, or -(CH2) m -R 61 is.

[0072] symbol [ka] indicates the point of attachment.

[0073] When any substituent or variable occurs more than one time in any constituent or compound of the present invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0074] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" refers to a solvate in which the solvent molecule is HO.

[0075] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0076] "I C 50 The term "concentration of a compound" is art-recognized and refers to the concentration of a compound needed to achieve 50% inhibition of a target.

[0077] As used herein, the term "effective amount" refers to an amount of a compound sufficient to achieve a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., alleviating, reducing, modulating, ameliorating, or eliminating, or alleviating the symptoms thereof.

[0078] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0079] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0080] Salts of the compounds of the invention are contemplated to be pharmaceutically acceptable for therapeutic use. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0081] Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, it may form zwitterions ("internal salts"). As used within the scope of the present invention, such acid and base salts are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the present invention may be formed, for example, by reacting the compound of the present invention with an amount, e.g., an equivalent amount, of acid or base in a medium such that the salt precipitates, or in an aqueous medium that is subsequently lyophilized.

[0082] Throughout this specification, when compositions are described as having, including, or comprising specific components, or processes and methods are described as having, including, or comprising specific steps, it is additionally contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0083] Generally, compositions specifying percentages are by weight unless otherwise specified.

[0084] I. Heterobifunctional Compounds One aspect of the present invention provides heterobifunctional compounds. The compounds can be used in the pharmaceutical compositions and treatment methods described herein. Exemplary compounds are described in the following section, along with exemplary procedures for making the compounds. Without being bound by theory, the compounds may promote therapeutic effects by binding to both the androgen receptor and BRD4 (bromodomain-containing protein 4).

[0085] Part A: Compounds of Formula I One aspect of the present invention is a compound represented by formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is cyano, halogen, and R 4 is phenyl substituted by m occurrences of R 2 independently for each occurrence, C 1-4 represents alkyl, R 3 is hydrogen or C 1-4 is alkyl, R 4 is C 1-4 is alkyl, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R 5 One occurrence of R 3 Together with C 1-3 Forming an alkylene A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 is replaced by n occurrences of A 2 is one of the following: [ka] R 1A is C 1-4 Alkyl or C3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 9A is a halo, R 10A independently for each occurrence, C 1-4 Alkyl or -N(R 11A )2, R 11A is, independently at each occurrence, a halogen or C 1-4 represents alkyl, R 12A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; L is a linker, k is 1, 2, 3, or 4; m, n, p, and q are independently 0, 1, or 2; s is 1 or 2.

[0086] The definitions of the variables in Formula I above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0087] In certain embodiments, the compound is a compound of Formula I:

[0088] As generally defined above, R 1 is cyano, halogen, and R 4In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, chloro, and R 4 In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0089] As generally defined above, R 2 independently for each occurrence, C 1-4 In certain embodiments, R 2 is C 1-2 In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0090] As generally defined above, R 3 is hydrogen or C 1-4 In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 1 below.

[0091] As generally defined above, R 4 is C 1-4 In certain embodiments, R 4 is CH3. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0092] As generally defined above, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is halogen. In certain embodiments, R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0093] As generally defined above, A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 In certain embodiments, A is substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyridazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with n occurrences of1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 is R 5 In certain embodiments, A is a pyrazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyridinylene substituted with n occurrences of 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with 0 occurrences of 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0094] As generally defined above, A 2 teeth, [ka] is.

[0095] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] is.

[0096] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] wherein q is 1. In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 is one of the following: [ka]

[0097] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0098] As generally defined above, R 1A is C 1-4 Alkyl or C 3-4 In certain embodiments, R 1A is C 1-4 In certain embodiments, R is alkyl. In certain embodiments, R is methyl. 1A is C 3-4 In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0099] As generally defined above, R 2A independently for each occurrence, C 1-4Alkyl or C 3-4 In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is C 3-4 In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0100] As generally defined above, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C-C alkyl, or C-C haloalkyl; and in certain embodiments, R 3A is phenyl substituted with halo. In certain embodiments, R 3A is phenyl substituted with one substituent selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with two substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with three substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is selected from the groups depicted in the compounds of Table 1 below.

[0101] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6alkylene)-CN, -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A In certain embodiments, R 4A is -(C 1-6 (Alkylene)-CO2R 8A In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In certain embodiments, R 4A is -(C 1-6 (alkylene)-OC(O)R 7A In certain embodiments, R 4A is -(C 1-6 In certain embodiments, R 4A is -(C 1-6 alkylene)-O-(C 1-6 In certain embodiments, R 4A is C 1-6 In certain embodiments, R 4A is C 3-6 In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl.4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 alkylene)-(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1 below.

[0102] As generally defined above, R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are independently hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 In certain embodiments, R 5A is C 3-6 In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 In certain embodiments, R 6A is C 3-6 In certain embodiments, R 5A and R 6Aare taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a three-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a four-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a five-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a six-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a seven-membered ring containing one nitrogen atom. 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0103] As generally defined above, R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 7A is C 1-6 In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 7A is C 3-6 In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0104] As generally defined above, R 8A is hydrogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 8A is hydrogen. In certain embodiments, R 8A is C 1-6 In certain embodiments, R 8A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 8A is C 3-6 In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0105] As generally defined above, R 9A is halo. In certain embodiments, R 9A is fluoro, chloro, or bromo. 9A is fluoro. In certain embodiments, R 9A is selected from the groups depicted in the compounds of Table 1 below.

[0106] As generally defined above, R 10A independently for each occurrence, C 1-4 Alkyl or -N(R 11A )2. In certain embodiments, R 10A is C 1-4 In certain embodiments, R 10A is N(R 11A )2. In certain embodiments, R 10A is N(H)CH. In certain embodiments, R 10A is selected from the groups depicted in the compounds of Table 1 below.

[0107] As generally defined above, R 11Ais independently hydrogen or C at each occurrence. 1-4 In certain embodiments, R 11A independently for each occurrence, C 1-4 In certain embodiments, R 11A is hydrogen. In certain embodiments, R 11A is C 1-4 In certain embodiments, R 11A is independently at each occurrence hydrogen or methyl. In certain embodiments, R 11A is selected from the groups depicted in the compounds of Table 1 below.

[0108] As generally defined above, R 12A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 12A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 12A is -(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R 12A is oxazolyl. In certain embodiments, R 12A is selected from the groups depicted in the compounds of Table 1 below.

[0109] As generally defined above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0110]

[0033] As generally defined above, m, n, p, and q are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, p is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, m is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, q is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0111] As generally defined above, s is 1 or 2. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0112] In certain embodiments, the compound of formula I is further defined by formula Ia, or a pharmaceutically acceptable salt thereof: [ka] In certain embodiments, the variable R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with formula I.

[0113] In certain embodiments, the compound of formula I is further defined by formula Ib, or a pharmaceutically acceptable salt thereof: [ka] In certain embodiments, the variable R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with formula I.

[0114] In certain embodiments, the compound of Formula I is further defined by Formula Ic, or a pharmaceutically acceptable salt thereof: [ka] In one particular embodiment, the variable A 1 and A 2 is one of the embodiments described above in connection with formula I.

[0115] In certain embodiments, the compound of formula I is further defined by formula Id, or a pharmaceutically acceptable salt thereof: [ka] In one particular embodiment, the variable A 1 and A 2 is one of the embodiments described above in connection with formula I.

[0116] In certain embodiments, the compound is of formula Ie, or a pharmaceutically acceptable salt thereof: [ka] wherein L is (i) Ψ-(an 8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie, or (ii) a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocycle is 1-4 Substituted with 0 or 1 occurrence of alkyl.

[0117] In certain embodiments, L is Ψ-(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie. In certain embodiments, L is Ψ-(9 membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie.

[0118] In certain embodiments, L is a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen. In certain embodiments, L is a 10 membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen.

[0119] In certain embodiments, the compound is of formula If, or a pharmaceutically acceptable salt thereof: [ka]

[0120] In certain embodiments, the compound is of formula Ig, or a pharmaceutically acceptable salt thereof: [ka]

[0121] In certain embodiments, the compound is of formula Ih, or a pharmaceutically acceptable salt thereof: [ka] wherein L is (i) Ψ-(an 8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie, or (ii) a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocycle is 1-4 Substituted with 0 or 1 occurrence of alkyl.

[0122] In certain embodiments, L is Ψ-(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ih. In certain embodiments, L is Ψ-(9 membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ih.

[0123] In certain embodiments, L is a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen. In certain embodiments, L is a 10 membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen.

[0124] In certain embodiments, the compound is of formula Ii, or a pharmaceutically acceptable salt thereof: [ka]

[0125] In certain embodiments, the compound is of formula Ij, or a pharmaceutically acceptable salt thereof: [ka]

[0126] The compounds can be further characterized, for example, according to the identity of L. Further exemplary embodiments of L are provided in Part C below.

[0127] Part A-1: ​​Compound of Formula I-1 One aspect of the present invention is a compound represented by formula I-1: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is cyano, halogen, and R 4 is phenyl substituted by m occurrences of R 2 independently for each occurrence, C 1-4 represents alkyl, R 3 is hydrogen or C 1-4 is alkyl, R 4 is C 1-4 is alkyl, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 is replaced by n occurrences of A 2 is one of the following: [ka] R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , or -(C 0-6 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, L is a linker, k is 1, 2, 3, or 4; m, n, and p are independently 0, 1, or 2.

[0128] The definitions of the variables in Formula I above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0129] In certain embodiments, the compound is a compound of Formula I:

[0130] As generally defined above, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, chloro, and R 4 In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0131] As generally defined above, R 2 independently for each occurrence, C 1-4 In certain embodiments, R 2 is C 1-2 In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0132] As generally defined above, R 3 is hydrogen or C 1-4 In certain embodiments, R 3is hydrogen. In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 1 below.

[0133] As generally defined above, R 4 is C 1-4 In certain embodiments, R 4 is CH3. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0134] As generally defined above, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0135] As generally defined above, A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 In certain embodiments, A is substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyridazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with n occurrences of 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 is R 5 In certain embodiments, A is a pyrazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyridinylene substituted with n occurrences of 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with 0 occurrences of 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0136] As generally defined above, A 2 teeth, [ka] is

[0137] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] is.

[0138] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0139] As generally defined above, R 1A is C 1-4 Alkyl or C 3-4 In certain embodiments, R 1A is C 1-4 In certain embodiments, R is alkyl. In certain embodiments, R is methyl. 1A is C 3-4 In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0140] As generally defined above, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2Ais methyl. In certain embodiments, R 2A is C 3-4 In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0141] As generally defined above, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with halo. In certain embodiments, R 3A is phenyl substituted with one substituent selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with two substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with three substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is selected from the groups depicted in the compounds of Table 1 below.

[0142] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-6alkylene)-C(O)N(R 5A )(R 6A In certain embodiments, R 4A is -(C 1-6 (Alkylene)-CO2R 8A In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In certain embodiments, R 4A is -(C 1-6 (alkylene)-OC(O)R 7A In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 alkylene)-(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1 below.

[0143] As generally defined above, R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are independently hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C1-6 In certain embodiments, R 5A is C 3-6 In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 In certain embodiments, R 6A is C 3-6 In certain embodiments, R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a three-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a four-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a five-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a six-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a seven-membered ring containing one nitrogen atom. 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0144] As generally defined above, R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6In certain embodiments, R 7A is C 1-6 In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 7A is C 3-6 In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0145] As generally defined above, R 8A is hydrogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 8A is hydrogen. In certain embodiments, R 8A is C 1-6 In certain embodiments, R 8A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 8A is C 3-6 In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0146] As generally defined above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0147] As generally defined above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, t is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, p is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, m is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0148] In certain embodiments, the compound of formula I-1 is further defined by formula Ia-1, or a pharmaceutically acceptable salt thereof: [ka] In certain embodiments, the variable R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with formula I.

[0149] In certain embodiments, the compound of formula I is further defined by formula Ib-1, or a pharmaceutically acceptable salt thereof: [ka] In certain embodiments, the variable R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with formula I-1.

[0150] In certain embodiments, the compound of Formula I is further defined by Formula Ic, or a pharmaceutically acceptable salt thereof: [ka] In one particular embodiment, the variable A 1 and A 2 is one of the embodiments described above in connection with formula I-1.

[0151] In certain embodiments, the compound of formula I is further defined by formula 1d-1, or a pharmaceutically acceptable salt thereof: [ka] In one particular embodiment, the variable A 1 and A 2 is one of the embodiments described above in connection with formula I-1.

[0152] The compounds can be further characterized, for example, according to the identity of L. Further exemplary embodiments of L are provided in Part C below.

[0153] Part A-2: Compounds of formula I* Another aspect of the present invention is a compound represented by formula I*: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is cyano, halogen, and R 4 is phenyl substituted by m occurrences of R 2 independently for each occurrence, C 1-4 represents alkyl, R 3 is hydrogen or C 1-4 is alkyl, R 4 is C 1-4 is alkyl, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R5 One occurrence of R 3 Together with C 1-3 Forming an alkylene A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 is replaced by n occurrences of A 2 teeth, [ka] and R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is C 1-6 Hydroxyalkyl, C 1-4 Haloalkyl, -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 9A is a halo, R 10A is hydrogen or C 1-4 alkyl or R 4A and R 10A together with the carbon atoms to which they are attached form a 3- to 5-membered saturated carbocyclic ring, L is a linker, k is 1, 2, 3, or 4; m, n, p, and q are independently 0, 1, or 2.

[0154] The definitions of the variables in formula I* above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0155] In certain embodiments, the compound is of formula I*.

[0156] As generally defined above, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, chloro, and R 4 In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0157] As generally defined above, R 2 independently for each occurrence, C 1-4 In certain embodiments, R 2 is C 1-2 In certain embodiments, R 2is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0158] As generally defined above, R 3 is hydrogen or C 1-4 In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 1 below.

[0159] As generally defined above, R 4 is C 1-4 In certain embodiments, R 4 is CH3. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0160] As generally defined above, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is halogen. In certain embodiments, R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0161] As generally defined above, A1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 In certain embodiments, A is substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyridazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with n occurrences of 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1 is R 5 In certain embodiments, A is a pyrazinylene substituted with n occurrences of 1 teeth, [ka] In certain embodiments, A 1 is R 5 In certain embodiments, A is pyridinylene substituted with n occurrences of 1 is R 5 In certain embodiments, A is pyrimidinylene substituted with 0 occurrences of 1 teeth, [ka] where ** is the point of attachment to L. In certain embodiments, A 1is selected from the groups depicted in the compounds of Table 1 below.

[0162] In certain embodiments, A 2 is one of the following: [ka]

[0163] As generally defined above, R 1A is C 1-4 Alkyl or C 3-4 In certain embodiments, R 1A is C 1-4 In certain embodiments, R is alkyl. In certain embodiments, R is methyl. 1A is C 3-4 In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0164] As generally defined above, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is C 3-4 In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0165] As generally defined above, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with halo. In certain embodiments, R 3Ais phenyl substituted with one substituent selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with two substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with three substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is selected from the groups depicted in the compounds of Table 1 below.

[0166] As generally defined above, R 4A is C 1-6 Hydroxyalkyl, C 1-4 Haloalkyl, -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A In certain embodiments, R 4A is -(C 1-6(Alkylene)-CO2R 8A In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In certain embodiments, R 4A is -(C 1-6 (alkylene)-OC(O)R 7A In certain embodiments, R 4A is -(C 1-6 In certain embodiments, R 4A is -(C 1-6 alkylene)-O-(C 1-6 In certain embodiments, R 4A is C 1-6 In certain embodiments, R 4A is C 3-6 In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 alkylene)-(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 In certain embodiments, R 4A is C 1-6 In certain embodiments, R 4A is C 1-4In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1 below.

[0167] As generally defined above, R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are independently hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 In certain embodiments, R 5A is C 3-6 In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 In certain embodiments, R 6A is C 3-6 In certain embodiments, R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a three-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a four-membered ring containing one nitrogen atom. 5A and R 6Aare taken together with the nitrogen atom to which they are attached to form a five-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a six-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a seven-membered ring containing one nitrogen atom. 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0168] As generally defined above, R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 7A is C 1-6 In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 7A is C 3-6 In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0169] As generally defined above, R 8A is hydrogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 8A is hydrogen. In certain embodiments, R 8A is C 1-6 In certain embodiments, R 8A is -(C1-6 alkylene)-(C 3-6 In certain embodiments, R 8A is C 3-6 In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0170] As generally defined above, R 9A is halo. In certain embodiments, R 9A is fluoro, chloro, or bromo. 9A is fluoro. In certain embodiments, R 9A is selected from the groups depicted in the compounds of Table 1 below.

[0171] As generally defined above, R 10A is hydrogen or C 1-4 alkyl or R 4A and R 10A together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. 10A is hydrogen. In certain embodiments, R 10A is C 1-4 In certain embodiments, R 4A and R 10A together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. 4A and R 10A together with the carbon atoms to which they are attached form a three-membered saturated carbocyclic ring. 10A is selected from the groups depicted in the compounds of Table 1 below.

[0172] As generally defined above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0173] As generally defined above, m, n, p, and q are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, p is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, m is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, n is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below. In certain embodiments, q is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0174] The compounds can be further characterized, for example, according to the identity of L. Further exemplary embodiments of L are provided in Part C below.

[0175] Part B: Compound of Formula II Another aspect of the present invention is a compound represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: TPL is R II-1Ais a group defined by formula II-1 substituted by one occurrence of [ka] wherein: R II-1A is the bond to L, R 1 is cyano, halogen, and R 4 is phenyl substituted by m occurrences of R 2 independently for each occurrence, C 1-4 represents alkyl, R 3 is hydrogen or C 1-4 is alkyl, R 4 is C 1-4 is alkyl, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R 5 One occurrence of R 3 Together with C 1-3 Forming an alkylene A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 is replaced by n occurrences of L is a linker, EPL is the moiety that binds to BRD4, k is 1, 2, 3, or 4; m and n are independently 0, 1, or 2.

[0176] The definitions of the variables in Formula II above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0177] In certain embodiments, the compound is a compound of formula II.

[0178] As generally defined above, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, halogen, and R 4 In certain embodiments, R 1 is cyano, Cl, and R 4 In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0179] As generally defined above, R 2 independently for each occurrence, C 1-4 In certain embodiments, R 2 is C 1-2 In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0180] As generally defined above, R 3 is hydrogen or C 1-4 In certain embodiments, R 3is hydrogen. In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 1 below.

[0181] As generally defined above, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, or R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is halogen. In certain embodiments, R 5 One occurrence of R 3 Together with C 1-3 In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0182] As generally defined above, A 1 is pyridazinyl, pyrimidinyl, pyrazinyl, or pyridinyl, each of which is R 5 In certain embodiments, A is substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyridazinyl substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyrimidinyl substituted with n occurrences of 1 is R 5 In certain embodiments, A is a pyrazinyl substituted with n occurrences of 1 is R 5 In certain embodiments, A is pyridinyl substituted with n occurrences of 1is selected from the groups depicted in the compounds of Table 1 below.

[0183] As generally defined above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0184] As generally defined above, m and n are independently 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the corresponding values ​​of the groups depicted for the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding values ​​of the groups depicted for the compounds in Table 1 below.

[0185] In certain embodiments, the TPL is R II-1A replaced by one occurrence of [ka] is.

[0186] In certain embodiments, the TPL is R II-1A replaced by one occurrence of [ka] In certain embodiments, the TPL is [ka] In certain embodiments, the TPL is [ka] is.

[0187] In certain embodiments, the EPL is R II-2A and Formula II-2 is defined by Formula II-2, which is substituted by one occurrence of [ka] wherein: R II-2A is the bond to L, R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , or -(C 0-6 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7Ais C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, p is 0, 1, or 2.

[0188] In certain embodiments, the EPL is R II-2A and Formula II-2 is defined by Formula II-2, which is substituted by one occurrence of [ka] wherein: R II-2A is the bond to L, R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6 alkylene)-CN, -(C1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 9A is a halo, R 10A independently for each occurrence, C 1-4 Alkyl or -N(R 11A )2, R 11A is, independently at each occurrence, a halogen or C 1-4 represents alkyl, R 12A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-65-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; p and q are independently 0, 1, or 2; s is 1 or 2.

[0189] In certain embodiments, the EPL is [ka] and each of these is R II-2A is replaced by one occurrence of R II-2A is the bond to L.

[0190] In certain embodiments, the EPL is [ka] and each of these is R II-2A is replaced by one occurrence of R II-2A is the bond to L.

[0191] In certain embodiments, the EPL is one of the following: [ka] R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R7A , -(C 1-6 (Alkylene)-CO2R 8A , or -(C 1-6 (alkylene)-OC(O)R 7A and R 5A and R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, p is 0, 1, or 2.

[0192] In certain embodiments, the EPL is [ka] In certain embodiments, the EPL is [ka] is.

[0193] In certain embodiments, the EPL is [ka] In certain embodiments, the EPL is [ka] is.

[0194] In certain embodiments, the EPL is [ka] In certain embodiments, the EPL is [ka] is.

[0195] As generally defined above, R 1A is C 1-4 Alkyl or C 3-4 In certain embodiments, R 1A is C 1-4 In certain embodiments, R is alkyl. In certain embodiments, R is methyl. 1A is C 3-4 In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1 below.

[0196] As generally defined above, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is C 3-4 In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1 below.

[0197] As generally defined above, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3Ais phenyl substituted with halo. In certain embodiments, R 3A is phenyl substituted with one substituent selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with two substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is phenyl substituted with three substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. 3A is selected from the groups depicted in the compounds of Table 1 below.

[0198] As generally defined above, R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , -(C 1-6 alkylene)-CN, -(C 1-6 alkylene)-O-(C 1-6 alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A In certain embodiments, R 4A is -(C 1-6(Alkylene)-CO2R 8A In certain embodiments, R 4A is -(C 1-6 alkylene)-N(R 5A )C(O)R 7A In certain embodiments, R 4A is -(C 1-6 (alkylene)-OC(O)R 7A In certain embodiments, R 4A is -(C 1-6 In certain embodiments, R 4A is -(C 1-6 alkylene)-O-(C 1-6 In certain embodiments, R 4A is C 1-6 In certain embodiments, R 4A is C 3-6 In certain embodiments, R 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 4A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 alkylene)-(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4A is -(C 1-3 In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1 below.

[0199] As generally defined above, R 5Aand R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are independently hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-6 In certain embodiments, R 5A is C 3-6 In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 In certain embodiments, R 6A is C 3-6 In certain embodiments, R 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a three-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a four-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a five-membered ring containing one nitrogen atom. 5A and R 6A are taken together with the nitrogen atom to which they are attached to form a six-membered ring containing one nitrogen atom. 5A and R 6Aare taken together with the nitrogen atom to which they are attached to form a seven-membered ring containing one nitrogen atom. 5A is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 6A is selected from the groups depicted in the compounds of Table 1 below.

[0200] As generally defined above, R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 7A is C 1-6 In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 7A is C 3-6 In certain embodiments, R 7A is selected from the groups depicted in the compounds of Table 1 below.

[0201] As generally defined above, R 8A is hydrogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 In certain embodiments, R 8A is hydrogen. In certain embodiments, R 8A is C 1-6 In certain embodiments, R 8A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 8A is C 3-6 In certain embodiments, R 8A is selected from the groups depicted in the compounds of Table 1 below.

[0202] As generally defined above, R 9A is halo. In certain embodiments, R 9A is fluoro, chloro, or bromo. 9A is fluoro. In certain embodiments, R 9A is selected from the groups depicted in the compounds of Table 1 below.

[0203] As generally defined above, R 10A independently for each occurrence, C 1-4 Alkyl or -N(R 11A )2. In certain embodiments, R 10A is C 1-4 In certain embodiments, R 10A is N(R 11A )2. In certain embodiments, R 10A is N(H)CH. In certain embodiments, R 10A is selected from the groups depicted in the compounds of Table 1 below.

[0204] As generally defined above, R 11A is independently hydrogen or C at each occurrence. 1-4 In certain embodiments, R 11A independently for each occurrence, C 1-4 In certain embodiments, R 11A is hydrogen. In certain embodiments, R 11A is C 1-4 In certain embodiments, R 11A is independently at each occurrence hydrogen or methyl. In certain embodiments, R 11A is selected from the groups depicted in the compounds of Table 1 below.

[0205] As generally defined above, R 12A is -(C 0-6alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein heteroaryl is C 1-6 In certain embodiments, R is a 5-6 membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl. 12A is -(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 12A is -(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, R 12A is oxazolyl. In certain embodiments, R 12A is selected from the groups depicted in the compounds of Table 1 below.

[0206] In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, p is selected from the corresponding values ​​of the groups depicted for the compounds in Table 1 below. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the corresponding values ​​of the groups depicted for the compounds in Table 1 below.

[0207] In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is selected from the corresponding values ​​of the groups depicted in the compounds of Table 1 below.

[0208] In certain embodiments, the EPL is a group selected from the group consisting of the variable A described above in connection with Formula I. 2 In certain embodiments, the EPL is defined by the variable A described in connection with formula I. 2 as defined by one or more of the embodiments.

[0209] The compounds can be further characterized, for example, according to the identity of L. Further exemplary embodiments of L are provided in Part C below.

[0210] Part C: Exemplary Further Description of the Linker (L) Moiety of Compounds of Formula I and II The compounds of Formulas I and II can be further characterized, for example, according to the identity of the linker (L) component. A variety of linkers are known to those of skill in the art and can be used in the heterobifunctional compounds described herein. For example, in certain embodiments, L comprises one or more optionally substituted groups selected from an amino acid, a polyether chain, an aliphatic group, and any combination thereof. In certain embodiments, L consists of one or more optionally substituted groups selected from an amino acid, a polyether chain, an aliphatic group, and any combination thereof. In certain embodiments, L consists of one or more groups selected from an amino acid, a polyether chain, an aliphatic group, and any combination thereof.

[0211] In some embodiments, L is symmetric. In some embodiments, L is asymmetric. In certain embodiments, L is a bond.

[0212] In certain embodiments, L is a covalent bond or a divalent C 1-30 A saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1 to 15 methylene units of L are optionally and independently selected from cyclopropylene, -N(H)-, -N(C 1-4 alkyl)-, -N(C 3-5 cycloalkyl)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-4 alkyl)-, -S(O)N(C 3-5 cycloalkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -N(C 3-5 Cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-4alkyl)-, -C(O)N(C 3-5 cycloalkyl), phenylene, 8-10-membered bicyclic arylene, 4-7-membered saturated or partially unsaturated carbocyclylene, 8-10-membered bicyclic saturated or partially unsaturated carbocyclylene, 3-7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10-membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0213] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-60 a hydrocarbon chain in which 0 to 20 methylene units of the hydrocarbon are independently replaced by -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R**)S(O)2-, -S(O)2N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R** at each occurrence is independently selected from hydrogen, C 1-6 Alkyl, or C 3-6 represents cycloalkyl.

[0214] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-60 A hydrocarbon chain in which 0 to 20 methylene units of the hydrocarbon are independently -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O—, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0215] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-60 A hydrocarbon chain in which 0 to 20 methylene units of the hydrocarbon are independently -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O-, -N(C 3-7 cycloalkyl)-, an optionally substituted 3- to 10-membered carbocyclyl, or an optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0216] In certain embodiments, L is a divalent saturated straight-chain or branched C 3-30A hydrocarbon chain in which 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, a 3- to 10-membered carbocyclyl, or a 3- to 10-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0217] In certain embodiments, L is a divalent saturated straight-chain or branched C 3-30 A hydrocarbon chain in which 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-6 is replaced by alkyl.

[0218] In still other embodiments, L comprises a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. In still other embodiments, L is a diradical of a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units.

[0219] In certain embodiments, L is a heteroalkylene having 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, L is heteroalkylene having 4 to 10 atoms selected from carbon and oxygen.

[0220] In additional embodiments, L is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to about 10 ethylene glycol units, 1 to about 8 ethylene glycol units, 1 to about 6 ethylene glycol units, 2 to about 4 ethylene glycol units, or an optionally substituted alkyl group interdispersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, L is substituted with an aryl group, a phenyl group, a benzyl group, an alkyl group, an alkylene group, or a heterocyclic group.

[0221] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-60a hydrocarbon chain in which 0 to 20 methylene units of the hydrocarbon are independently replaced by -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R**)S(O)2-, -S(O)2N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, wherein R** is, independently at each occurrence, hydrogen, C 1-6 Alkyl, or C 3-6 represents cycloalkyl.

[0222] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-45 a hydrocarbon chain in which 0 to 10 methylene units of the hydrocarbon are independently replaced by -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(R**)S(O)2-, -S(O)2N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R** is, independently at each occurrence, hydrogen, C 1-6 Alkyl, or C 3-6 represents cycloalkyl.

[0223] In certain embodiments, L has the formula —N(R)—(optionally substituted 3-20 membered heteroalkylene). p It has the formula -CH2-C(O)-, where R is hydrogen or optionally substituted C1-C6 alkyl, and p is 0 or 1.

[0224] In certain embodiments, L is a group of formula -N(R)-(3-20 membered heteroalkylene) pand p is 0 or 1.

[0225] In certain embodiments, L is a group of formula -N(R)-(3-20 membered heteroalkylene) p and p is 0 or 1.

[0226] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 1-60 A hydrocarbon chain in which 0 to 20 methylene units of the hydrocarbon are independently -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6 alkyl)C(O)O—, optionally substituted 3- to 10-membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0227] In certain embodiments, L is a divalent saturated straight-chain or branched C 3-30A hydrocarbon chain in which 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, a 3- to 10-membered carbocyclyl, or a 3- to 10-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0228] In certain embodiments, L is a divalent saturated straight-chain or branched C 3-30 A hydrocarbon chain in which 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-6 is replaced by alkyl.

[0229] In certain embodiments, L is a divalent saturated or unsaturated, linear or branched C 5-40 It is a hydrocarbon chain, and 1 to 20 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, an optionally substituted 3- to 10-membered carbocyclyl, or an optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0230] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 1-15 -O-***, where *** is A 2It is the connection point to

[0231] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 1-5 -O-***, where *** is A 2 It is the connection point to

[0232] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 6-10 -O-***, where *** is A 2 It is the connection point to

[0233] In certain embodiments, L is -piperidinylene-(OCH2CH2). 1-15 -O-***, where *** is A 2 It is the connection point to

[0234] In certain embodiments, L is [ka] where *** is A 2 In certain embodiments, L is the point of attachment to [ka] where *** is A 2 In certain embodiments, L is the point of attachment to [ka] where *** is A 2 It is the connection point to

[0235] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 1-15 -N(H)C(O)-C 1-10Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 alkyl)C(O)-C 1-10 Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 Alkylene-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 Alkyl)-C 1-10 alkylene-***, where *** is A 2 It is the connection point to

[0236] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 1-10 -N(H)C(O)-C 1-5 Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -N(C 1-4 alkyl)C(O)-C 1-5 Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -C(O)N(H)-C 1-5 alkylene-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-OCH2CH2) 1-10 -C(O)N(C 1-4 Alkyl)-C 1-5 alkylene-***, where *** is A 2 It is the connection point to

[0237] In certain embodiments, L is -piperidinylene-(OCH2CH2). 1-5 -N(H)C(O)-C1-5 Alkylene-***, -piperidinylene-(OCH2CH2) 1-5 -N(C 1-4 alkyl)C(O)-C 1-5 Alkylene-***, -piperidinylene-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 Alkylene-***, or -piperidinylene-(OCH2CH2) 1-5 -C(O)N(C 1-4 Alkyl)-C 1-5 alkylene-***, where *** is A 2 It is the connection point to

[0238] In certain embodiments, L is -(a 3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCHCH). 1-10 -***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene)-O-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, where *** is A 2 It is the connection point to

[0239] In certain embodiments, L is -piperidinylene-(OCH2CH2). 1-5 -***, -piperidinylene-(C 0-5 alkylene)-O-***, or -piperidinylene-(C 1-5 alkylene)-***, where *** is A 2 It is the connection point to

[0240] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is A 2 is the attachment point to X 1 (i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4C optionally replaced by alkyl)- 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene).

[0241] In certain embodiments, L is -(piperidinylene)-X 1 -***, where *** is A 2 is the attachment point to X 1 (i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4 C optionally replaced by alkyl)- 1-5 (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 alkylene).

[0242] In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 1 (i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4 C optionally replaced by alkyl)- 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene).

[0243] In certain embodiments, L is -(piperazinylene)-X 1 -***, where *** is A 2is the attachment point to X 1 (i) C in which one or two methylene groups are optionally replaced by —O— 1-5 (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 alkylene).

[0244] In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 1 (i) C in which one or two methylene groups are optionally replaced by —O— 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene).

[0245] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, where *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 In certain embodiments, L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, where *** is A 2 is the attachment point to X 2 is -O-.

[0246] In certain embodiments, L is -(piperidinylene)-X2 -(C 1-10 alkylene)-***, where *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 In certain embodiments, L is -(piperidinylene)-X 2 -(C 1-10 alkylene)-***, where *** is A 2 is the attachment point to X 2 is -O-.

[0247] In certain embodiments, L is -(piperidinylene)-X 2 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 In certain embodiments, L is -(piperidinylene)-X 2 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is A 2 is the attachment point to X 2 is -O-.

[0248] In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 2 is -O-.

[0249] In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 In certain embodiments, L is [ka] where *** is A 2 is the attachment point to X 2 is -O-.

[0250] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is A 2 is the attachment point to X 1 is a compound in which one CH2 group is -C(H)(C 3-6 -(OCH2CH2) optionally replaced by cycloalkyl)- 1-10 is.

[0251] In certain embodiments, L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen. In certain embodiments, L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocycle containing two heteroatoms selected from nitrogen.

[0252] In certain embodiments, L is -(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-***, where *** is A 2 It is the connection point to

[0253] In certain embodiments, L is -(9-membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-O-***, where *** is A 2 It is the connection point to

[0254] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X 3 is C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)-, or a bond.

[0255] In certain embodiments, L is -(piperidinylene)-(C 1-5 alkylene)-(piperazinylene)-***, where *** is A 2 It is the connection point to

[0256] In certain embodiments, L is -(piperazinylene)-(azetidinylene)-*** or (azetidinylene)-(piperazinylene)-***, where *** is A 2 It is the connection point to

[0257] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6alkylene)-***, and L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 alkylene)-***, wherein X 3 is C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)-, or a bond.

[0258] In certain embodiments, L is -(piperidinylene)-(C 1-5 Alkylene)-(piperazinylene)-(C 2-5 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0259] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-O-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 -(cycloalkylene)-N(H)-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 Cycloalkylene)-N(C 1-4 alkyl)-***, where *** is A 2is the attachment point to X 3 is C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)-, or a bond.

[0260] In certain embodiments, L is -(piperidinylene)-X 3 -(C 3-6 Cycloalkylene)-O-***, -(piperidinylene)-X 3 -(C 3-6 Cycloalkylene)-N(H)-***, or -(piperidinylene)-X 3 -(C 3-6 cycloalkylene)-***, where *** is A 2 is the attachment point to X 3 is C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 alkyl)-, or a bond.

[0261] In certain embodiments, L is —N(C 1-3 alkyl)-(C 2-7 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-***, -N(H)-(C 2-7 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -N(H)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C2-7 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, or -N(H)-(C 2-7 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0262] In certain embodiments, L is —N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-, -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-, -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-, or -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C2-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-, -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-, where *** is A 2 is the connection point to

[0263] In certain embodiments, L is —N(CH 3 )—[(CH 2 CH 2 )—O—] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 Alkylene)-***, -N(CH3)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(CH3)C(O)-(C 1-6 Alkylene)-***, -N(H)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, or -N(H)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0264] In certain embodiments, L is a group of formula -(C 0-12 alkylene)-(optionally substituted 3- to 40-membered heteroalkylene)-(C 0-12 alkylene)-.

[0265] In certain embodiments, L is one of the following: [ka] In the formula, *** represents A 2 It is the connection point to

[0266] In certain embodiments, L is one of the following: [ka] In the formula, *** represents A 2 It is the connection point to

[0267] In certain embodiments, L is [ka] where *** is A 2 It is the connection point to

[0268] In certain embodiments, L is [ka] where *** is A 2 It is the connection point to

[0269] In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 cycloalkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(3- to 5-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-(C 0-4 alkylene)-O-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen)-O-(C 0-6 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-O-(C 0-6 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 alkylene)-***, -(N(C 1-6 alkyl)-(C 0-6 alkylene)-C(O)N(H)-(C 0-6 alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 alkynylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 1-6 alkyl)-(3- to 5-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen)-C(O)N(H)-(C 0-6 alkylene)-N(H))-***, -(C(O)N(H)-(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C 1-6alkyl)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen)-C(O)-***, -(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 alkylene)***, -C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-***, -(C(O)N(H)-(C 1-6 alkylene)-C(O)N(H)-(C 0-6 alkylene)-***, or -(8- to 11-membered fused bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 alkylene)-***, where *** is A 2 It is the connection point to

[0270] In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 3-4 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C 1-4In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(3-5 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***. In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***. In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-(C 0-4 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***. In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen)-(C 0-6 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-C(O)N(H)-(C 0-6 In certain embodiments, L is -(N(C 1-6 alkyl)-(C 0-6 alkylene)-C(O)N(H)-(C 0-6 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 1-6In certain embodiments, L is -(a 3- to 5-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***. In certain embodiments, L is -(a 5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen)-C(O)N(H)-(C 0-6 In certain embodiments, L is -(C(O)N(H)-(C 0-6 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C 1-6 In certain embodiments, L is -C(O)-(a 5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-C(O)-***. In certain embodiments, L is -C(O)-(a 5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-C(O)-***. In certain embodiments, L is -C(O)-(a 5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-C(O)-***. 0-6 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***. In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 In certain embodiments, L is -C(O)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-***, -(C(O)N(H)-(C 1-6 alkylene)-C(O)N(H)-(C 0-6 In certain embodiments, L is -(8-11 membered fused bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 1-4 alkylene)-***.

[0271] In certain embodiments, —N(C 1-6 alkyl)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-O-***, -(C 0-6 alkylene)-N(H)C(O)N(H)-(C 0-6 alkylene)-***, -N(H)-(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C 1-6 )-(C 0-6 alkylene)-***, -(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-N(C 1-6 alkyl)-(3- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-O-(5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6alkylene)-(5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen and substituted with 1 or 2 fluoro)-(C 1-4 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-(C 3-6 Cycloalkylene)-(C 0-4 alkylene)-O-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-(C 3-6 Cycloalkylene)-(C 0-4 alkylene)-***, -(C 0-4 alkylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C 0-4 alkylene)-(C 3-6 Cycloalkylene)-(C 2-4 alkynylene)-***, -(C 0-4 alkylene)-(8-10 membered fused bicyclic heterocyclyl substituted with 1 or 2 fluoro groups containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C 0-4alkylene)-(4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with trifluoromethyl)-(C 0-4 alkylene)-N(H)-***, or -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(C 3-6 Cycloalkylene)-C(O)N(C 1-6 Alkyl)(C 0-6 alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with 0 or 1 occurrence of methyl or halo)-(C 0-6 alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic oxo-substituted heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-***, -(8-12 membered spirocyclic C containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen 1-4 Alkyl-substituted heterocyclyl)-(C 0-6 Alkylene)-(O) 0-1 ***, -(C 2-4 alkynylene)-(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(C 0-4 alkylene)-(C 3-7 Cycloalkylene)-(C 2-4 alkynylene)-***, -(C 1-4 alkylene)-(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(C 1-4alkylene)-(5- to 7-membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C 0-4 alkylene)-***, -(C 0-4 alkylene)-(5- to 7-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C 2-4 alkenylene)-***, or -(C 0-4 alkylene)-(6-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen and substituted with 1 or 2 fluoro)-(C 0-4 alkylene)-***, where *** is A 2 It is the connection point to

[0272] In certain embodiments, L is —N(C 1-6 alkyl)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C 0-6 In certain embodiments, L is -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 In certain embodiments, L is -(C alkylene)-O-***. 0-6 alkylene)-N(H)C(O)N(H)-(C 0-6 In certain embodiments, L is -N(H)-(C 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 In certain embodiments, L is -(C alkylene)-***. 0-6 alkylene)-C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 In certain embodiments, L is -(C alkylene)-***. 0-6alkylene)-(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C 1-6 alkyl)-(C 0-6 In certain embodiments, L is -(C alkylene)-***. 0-6 alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 alkylene)-N(C 1-6 In certain embodiments, L is -(4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 In certain embodiments, L is -(4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-6 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen and substituted with 1 or 2 fluoro)-(C 1-4 In certain embodiments, L is -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-(C 3-6 Cycloalkylene)-(C 0-4 In certain embodiments, L is -(C alkylene)-O-***. 0-4 In certain embodiments, L is -(C alkylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-***. 0-4 alkylene)-(C 3-6 Cycloalkylene)-(C 2-4In certain embodiments, L is -(C alkynylene)-***. 0-4 alkylene)-(8-10 membered fused bicyclic heterocyclyl substituted with 1 or 2 fluoro groups containing 1 or 2 heteroatoms selected from nitrogen)--(C 0-4 In certain embodiments, L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***. In certain embodiments, L is -(C 0-4 alkylene)-(4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with trifluoromethyl)-(C 0-4 alkylene)-N(H)-***.

[0273] Additional Exemplary Embodiments of L In certain embodiments, L is —N(H)—(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)-***, -N(H)-(C 10-20 alkylene)-O-(C 1-6 alkylene)-C(O)-***, -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-C(O)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-C(O)-***, -N(H)-(C 7-15 alkylene)-C(O)-***, -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(C1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, or -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0274] In certain embodiments, L is —N(H)—(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)-***, -N(H)-(C 10-20 alkylene)-O-(C 1-6 Alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 Alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-C(O)-***, -N(H)-(C 7-15 Alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 2-6-(C 1-6 Alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-***, -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 2-9 alkylene)-O-(C 1-6 alkylene)-C(O)N(H)-(C 1-6 Alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)-(C 1-6 Alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)-(C 1-6 Alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, or -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0275] In certain embodiments, L is —N(H)—[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-C(O)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 alkylene)***, -N(H)-(C 1-6alkylene)-N(H)C(O)-(C 1-6 alkylene)***, -N(H)-(C 2-6 alkylene)-***, -N(H)-(C 7-15 alkylene)-***, -N(C 1-6 alkyl)-(C 2-6 alkylene)-***, -N(C 1-6 alkyl)-(C 7-15 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heterocycloalkylene)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heterocycloalkylene)-(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 alkylene)-***, or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0276] In certain embodiments, L is —N(H)—[CH2CH2—O—] 2-6 -(C 1-6 Alkylene)-C(O)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-C(O)-***, -N(H)-(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 alkylene)***, -N(H)-(C1-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)***, -N(H)-(C 2-6 alkylene)-***, -N(H)-(C 7-15 alkylene)-***, -N(C 1-6 alkyl)-(C 2-6 alkylene)-***, -N(C 1-6 alkyl)-(C 7-15 Alkylene)-***, -N(H)-[CH2CH2-O-] 2-6 -(C 1-6 Alkylene)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heterocycloalkylene)-(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 1-6 alkylene)-(3- to 6-membered heterocycloalkylene)-(C 1-6 alkylene)-N(H)-(C 1-6 alkylene)-***, -N(H)-(C 2-6 alkylene)-N(H)-(C 1-6 alkylene)-***, or -N(H)-(C 2-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0277] In certain embodiments, L is -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -(C 1-9 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -(C 1-9alkylene)-N(H)C(O)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, or -(C 1-9 alkylene)-N(H)C(O)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0278] In certain embodiments, L is —[CH 2 CH 2 —O—] 2-6 -(C 1-6 Alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 Alkylene)-***, -[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 Alkyl)(C 1-6 Alkylene)-***, -[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 Alkylene)-***, -[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -(C 1-9 alkylene)-C(O)N(H)-(C 1-6alkylene)-***, -(C 1-9 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-N(H)C(O)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, -(C 1-9 Alkylene)-C(O)N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, or -(C 1-9 alkylene)-N(H)C(O)-[(CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-(C 1-6 alkylene)-***, where *** is A 2 It is the connection point to

[0279] In certain embodiments, L is —N(H)—[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(H)-***, -N(H)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[(C 2-4 alkylene)-O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)-***, or -N(C 1-6 alkyl)-[(C 2-4 alkylene)-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-***, where *** is A 2 It is the connection point to

[0280] In certain embodiments, L is —N(H)—[CH2CH2—O—] 2-6 -(C 1-6 Alkylene)-N(H)-***, -N(H)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 2-6 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH2CH2-O-] 2-6-(C 1-6 alkylene)-N(C 1-6 alkyl)-***, or -N(C 1-6 alkyl)-[CH2CH2-O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)-***, where *** is A 2 It is the connection point to

[0281] In some embodiments, L is one of the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] In the formulae, the dashed bond indicates the point of attachment.

[0282] In certain embodiments, L is —C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101)-, -S(O)2-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkylene or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0283] In certain embodiments, L is —CH—Y 20 -, -C(H)(R 100 )-Y 20 -, -C(R 100 )2-Y 20 -, -OY 20 -, -N(R 101 )-Y 20 -, -S(O)2-Y 20 -, -C(O)-Y 20 -, -(optionally substituted C 3-7 Cycloalkylene)-Y 20 -, -(optionally substituted C 4-7 Cycloalkenylene)-Y 20 -, -(optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-Y 20 -, -Y 20 -CH2-, -Y 20 -C(H)(R 100 )-, -Y 20 -C(R 100 )2-, -Y 20-O-, -Y 20 -N(R 101 )-, -Y 20 -S(O)2-, -Y 20 -C(O)-, -Y 20 -(optionally substituted C 3-7 Cycloalkylene)-, -Y 20 -(optionally substituted C 4-7 cycloalkenylene)-, or -Y 20 -(optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0284] In certain embodiments, L is one of the following: [ka]

[0285] In the formula, X 20 , Y 20 , and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, or optionally substituted C 4-7 cycloalkenylene, wherein R 100are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0286] In certain embodiments, L is one of the following: [ka]

[0287] In the formula, X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0288] In certain embodiments, L is -X 20 -Y 20 -Z 20 - in which X 20 , Y 20 , and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0289] In certain embodiments, L is -X 20 =Y 20 -Z 21 - in which X 20 and Y 20 are independently -C(R 100 )- or -N-, and Z 21 -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, or optionally substituted C 4-7 cycloalkenylene, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0290] In certain embodiments, L is -C≡CZ 20 -, wherein Z 20 -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, or optionally substituted C 4-7 cycloalkenylene, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0291] In certain embodiments, L is one of the following: [ka]

[0292] In the formula, X 20 , Y 20 , and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101)-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0293] In certain embodiments, L is one of the following: [ka] [ka]

[0294] In the formula, V 20 , W 20 , X 20 , Y 20 , and Z 20 are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0295] In certain embodiments, L is one of the following: [ka]

[0296] In the formula, W 20 , X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0297] In certain embodiments, L is one of the following: [ka]

[0298] In the formula, W 20 , X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 In certain embodiments, R 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0299] In certain embodiments, L is one of the following: [ka]

[0300] In the formula, U, V, W, X, Y, and Z are independently —CH—, —C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0301] In certain embodiments, L is one of the following: [ka]

[0302] wherein X, Y, and Z are independently —C(R 100 )- or -N-, and V and W are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0303] In certain embodiments, L is one of the following: [ka]

[0304] wherein W, X, Y, and Z are independently —C(R 100 )- or -N-, and V is -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0305] In certain embodiments, L is one of the following: [ka]

[0306] In the formula, T, U, V, W, X, Y, and Z are independently —CH—, —C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0307] In certain embodiments, L is one of the following: [ka]

[0308] wherein W, X, Y, and Z are independently —C(R 100 )- or -N-, and U and V are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0309] In certain embodiments, L is one of the following: [ka]

[0310] wherein X, Y, and Z are independently —C(R 100 )- or -N-, and U, V, and W are independently -CH2-, -C(H)(R 100 )-, -C(R 100 )2-, O, -N(R 101 )-, -S(O)2-, -C(O)-, optionally substituted C 3-7 Cycloalkylene, optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3- to 7-membered heterocyclylene containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 100 are independently hydrogen, halogen, and C 1-6 Alkyl, or C 3-6 represents cycloalkyl, and R 101 is hydrogen, C 1-6 Alkyl, or C 3-6 cycloalkyl, where the dashed bond indicates the point of attachment. 100 represents independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0311] In certain embodiments, L is one of the following: [ka] [ka]

[0312] The variables m, n, o, p, and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0313] In certain embodiments, L is one of the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein any m or n is independently 0, 1, 2, 3, 4, 5, or 6, and any X is H or F.

[0314] In certain embodiments, L is one of the following: [ka] [ka] [ka] [ka] wherein any m or n is independently 0, 1, 2, 3, 4, 5, or 6.

[0315] In certain embodiments, L is one of the following: [ka] [ka] [ka]

[0316] wherein any m or n is independently 0, 1, 2, 3, 4, 5, or 6.

[0317] In certain embodiments, L is one of the following: [ka] [ka] [ka]

[0318] In certain embodiments, L is one of the following: [ka] [ka] [ka] [ka] [ka] [ka]

[0319] In certain embodiments, L is a group of formula -(C 0-12 alkylene)-(optionally substituted 3- to 40-membered heteroalkylene)-(C 0-12 In certain embodiments, L has C 4-14 In certain embodiments, L is -(CH) 6-10 -It is.

[0320] In certain embodiments, L is -CH2CH2(OCH2CH2)-***, -CH2CH2(OCH2CH2)2-***, -CH2CH2(OCH2CH2)3-***, -CH2CH2(OCH2CH2)4-***, -CH2CH2(OCH2CH2)5-***, -CH2CH2(OCH2CH2)6-***, -CH2CH2(OCH2CH2)7-***, -CH2CH2(OCH2CH2)8-***, -CH2CH2(OCH2CH2)9-***, -CH2CH2(OCH2CH2) 10 -***, -CH2CH2(OCH2CH2) 11 -***, -CH2CH2(OCH2CH2) 12 -***, -CH2CH2(OCH2CH2) 13 -***, -CH2CH2(OCH2CH2) 14 -***, -CH2CH2(OCH2CH2) 15 -***, or -CH2CH2(OCH2CH2) 16-20 -***, where *** is A 2 It is the connection point to

[0321] In certain embodiments, L is -(C 2-20Alkylene)-(OCH2CH2) 2-4 -(C 0-4 alkylene)-***, -(C 2-20 Alkylene)-(OCH2CH2) 5-7 -(C 0-4 alkylene)-***, -(C 2-20 Alkylene)-(OCH2CH2) 8-10 -(C 0-4 alkylene)-***, -(C 2-20 Alkylene)-(OCH2CH2) 11-13 -(C 0-4 alkylene)-***, -(C 2-20 Alkylene)-(OCH2CH2) 14-16 -(C 0-4 alkylene)-***, -(C 2-20 Alkylene)-(OCH2CH2) 17-20 -(C 0-4 alkylene)-***, -(C 1-20 Alkylene)-(OCH2CH2) 1-10 -(C 0-4 alkylene)-C(O)-***, or -(C 1-20 Alkylene)-(OCH2CH2) 11-20 -(C 0-4 alkylene)-C(O)-***, where *** is A 2 It is the connection point to

[0322] In certain embodiments, L is —O(CH2CH2O) 2-4 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 5-7 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 8-10 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 11-13 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 14-16 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 16-20 -(C 0-4 Alkylene)-***, -O(CH2CH2O) 2-10 -(C0-4 Alkylene)C(O)-***, or -O(CH2CH2O) 11-20 -(C 0-4 alkylene)C(O)-***, where *** is A 2 It is the connection point to

[0323] In certain embodiments, L is -(C 0-20 Alkylene)-(OCH2CH2) 1-10 -(N(C 1-4 Alkyl))-***, -(C 0-20 Alkylene)-(OCH2CH2) 11-20 -(N(C 1-4 Alkyl))-***, -(C 0-20 Alkylene)-(CH2CH2O) 1-10 -(C 2-10 Alkylene)-(N(C 1-4 Alkyl))-(C 0-10 alkylene)-***, or -(C 0-20 Alkylene)-(CH2CH2O) 11-20 -(C 2-10 Alkylene)-(N(C 1-4 Alkyl))-(C 0-10 alkylene)-***, where *** is A 2 It is the connection point to

[0324] In certain embodiments, L is selected from those depicted in the compounds of Table 1 below.

[0325] Exemplary Specific Compounds In certain embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-48 of Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-48 of Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-52 of Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-52 of Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-236 of Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-236 of Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-141

Table 1-145

Table 1-147

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-161

Table 1-166

Table 1-167

Table 1-171

Table 1-176

Table 1-177

Table 1-178

Table 1-179

[0326] Synthesis method Methods for preparing the compounds described herein are illustrated in the following synthetic schemes. The schemes are included for the purpose of illustrating the invention and are not intended to limit the scope or spirit of the invention. The starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on literature procedures.

[0327] In the schemes, it is understood by one skilled in the art of organic synthesis that the functional groups present on various portions of the molecules must be compatible with the reagents and reactions proposed. Substituents incompatible with the reaction conditions will be apparent to one skilled in the art and alternative methods (e.g., use of protecting groups or alternative reactions) are suggested accordingly. Protecting group chemistry and strategies are described, for example, in "Protecting Groups in Organic Synthesis," T.W. Greene and P.G.M. Buts, 3004, incorporated herein by reference in its entirety. rd This is well known, as described in detail in the 1999 edition of John Wiley & Sons.

[0328] The synthetic route shown in Scheme 1 is a general method for preparing compounds of formula F. Carboxylic acid A and amine B are reacted under amide coupling conditions to give amide C. Removal of a protecting group (Pg) from compound C gives compound D. Pg can be, for example, a Boc protecting group that can be removed by treating the compound with trifluoroacetic acid. Coupling of compound D with compound E (e.g., a nucleophilic aromatic substitution reaction where X is an amino group and the leaving group in compound E is chloro) gives the final compound of formula F.

[0329] Scheme 1. [ka] The modular synthetic route shown in Scheme 1 can be easily modified to provide additional compounds by performing functional group transformations on the intermediates and / or final compounds. Such functional group transformations are well known in the art and are described, for example, in Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992), Organic Synthesis, 3 rd Ed. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010), Modern Methods of Organic Synthesis, 4 th Ed. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8 thEd., (Michael B. Smith, John Wiley & Sons, New York: 2020), and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). Protecting group strategies may be developed appropriately to accommodate different functional groups of molecules used in the synthetic pathway. Protecting group chemistry and strategies are described, for example, in Protecting Groups in Organic Synthesis, 3rd Ed. rd Edition, T.W. Greene and P.G.M.Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Ed., (Peter G.M.Wuts, John Wiley & Sons: 2014).

[0330] II. Therapeutic Applications The heterobifunctional compounds described herein, e.g., compounds of Formula I, II, or other compounds of Section I, provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the present invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, II, or other compounds of Section I, to treat the cancer. In certain embodiments, the compound is a compound of Formula I. In certain embodiments, the particular compound of Formula I is a compound defined by one of the above embodiments.

[0331] cancer In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer is prostate cancer.

[0332] In certain embodiments, the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, vulvar cancer, thyroid cancer, lung cancer including adenocarcinoma of the lung and squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular carcinoma, gastric cancer including gastrointestinal cancer or stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of ALL, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative disorder, large B-cell lymphoma, or B-cell lymphoma.

[0333] In certain embodiments, the cancer is a solid tumor or leukemia.In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, or diffuse large B-cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.

[0334] In certain embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma.

[0335] In certain embodiments, the cancer is selected from the group consisting of neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, gliosarcoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypic acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, serous papillary carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone-refractory prostate cancer, post-resection high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, asymptomatic myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-independent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castration-resistant prostate cancer, castration-resistant metastatic prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

[0336] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal (stomach, colorectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0337] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous adenocarcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0338] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube carcinoma, papillary serous cystadenocarcinoma, uterine serous adenocarcinoma (UPSC), hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0339] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, a carcinoma, or a lymphoma. In certain embodiments, the cancer is renal cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian cancer. carcinoma), or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous adenocarcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepato-bile duct cancer; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0340] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous adenocarcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0341] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous adenocarcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0342] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial carcinoma. In some embodiments, the cancer is fallopian tube carcinoma. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine serous adenocarcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0343] Inducing cancer cell death Another aspect of the present invention provides a method for causing cancer cell death. The method includes contacting cancer cells with an effective amount of a compound described herein, such as a compound of Formula I or II, or other compounds in Section I, to cause cancer cell death. In certain embodiments, the compound of Formula I or II is a compound defined by one of the embodiments described above.

[0344] In certain embodiments, the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer and gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer cells are one or more of the cancers listed in the section above entitled "Cancer." In certain embodiments, the cancer cells are prostate cancer cells.

[0345] Combination therapy The compounds useful in the method of the present invention can be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein.These additional therapeutic agents can include compounds that are commercially available or can be synthesized by those skilled in the art.These additional therapeutic agents are known to treat, prevent or alleviate the symptoms of the disease or disorder contemplated herein.

[0346] Thus, in certain embodiments, the methods further comprise administering to the subject an additional therapeutic agent that treats a disease contemplated herein.

[0347] In certain embodiments, administering a compound of the present invention to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating a disease contemplated herein. For example, in certain embodiments, the compound of the present invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing a lower dose of the additional therapeutic compound to achieve the same effect.

[0348] The synergistic effect can be achieved, for example, by a suitable method, e.g., Sigmoid-E max The drug effect can be calculated using the following equations: (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each of the above equations can be applied to experimental data to generate corresponding graphs that aid in assessing the effect of drug combinations. The corresponding graphs associated with the above equations are the concentration-effect curve, the isobologram curve, and the combination coefficient curve, respectively.

[0349] In certain embodiments, a compound of the invention and a therapeutic agent are co-administered to a subject. In other embodiments, a compound of the invention and a therapeutic agent are co-formulated and co-administered to a subject.

[0350] In certain embodiments, the compound is administered in combination with a second therapeutic agent active against cancer. In certain embodiments, the second therapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustine, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozotocin, and the like. The following are steroids: flucloxone, nimustine, vindesine, flutamide, drogenil, butosin, carmofur, razoxane, sizofiran, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon alpha, interferon-2 alpha, interferon beta, interferon gamma, colony-stimulating factor-1, colony-stimulating factor-2, denileukin diftitox, interleukin-2, and luteinizing hormone-releasing factor.

[0351] In certain embodiments, the second therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis), temsirolimus (Torisel®, Pfizer), and sirolimus (Rapamune®, Pfizer).

[0352] In certain embodiments, the second therapeutic agent is a poly ADP-ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca), rucaparib (Rubraca®, Clovis Oncology), and niraparib (Zejula®, Tesaro). Other PARP inhibitors under investigation that can be used in the present invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin), veliparib (ABT-888, AbbVie), and BGB-290 (BeiGene, Inc.).

[0353] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors that can be used in the present invention include idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche), pictilisib (GDC-0941, Genentech / Roche), copanlisib (BAY806946, Bayer), duvelisib (formerly known as IPI-145, Infinity Pharmaceuticals), PQR309 (Piqur Therapeutics, Switzerland), and TGR1202 (formerly known as RP5230, TG Therapeutics).

[0354] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda), carfilzomib (Kyprolis®, Amgen), and ixazomib (Ninlaro®, Takeda).

[0355] In certain embodiments, the second therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck), romidepsin (Itodax®, Celgene), panobinostat (Farydak®, Novartis), and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors under investigation that can be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333) and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0356] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK4 / 6 inhibitor. Approved CDK4 / 6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer) and ribociclib (Kisqali®, Novartis). Other CDK4 / 6 inhibitors under investigation that can be used in the present invention include abemaciclib (Ly2835219, Eli Lilly) and trilaciclib (G1T28, G1 Therapeutics).

[0357] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. IDO inhibitors that can be used in the present invention include epacadostat (INCB024360, Incyte), indoximod (NLG-8189, NewLink Genetics Corporation), capmanitib (INC280, Novartis), GDC-0919 (Genentech / Roche), PF-06840003 (Pfizer), BMS:F001287 (Bristol-Myers Squibb), Phy906 / KD108 (Phytoceutica), and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).

[0358] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®, Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly), necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen), and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0359] In certain embodiments, the second therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors that can be used in the present invention include exemestane (Aromasin®, Pfizer), anastrozole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0360] In certain embodiments, the second therapeutic agent is a hedgehog pathway antagonist. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals) and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[0361] In certain embodiments, the second therapeutic agent is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0362] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. Investigational CCR4 inhibitors that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0363] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.The IDH inhibitors under investigation that can be used in the present invention include AG120 (Celgene, NCT02677922), AG221 (Celgene, NCT02677922, NCT02577406), BAY1436032 (Bayer, NCT02746081), IDH305 (Novartis, NCT02987010).

[0364] In certain embodiments, the second therapeutic agent is an arginase inhibitor. Arginase inhibitors under investigation that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being tested in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234), and CB-1158 (Calithera Biosciences).

[0365] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Investigational glutaminase inhibitors that can be used in the present invention include CB-839 (Calithera Biosciences).

[0366] In certain embodiments, the second therapeutic agent is an antibody that binds to a tumor antigen, i.e., a protein expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec), ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline), obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals), daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics), trastuzumab (anti-HER2, Herceptin®, Genentech), ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech), and pertuzumab (anti-HER2, Perjeta®, Genentech), and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0367] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals) and topotecan (Hycamtin®, GlaxoSmithKline). Investigational topoisomerase inhibitors that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0368] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor, i.e., another therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibits rapidly proliferating cells. Such nucleoside inhibitors or other therapeutic agents include trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals), vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics), temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck), cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer), lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource), and others. Biotechnology), azacitidine (a pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene), omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®, Teva Pharmaceuticals), asparaginase Erwinia chrysanthemi (an enzyme for asparagine depletion, Elspar®, Lundbeck;Erwinaze®, EUSA Pharma), eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Halaven®, Eisai), cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Jevtana®, Sanofi-Aventis), capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech), bendamustine (bifunctional mechlorethamine derivative, thought to form DNA interstrand crosslinks, Treanda®, Cephalon / Teva), ixabepilone (semi-synthetic analogue of epothilone B, microtubule inhibitor, tubulin-based antimitotic agent, Ixempra®, Bristol-Myers Squibb), nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolic inhibitor, Arranon®, Novartis), clorafabine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis), and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0369] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic agent, also known as a platin. Platins cause cross-linking of DNA, primarily in rapidly replicating cells such as cancer cells, such that they inhibit DNA repair and / or DNA synthesis. Approved platinum-based therapeutic agents that can be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb), carboplatin (Paraplatin®, Bristol-Myers Squibb, also Teva, Pfizer), oxaliplatin (Eloxitin®, Sanofi-Aventis), and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutic agents undergoing clinical trials and that can be used in the present invention include picoplatin (Ponard Pharmaceuticals) and satraplatin (JM-216, Agennix).

[0370] In certain embodiments, the second therapeutic agent is a taxane compound that causes disruption of microtubules, which are essential for cell division. Approved taxane compounds that can be used in the present invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis, DoceFRez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®, Abraxis / Celgene), and cabazitaxel (Jevtana®, Sanofi-Aventis). Other taxane compounds undergoing clinical trials that can be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0371] In certain embodiments, the second therapeutic agent is an inhibitor of an anti-apoptotic protein, such as BCL-2. Approved anti-apoptotic drugs that may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech) and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that are undergoing clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0372] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM) that interferes with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0373] In certain embodiments, the second therapeutic agent is an inhibitor of the interaction between MDMX and MDM2, two major p53 inhibitor proteins. Investigational inhibitors of p53 inhibitor proteins that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds equipotently to MDMX and MDM2 and disrupts their interaction with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972, NCT02264613).

[0374] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFβ). Investigational inhibitors of TGF-beta proteins that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in clinical settings for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008, Sanofi-Genzyme), which is being tested for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, the additional therapeutic agent is a TGF-beta trap, e.g., as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), a bispecific anti-PD-L1 / TGFβ trap compound (NCT02699515) and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "trap."

[0375] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer, and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly T-VEC), a genetically modified oncolytic virotherapy approved for the treatment of cutaneous, subcutaneous, and nodal lesions of unresectable melanoma. In some embodiments, the cancer immunotherapeutic agent is an oncolytic virotherapy agent, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT peraleorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) that does not replicate in cells in which RAS is not activated, in numerous cancers, including (NCT00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036);ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676), and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express beta-galactosidase (beta-gal) / beta-glucuronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, studied in peritoneal carcinomatosis (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818). ;

[0376] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb), pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck), ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb), durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca), or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody that has been studied in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; and avelumab (Bavencio®, Pfizer / Merck), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer. KGaA), also known as MSB0010718C; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors.Tremelimumab (CP-675,206, Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that is being studied in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer of the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0377] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease described herein, such as cancer.

[0378] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, II, or other compound in Section I) for treating a medical disorder, such as a disorder described herein (e.g., cancer).

[0379] Evaluation of cell proliferation inhibition in HEK293 and HeLa cells Compounds can be evaluated for their ability to inhibit the growth of HEK293 or HeLa cells according to the following procedure. HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn / Strep. Cells are seeded into white 384-well plates at 500 cells / well in 25 mL of complete medium. After seeding, plates are centrifuged at 300 x g for 3 minutes and cultured at 37°C with 5% CO2 in a humidified tissue culture incubator. After 24 hours, compounds are titrated into 100% DMSO and diluted in complete cell culture medium. A 25 mL aliquot of the compound / medium mixture is added to the cells to bring the total volume in the well to 50 mL. DMSO alone is used as a negative control. Plates are then centrifuged at 300 x g for 3 minutes and stored at 37°C with 5% CO2 for 3 days. On days 0 and 3 of compound treatment, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating the microplate at room temperature for 30 minutes, 25 μL of CellTiter-Glo 2.0 reagent is dispensed into each well to a total volume of 75 mL. The plate is mixed on a shaker at 500 rpm for 2 minutes, followed by a 10-minute incubation at room temperature. After a quick spin, luminescence is measured on an EnVision plate reader. Data are normalized to readings on days 0 and 3 of DMSO treatment. A four-parameter nonlinear regression curve fit was applied to the dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI) for each compound. 50 ) is determined.

[0380] III. Pharmaceutical Composition and Administration Considerations As mentioned above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above-described compounds formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those intended for systemic absorption, boluses, powders, granules, and pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) vaginal or rectal administration, e.g., as a suppository, cream, or foam; (5) sublingual; (6) ocular; (7) transdermal; or (8) nasal administration. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein (eg, a compound of Formula I) and a pharmaceutically acceptable carrier.

[0381] The phrase "therapeutically effective amount," as used herein, means an amount of a compound, material, or composition, including a compound of the invention, that is effective to produce a desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0382] The phrase "pharmaceutically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0383] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0384] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0385] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0386] In certain embodiments, formulations of the invention comprise an additive selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the invention. In certain embodiments, the above-described formulations render the compounds of the invention orally bioavailable.

[0387] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0388] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as the active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0389] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is incorporated into a pharmaceutical composition, such as sodium citrate or dicalcium phosphate, and / or one or more of the following pharmaceutically acceptable carriers: (1) excipients and fillers, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) soluble solids, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, etc. (5) disintegrants such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamer and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) sustained-release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shell gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0390] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0391] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These dosage forms may be formulated for sustained or controlled release of the active ingredient therein, for example, using various ratios of hydroxypropylmethylcellulose to provide the desired release profile, and using other polymer matrices, liposomes, and / or microparticles. They can also be formulated for rapid release, e.g., lyophilized. They can also be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient(s) only, or preferentially, in a certain portion of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0392] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, for example, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0393] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0394] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0395] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound(s).

[0396] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0397] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0398] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0399] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0400] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0401] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0402] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0403] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0404] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action on the target compounds can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0405] In some cases, in order to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0406] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0407] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered as they are or, for example, in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0408] The preparations of the present invention can be administered orally, parenterally, topically, or rectally. They are naturally administered in a form suitable for each administration route. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion, or inhalation, by topical administration with lotion or ointment, and by rectal administration with suppositories. Oral administration is preferred.

[0409] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0410] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and therefore is subject to metabolic and other similar processes.

[0411] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally, and topically, including buccal and sublingually, as by powders, ointments, or drops.

[0412] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0413] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0414] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt, or amide, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0415] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start dosages of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0416] In general, a suitable daily dose of a compound of the present invention will be that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as a sensitizer), the effective amount may be less than when the agent is used alone.

[0417] If desired, the effective daily amount of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Preferred administration is a once-daily administration.

[0418] The present invention further provides unit dosage forms (such as tablets or capsules) comprising a heterobifunctionally substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of the medical disorders described herein.

[0419] IV. Medical Kit Another aspect of the invention is a kit that includes (i) a compound described herein, eg, a compound of Formula I, and (ii) instructions for use, such as for treating cancer.

[0420] V. Enumerated Embodiments Another aspect of the invention provides the following enumerated embodiments:

[0421] Embodiment No. 1. A compound represented by formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 is cyano, halogen, and R 4 is phenyl substituted by m occurrences of R 2independently for each occurrence, C 1-4 represents alkyl, R 3 is hydrogen or C 1-4 is alkyl, R 4 is C 1-4 is alkyl, R 5 independently for each occurrence, C 1-4 represents alkyl or halogen, A 1 is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R 5 is replaced by n occurrences of A 2 is one of the following: [ka] R 1A is C 1-4 Alkyl or C 3-4 is cycloalkyl, R 2A independently for each occurrence, C 1-4 Alkyl or C 3-4 represents cycloalkyl, R 3A is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl; R 4A is -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A ), -(C 1-6 alkylene)-N(R 5A )C(O)R 7A , -(C 1-6 (Alkylene)-CO2R 8A , -(C 1-6 (alkylene)-OC(O)R 7A , or -(C 0-6 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R 5Aand R 6A are independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl or R 5A and R 6A form, together with the nitrogen atom to which they are attached, a 3- to 7-membered ring containing one nitrogen atom; R 7A is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, R 8A is a halogen, C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl, L is a linker, k is 1, 2, 3, or 4; m, n, and p are independently 0, 1, or 2.

[0422] Embodiment No. 2.R 2 is methyl.

[0423] Embodiment No. 3.R 3 The compound of embodiment 1 or 2, wherein is hydrogen.

[0424] Embodiment No. 4. The compound of any one of embodiments 1 to 3, wherein m is 0.

[0425] Embodiment No. 5.R 1 but, [ka] The compound of any one of embodiments 1 to 3, wherein

[0426] Embodiment No. 6. The compound of any one of embodiments 1 to 5, wherein k is 4.

[0427] Embodiment No. 7. The compound according to any one of embodiments 1 to 6, wherein said compound is a compound of formula I:

[0428] Embodiment No. 8. The compound according to embodiment 1 or 2, wherein the compound is a compound of formula Ia, or a pharmaceutically acceptable salt thereof: [ka]

[0429] Embodiment No. 9. The compound according to embodiment 1 or 2, wherein the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof: [ka]

[0430] Embodiment No. 10. The compound of embodiment 1, wherein the compound is a compound of formula Ic, or a pharmaceutically acceptable salt thereof: [ka]

[0431] Embodiment No. 11. The compound according to embodiment 1, wherein the compound is a compound of formula Id, or a pharmaceutically acceptable salt thereof: [ka]

[0432] Embodiment No. 12.A 1 But R 5 The compound of any one of embodiments 1-11, which is pyridazinylene substituted with n occurrences of:

[0433] Embodiment No. 13.A 1 but, [ka] 12. The compound of any one of embodiments 1-11, wherein

[0434] Embodiment No. 14.A 1 But R 5 The compound of any one of embodiments 1-11, wherein the compound is pyrimidinylene substituted with n occurrences of:

[0435] Embodiment No. 15.A 1 but, [ka] The compound of any one of embodiments 1-11, wherein ** is the point of attachment to L.

[0436] Embodiment No. 16.A 1 but, [ka] The compound of any one of embodiments 1-11, wherein ** is the point of attachment to L.

[0437] Embodiment No. 17.A 1 But R 5 The compound of any one of embodiments 1-11, which is pyrazinylene substituted with n occurrences of:

[0438] Embodiment No. 18.A 1 but, [ka] 12. The compound of any one of embodiments 1-11, wherein

[0439] Embodiment No. 19.A 1 But R 5 The compound of any one of embodiments 1-11, wherein the compound is pyridinylene substituted with n occurrences of:

[0440] Embodiment No. 20.A 1 but, [ka] The compound of any one of embodiments 1-11, wherein ** is the point of attachment to L.

[0441] Embodiment No. 21. The compound of any one of embodiments 1-12, 14, 17, or 19, wherein n is 0.

[0442] Embodiment No. 22.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0443] Embodiment No. 23.R 3A The compound of any one of embodiments 1-22, wherein is phenyl substituted with halo.

[0444] Embodiment No. 24.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0445] Embodiment No. 25.R 4A But -(C 1-6 alkylene)-C(O)N(R 5A )(R 6A 25. The compound of any one of embodiments 1-21 or 24, wherein

[0446] Embodiment No. 26.R 4A But -(C 1-6 (Alkylene)-CO2R 8A 25. The compound of any one of embodiments 1-21 or 24, wherein

[0447] Embodiment No. 27.R 4A But -(C 0-625. The compound of any one of embodiments 1-21 or 24, wherein the compound is alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0448] Embodiment No. 28.R 4A But -(C 1-3 The compound of any one of embodiments 1-21 or 24, wherein the aryl is alkylene)-(5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0449] Embodiment No. 29.R 4A But -(C 1-3 The compound of any one of embodiments 1-21 or 24, wherein the compound is (alkylene)-(oxazolyl).

[0450] Embodiment No. 30.R 1A But C 1-4 The compound of any one of embodiments 1-29, wherein is alkyl.

[0451] Embodiment No. 31.R 1A The compound of any one of embodiments 1-29, wherein is methyl.

[0452] Embodiment No. 32.R 2A But C 1-4 The compound of any one of embodiments 1-31, wherein is alkyl.

[0453] Embodiment No. 33.R 2A The compound of any one of embodiments 1-31, wherein is methyl.

[0454] Embodiment No. 34. A compound according to any one of embodiments 1 to 33, wherein p is 2.

[0455] Embodiment No. 35.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0456] Embodiment No. 36.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0457] Embodiment No. 37.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0458] Embodiment No. 38.A 2 but, [ka] 22. The compound of any one of embodiments 1-21, wherein:

[0459] Embodiment No. 39. L is a divalent saturated or unsaturated, linear or branched C 1-60 a hydrocarbon chain, wherein 0 to 20 methylene units of the hydrocarbon are independently selected from the group consisting of -O-, -S-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C 1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C 1-6 alkyl)-, -N(H)C(O)O-, -N(C 1-6The compound of any one of embodiments 1-38, wherein the aryl group is substituted with alkyl)C(O)O—, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0460] Embodiment No. 40.L is a divalent saturated linear or branched C 3-30 a hydrocarbon chain, wherein 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6 The compound of any one of embodiments 1-38, wherein the aryl group is substituted with aryl, ...

[0461] Embodiment No. 41. L is a divalent saturated linear or branched C 3-30 a hydrocarbon chain, wherein 0 to 15 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-6 The compound of any one of embodiments 1-38, wherein the compound is substituted with (alkyl)-.

[0462] Embodiment No. 42. L is a divalent saturated or unsaturated, linear or branched C 5-40 a hydrocarbon chain, wherein 1 to 20 methylene units of the hydrocarbon are independently -O-, -N(H)-, -N(C 1-6 alkyl)-, -N(H)C(O)-, -N(C 1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C 1-6The compound of any one of embodiments 1-38, wherein the substituted 3- to 10-membered heterocyclyl is substituted with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0463] Embodiment No. 43. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0464] Embodiment No. 44. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-5 -O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0465] Embodiment No. 45. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 6-10 -O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0466] Embodiment No. 46. L is -piperidinylene-(OCH2CH2) 1-15 -O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0467] Embodiment number 47.L is [ka] wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0468] Embodiment number 48.L is [ka] wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0469] Embodiment number 49.L is [ka] wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0470] Embodiment No. 50. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(H)C(O)-C 1-10 Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -N(C 1-4 alkyl)C(O)-C 1-10 Alkylene-***, -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(H)-C 1-10 Alkylene-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-15 -C(O)N(C 1-4 Alkyl)-C 1-10 alkylene-***, where *** is A 2 The compound of any one of embodiments 1-38, wherein

[0471] Embodiment No. 51. L is -piperidinylene-(OCH2CH2) 1-5 -N(H)C(O)-C 1-5Alkylene-***, -piperidinylene-(OCH2CH2) 1-5 -N(C 1-4 alkyl)C(O)-C 1-5 Alkylene-***, -piperidinylene-(OCH2CH2) 1-5 -C(O)N(H)-C 1-5 Alkylene-***, or -piperidinylene-(OCH2CH2) 1-5 -C(O)N(C 1-4 Alkyl)-C 1-5 alkylene-***, where *** is A 2 The compound of any one of embodiments 1-38, wherein

[0472] Embodiment No. 52. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2) 1-10 -***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene)-O-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0473] Embodiment No. 53. L is -piperidinylene-(OCH2CH2) 1-5 -***, -piperidinylene-(C 0-5 alkylene)-O-***, or -piperidinylene-(C 1-5 alkylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0474] Embodiment No. 54. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is A 2 is the attachment point to X 1(i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4 C optionally replaced by alkyl)- 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 The compound of any one of embodiments 1-38, wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 60, 61, 62, 63, 64, 65,

[0475] Embodiment No. 55. L is -(piperidinylene)-X 1 -***, where *** is A 2 is the attachment point to X 1 (i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4 C optionally replaced by alkyl)- 1-5 (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 The compound of any one of embodiments 1-38, wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 60, 61, 62, 63, 64, 65,

[0476] Embodiment number 56.L is [ka] wherein *** is A 2 is the attachment point to X 1 (i) one or two methylene groups are -O-, -N(H)-, or -N(C 1-4 C optionally replaced by alkyl)- 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10The compound of any one of embodiments 1-38, wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 60, 61, 62, 63, 64, 65,

[0477] Embodiment No. 57. L is -(piperazinylene)-X 1 -***, where *** is A 2 is the attachment point to X 1 (i) C in which one or two methylene groups are optionally replaced by —O— 1-5 (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C 1-5 The compound of any one of embodiments 1-38, wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 60, 61, 62, 63, 64, 65,

[0478] Embodiment number 58.L is [ka] wherein *** is A 2 is the attachment point to X 1 (i) C in which one or two methylene groups are optionally replaced by —O— 1-10 (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 The compound of any one of embodiments 1-38, wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 59, 60, 61, 62, 63, 64, 65,

[0479] Embodiment No. 59. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 2 -(C 1-10 alkylene)-***, wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 The compound of any one of embodiments 1-38, wherein R is 1 or 2;

[0480] Embodiment No. 60. L is -(piperidinylene)-X 2 -(C 1-10 alkylene)-***, wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 The compound of any one of embodiments 1-38, wherein R is 1 or 2;

[0481] Embodiment No. 61. L is -(piperidinylene)-X 2 -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 The compound of any one of embodiments 1-38, wherein R is 1 or 2;

[0482] Embodiment No. 62.L is [ka] wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 The compound of any one of embodiments 1-38, wherein R is 1 or 2;

[0483] Embodiment No. 63.L is [ka] wherein *** is A 2 is the attachment point to X 2 is -O-, -N(H)-, or -N(C 1-6 The compound of any one of embodiments 1-38, wherein R is 1 or 2;

[0484] Embodiment No. 64.X 2The compound of any one of embodiments 59-63, wherein is —O—.

[0485] Embodiment No. 65. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, where *** is A 2 is the attachment point to X 1 However, one CH2 group is -C(H)(C 3-6 -(OCH2CH2) optionally replaced by cycloalkyl)- 1-10 The compound of any one of embodiments 1-38, wherein

[0486] Embodiment No. 66. A compound according to any one of embodiments 1 to 38, wherein L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen.

[0487] Embodiment No. 67. A compound according to any one of embodiments 1 to 38, wherein L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocycle containing two heteroatoms selected from nitrogen.

[0488] Embodiment No. 68. L is -(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0489] Embodiment No. 69. L is -(9-membered spirocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-O-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0490] Embodiment No. 70. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3-(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X 3 But C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 The compound of any one of embodiments 1-38, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 3C, 3D, 3D, 3E, 3F, 3G, 3H, 3H, 3H, 3H, 3H, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,

[0491] Embodiment No. 71. L is -(piperidinylene)-(C 1-5 alkylene)-(piperazinylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0492] Embodiment No. 72. L is -(piperazinylene)-(azetidinylene)-*** or (azetidinylene)-(piperazinylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0493] Embodiment No. 73. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-N(C 1-6 alkyl)C(O)-(C 1-6 alkylene)-***, and L is -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-C(O)N(H)-(C 1-6alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C 2-6 alkylene)-C(O)N(C 1-6 alkyl)-(C 1-6 alkylene)-***, wherein X 3 But C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 The compound of any one of embodiments 1-38, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 3C, 3D, 3D, 3E, 3F, 3G, 3H, 3H, 3H, 3H, 3H, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,

[0494] Embodiment No. 74. L is -(piperidinylene)-(C 1-5 Alkylene)-(piperazinylene)-(C 2-5 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0495] Embodiment No. 75. L is -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 cycloalkylene)-O-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 -(cycloalkylene)-N(H)-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X 3 -(C 3-6 Cycloalkylene)-N(C 1-4 alkyl)-***, wherein *** is A 2 is the attachment point to X 3 But C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 The compound of any one of embodiments 1-38, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 3C, 3D, 3D, 3E, 3F, 3G, 3H, 3H, 3H, 3H, 3H, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,

[0496] Embodiment No. 76. L is -(piperidinylene)-X 3 -(C 3-6 Cycloalkylene)-O-***, -(piperidinylene)-X 3 -(C 3-6 Cycloalkylene)-N(H)-***, or -(piperidinylene)-X 3 -(C 3-6 cycloalkylene)-***, wherein *** is A 2 is the attachment point to X 3 But C 1-10 Alkylene, -O-, -N(H)-, -N(C 1-4 The compound of any one of embodiments 1-38, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 3A, 3B, 3B, 3C, 3D, 3D, 3E, 3F, 3G, 3H, 3H, 3H, 3H, 3H, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,

[0497] Embodiment No. 77.L is -N(C 1-3 alkyl)-(C 2-7 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-***, -N(H)-(C 2-7 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, -N(H)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-***, -N(H)-(C 2-7 alkylene)-C(O)N(H)-(C 1-6 alkylene)-***, or -N(H)-(C 2-7 alkylene)-C(O)N(C1-3 alkyl)-(C 1-6 alkylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0498] Embodiment No. 78.L is -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-, -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-, -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-N(C 1-3 alkyl)C(O)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-, -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-, or -N(H)-[(C 2-4 alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(H)-(C 1-6 alkylene)-, -N(H)-[(C 2-4alkylene)-O-] 2-8 -(C 2-6 alkylene)-C(O)N(C 1-3 alkyl)-(C 1-6 alkylene)-, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0499] Embodiment No. 79.L is -N(CH3)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 Alkylene)-***, -N(CH3)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(CH3)C(O)-(C 1-6 Alkylene)-***, -N(H)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, or -N(H)-[(CH2CH2)-O-] 2-8 -(C 2-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)-***, wherein *** is A 2 The compound of any one of embodiments 1-38, wherein

[0500] Embodiment No. 80.L is a compound of the formula -(C 0-12 alkylene)-(optionally substituted 3- to 40-membered heteroalkylene)-(C 0-12 The compound of any one of embodiments 1-38, having (alkylene)-.

[0501] Embodiment No. 81. The compound of any one of embodiments 1 to 38, wherein L is one of the following: [ka] (Wherein, *** represents A 2 (This is the connection point to the

[0502] Embodiment No. 82. The compound according to any one of embodiments 1 to 38, wherein L is one of the following: [ka] (Wherein, *** represents A 2 (This is the connection point to the

[0503] Embodiment No. 83.L is [ka] wherein *** is A 2 The compound of any one of embodiments 1-38, wherein [Example]

[0504] The invention generally described herein will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0505] General method All reactions were carried out under an atmosphere of dry nitrogen or argon. Glassware was oven-dried before use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. N,N-Diisopropylethylamine (DIPEA) was obtained anhydrous by distillation over potassium hydroxide. Tetrahydrofuran (THF), dichloromethane (CHCl), and dimethylformamide (DMF) were dried using a PureSolv™ solvent drying system. PTLC refers to preparative thin-layer chromatography separation. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin-layer chromatography (TLC) was performed on Merck silica gel plates using QF-254 indicator and visualized by UV or KMnO.

[0506] 1 H and 13 C NMR spectra were recorded on an Agilent DD2500 (500 MHz 1 H: 125MHz 13 C) or Agilent DD2600 (600MHz 1 H: 150MHz 13 C) or Agilent DD2400 (400MHz 1 H: 100 MHz 13 C) spectrometer at room temperature. Chemical shifts were recorded relative to residual CDCl3 (δ 7.26 ppm 1 H;δ77.0ppm 13 C), CD3OD (δ 3.31 ppm 1 H;δ49.00ppm 13 C), or d6-DMSO (δ 2.50 ppm 1 H;δ39.52 ppm 13 C). NMR chemical shifts are expressed in ppm relative to the internal solvent peak and coupling constants are measured in Hz (bs = broad signal). In most cases, only the peak of the major rotamer is reported.

[0507] Mass spectra were obtained using an Agilent 1100 Series LC / MSD spectrometer. Analytical HPLC analyses were performed on a 250 × 4.6 mm C-18 column using gradient conditions (10–100% B, flow rate = 1.0 mL / min, 20 min) or as described in the LC-MS method table.

[0508] Unless otherwise indicated, preparative HPLC was performed on a 250 × 21.2 mm C-18 column using gradient conditions (10–100% B, flow rate = 10.0 mL / min, 20 min). The eluents used were solvent A (HO containing 0.1% TFA) and solvent B (CHCN containing 0.1% TFA). Final products were typically purified by reverse-phase HPLC, PTLC, or flash column chromatography. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0509] The following abbreviations are used herein: ACN: acetonitrile, Bn: benzyl, Boc: tert-butoxycarbonyl, DCM: dichloromethane, DIEA: diisopropylethylamine, DMF: dimethylformamide, DMSO: dimethylsulfoxide, EtOH: ethanol, EA or EtOAc: ethyl acetate, equivalents or equivalents: molar equivalents, FA: formic acid, h: hour(s), HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate, HPLC: high pressure liquid chromatography, LCMS or LC-MS: liquid chromatography mass spectrometry, MeCN: acetonitrile, MeOH: methanol, MS: mass spectrometry, NMP: N-methylpyrrolidone, NMR: nuclear magnetic resonance, PE: petroleum ether, rt: room temperature, TEA: triethylamine, TFA: trifluoroacetic acid, THF: tetrahydrofuran, TLC: thin layer chromatography, psi: pounds per square inch, and Tos or Ts: p-toluenesulfonyl.

[0510] Example 1 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[2-[(9S)-7]-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl-methyl-amino]pyrimidine-5-carboxamide (I-1) [ka] 1.1 Synthesis of Compound 3 [ka] To a solution of tert-butyl N-[2-(methylamino)ethyl]carbamate (0.50 g, 2.8 μmol, 1.0 equiv.) and ethyl 2-chloropyrimidine-5-carboxylate (535 mg, 2.80 μmol, 1.0 equiv.) in MeCN (3 mL) was added K2CO3 (396 mg, 2.80 μmol, 1.0 equiv.). The mixture was stirred at 80 °C for 12 h. After filtration, the filtrate was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%–65%, 11 min) to give ethyl 2-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]pyrimidine-5-carboxylate (0.45 g, 48% yield) as a white solid.

[0511] 1.2 Synthesis of Compound 4 [ka] To a solution of ethyl 2-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]pyrimidine-5-carboxylate (300 mg, 924 μmol, 1 equiv.) in THF (2 mL) and HO (2 mL) was added LiOH.HO (155 mg, 3.70 μmol, 4 equiv.). The mixture was stirred at 25 °C for 0.5 h. The pH was adjusted to 5-6 with HCl (1 M). The resulting solution was concentrated to give the compound 2-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]pyrimidine-5-carboxylic acid (0.25 g, 91% yield) as a white solid.

[0512] 1.3 Synthesis of Compound 6 [ka] To a solution of 2-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]pyrimidine-5-carboxylic acid (120 mg, 405 μmol, 1.0 equiv.) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (238 mg, 607 μmol, 1.5 equiv., TFA salt) in DMF (1 mL) was added DIEA (157 mg, 1.20 μmol, 211 μL, 3.0 equiv.) and HATU (169 mg, 445 μmol, 1.1 equiv.). The mixture was stirred at 25° C. for 0.5 h. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 48%-78%, 11 min) to give the compound tert-butyl N-[2-[[5-[[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamoyl]pyrimidin-2-yl]-methyl-amino]ethyl]carbamate (0.18 g, 80% yield) as a white solid.

[0513] 1.4 Synthesis of Compound 7 [ka] To a solution of tert-butyl N-[2-[[5-[[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamoyl]pyrimidin-2-yl]-methyl-amino]ethyl]carbamate (70 mg, 0.13 μmol, 1.0 equivalent) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated to give the compound 2-[2-aminoethyl(methyl)amino]-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (71 mg, 98% yield, TFA salt) as a white solid.

[0514] 1.5 Synthesis of Compound I-1 [ka] To a solution of 2-[2-aminoethyl(methyl)amino]-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (65 mg, 0.11 μmol, 1.0 equiv., TFA salt) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (70 mg, 0.14 μmol, 1.2 equiv., TFA salt) in DMF (1 mL) was added HATU (47 mg, 0.13 μmol, 1.1 equiv.) and DIEA (44 mg, 0.34 μmol, 60 μL, 3.0 equiv.). The mixture was stirred at 25° C. for 0.5 hours. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm, 5 μm, mobile phase: [water (NH4HCO3)-ACN]; B%: 56%-86%, 9 min) to obtain the compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl-methyl-amino]pyrimidine-5-carboxamide (26 mg, 27% yield) as an off-white solid. 1 H NMR (400 MHz, CD3OD): 8.74 (s, 2 H), 7.72 (d, J = 8.63 Hz, 1 H), 7.48 - 7.38 (m, 4 H), 7.12 (d, J = 2.38 Hz, 1 H), 6.98 (m, 1 H), 4.68 - 4.68 (m, 4 H), 4.26 (s, 1 H), 4.12 (s, 1 H), 3.90 - 3.68 (m, 2 H), 3.65 - 3.52 (m, 2 H), 3.28 (s, 2 H), 2.69 (s, 3 H), 2.45 (s, 3 H), 1.70 (s, 3 H), 1.25 (s, 6 H), 1.20 (s, 6 H).

[0515] Example 2 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[2-[2-[[2-[(9S)-7]-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethyl-methylamino]pyrimidine-5-carboxamide (I-2) [ka] 1.1 Synthesis of Compound 3 [ka] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (200 mg, 476 μmol, 1.0 equiv.) in NMP (3 mL) was added KCO (131 mg, 953 μmol, 2.0 equiv.) and tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethyl]carbamate (173 mg, 477 μmol, 1.0 equiv.). The mixture was stirred at 50 °C for 2 h and purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 56%-86%, 11 min) to give tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[[5-[[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]pyrimidin-2-yl]-methyl-amino]ethoxy]ethoxy]ethyl]carbamate (280 mg, 79% yield) as a brown-black gum.

[0516] 1.2 Synthesis of Compound 4 [ka] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[[5-[[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]pyrimidin-2-yl]-methyl-amino]ethoxy]ethoxy]ethyl]carbamate (100 mg, 134 μmol, 1.0 equiv) in DCM (3 mL) was added TFA (500 μL). The mixture was stirred at 20° C. for 0.3 h and concentrated to give 2-[2-[2-(2-aminoethoxy)ethoxy]ethyl-methyl-amino]-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide (85 mg, 96% yield, TFA salt) as a yellow gum.

[0517] 1.3 Synthesis of Compound I-2 [ka] To a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethyl-methyl-amino]-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide (85 mg, 129 μmol, 1.0 equiv., TFA salt) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (52 mg, 129 μmol, 1.0 equiv.) in DMF (3 mL) was added HATU (59 mg, 154 μmol, 1.2 equiv.) and DIEA (50 mg, 387 μmol, 3.0 equiv.). The mixture was stirred at 20°C for 0.5 h and then purified by preparative HPLC (column: Phenomenex luna C18 Purification by chromatography (250 × 50 mm, 15 μm; mobile phase: [water (FA)-ACN]; B%: 80%-100%, 10 min) gave N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethyl-methylamino]pyrimidine-5-carboxamide (60 mg, 49% yield) as an off-white solid. 1H NMR (400 MHz, MeOD): δ 8.74 (s, 2H), 8.45-8.37 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.49-7.41 (m, 4H), 7.13 (d, J = 2.4 Hz, 1H), 7.00-6.98 (m, 1H), 4.67-4.65 (m, 1H), 4.27 (s, 1H), 4.14 (d, J = 8.8 Hz, 1H), 3.95-3.89 (m, 2H), 3.78-3.73 (m, 2H), 3.67-3.63 (m, 4H), 3.61-3.57 (m, 2H), 3.49-3.38 (m, 4H), 3.28 (s, 3H), 2.71 (s, 3H), 2.46 (s, 3H), 1.71 (s, 3H), 1.27 (s, 6H), 1.22 (s, 6H).

[0518] Example 3 - Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl)(methyl)amino)pyrimidine-5-carboxamide (I-3) [ka] 1.1 Synthesis of Compound 2 [ka] To a solution of compound 1 (1.90 g, 4.34 μmol, 1.0 equiv.) and TEA (878 mg, 8.69 μmol, 1.2 mL, 2.0 equiv.) in DCM (25 mL) was added TosCl (827 mg, 4.34 μmol, 1.0 equiv.). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give compound 2 (1.88 g, 3.18 μmol, 73% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): 7.81 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.19 - 4.14 (m, 2H), 3.81 - 3.77 (m, 2H), 3.71 - 3.67 (m, 2H), 3.63 - 3.58 (m, 14H), 2.45 (s, 3H), 1.50 (s, 18H).

[0519] 1.2 Synthesis of Compound 4 [ka] To a solution of compound 2 (1.80 g, 3.04 μmol, 1.0 equiv.) and compound 3 (736 mg, 6.08 μmol, 784 μL, 2.0 equiv.) in CHCN (25 mL) was added KCO (1.26 g, 9.12 μmol, 3.0 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters X bridge C18 150 × 50 mm, 10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 54%-84%, 11 min) to give the desired compound 4 (1.43 g, 2.64 μmol, 87% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): 7.31 (d, J = 4.2 Hz, 4H), 7.26 - 7.21 (m, 1H), 3.83 - 3.74 (m, 2H), 3.65 - 3.59 (m, 16H), 3.56 (s, 2H), 2.63 (t, J = 6.1 Hz, 2H), 2.26 (s, 3H), 1.50 (s, 18H).

[0520] 1.3 Synthesis of Compound 5 [ka] To a solution of compound 4 (600 mg, 1.11 μmol, 1.0 equiv) in TFE (8 mL) under a N atmosphere was added Pd(OH) (155 mg). The suspension was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 5 (480 mg, 90% yield) as a yellow oil, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3): 3.81 - 3.77 (m, 2H), 3.65 - 3.57 (m, 18H), 2.75 (t, J = 5.2 Hz, 2H), 2.44 (s, 3H), 1.51 (s, 18H).

[0521] 1.4 Synthesis of Compound 7 [ka] To a solution of compound 5 (240 mg, 532 μmol, 1.0 equiv.) and compound 6 (99 mg, 0.53 μmol, 1.0 equiv.) in CH3CN (4 mL) was added DIEA (206 mg, 1.60 μmol, 278 μL, 3.0 equiv.). The mixture was stirred at 20 °C for 12 h. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 40 mm, 15 μm, mobile phase: [water (TFA)-ACN]; B%: 55% to 85%, 11 min) to give the desired compound 7 (277 mg, 461 μmol, 86% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): 8.90 (m, 2H), 4.41 - 4.29 (m, 2H), 3.98 - 3.91 (m, 2H), 3.82 - 3.77 (m, 2H), 3.74 (t, J = 5.5 Hz, 2H), 3.65 - 3.59 (m, 13H), 3.37 (s, 3H), 1.50 (s, 18H), 1.37 - 1.37 (m, 1H), 1.38 (t, J = 7.1 Hz, 2H).

[0522] 1.5 Synthesis of Compound 8 [ka] To a solution of compound 7 (150 mg, 249 μmol, 1.0 equiv.) in THF (2 mL) was added LiOH.HO (1 M, 2.0 mL, 6.0 equiv.). The mixture was stirred at 20 °C for 12 h. The pH was adjusted to 6-7 with 1 N HCl. After extraction with DCM / MeOH (10:1, 30 mL × 3), the organic layer was dried over anhydrous NaSO, filtered, and concentrated to give compound 8 (142 mg, 87% yield) as a colorless oil, which was used directly in the next step.

[0523] 1.6 Synthesis of Compound 10 [ka] To a solution of compound 8 (105 mg, 268 μmol, 1.1 equiv., TFA salt) and compound 9 (140 mg, 244 μmol, 1.0 equiv.) in DMF (1 mL) was added DIEA (94 mg, 0.73 μmol, 127 μL, 3.0 equiv.) and HATU (139 mg, 366 μmol, 1.5 equiv.). The mixture was stirred at 20 °C for 0.5 h. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 mm × 30 mm, 3 μm; mobile phase: [water (TFA)-ACN]; B%: 63%-93%, 7 min) to give compound 10 (35 mg, 27 μmol, 11% yield) as a yellow gum.

[0524] 1.7 Synthesis of Compound 11 [ka] To a solution of compound 10 (110 mg, 150 μmol, 1.0 equiv.) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give compound 10 (112 mg, 95% yield, TFA salt) as a yellow oil, which was used directly in the next step.

[0525] 1.8 Synthesis of Compound I-3 [ka] To a solution of compound 11 (112 mg, 149 μmol, 1.0 equiv., TFA salt) and compound 12 (60 mg, 0.15 μmol, 1.0 equiv., TFA salt) in DMF (2 mL) was added DIEA (58 mg, 0.45 μmol, 78 μL, 3.0 equiv.) and HATU (85 mg, 0.23 μmol, 1.5 equiv.), and the mixture was stirred at 20° C. for 0.5 h. The residue was purified by preparative HPLC (column: Phenomenex C18 75 mm × 30 mm, 3 μm; mobile phase: [water (FA)-ACN]; B%: 58%-88%, 7 min) to give the compound N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl)(methyl)amino)pyrimidine-5-carboxamide (49 mg, 48 μmol, 32% yield) as an off-white solid. 1H NMR (400 MHz, CD3OD): 8.74 (s, 2H), 7.73 (d, J = 8.7 Hz, 1H), 7.48 - 7.40 (m, 4H), 7.13 (d, J = 2.3 Hz, 1H), 6.99 (m, 1H), 4.79 - 4.73 (m, 3H), 4.30 - 4.25 (m, 1H), 4.17 - 4.12 (m, 1H), 3.99 - 3.87 (m, 1H), 3.92 - 3.86 (m, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.66 (s, 4H), 3.64 - 3.61 (m, 9H), 3.49 - 3.44 (m, 3H), 3.26 (s, 3H), 2.71 (s, 3H), 2.46 (s, 3H), 1.71 (s, 3H), 1.28 (d, J = 2.9 Hz, 6H), 1.22 (s, 6H).

[0526] Example 4 - Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((3-(4-(3-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propyl)piperazin-1-yl)propyl)(methyl)amino)pyrimidine-5-carboxamide (I-5) [ka] 1.1 Synthesis of Compound 2 [ka] To a solution of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (8.0 g, 42 μmol, 1.0 equiv.) in DCM (80 mL) was added TosCl (16 g, 84 μmol, 2.0 equiv.) and TEA (16.0 g, 158 μmol, 22.0 mL, 3.7 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the compound 3-[tert-butoxycarbonyl(methyl)amino]propyl 4-methylbenzenesulfonate (7.0 g, 20 μmol, 48% yield) as a colorless oil.

[0527] 1.2 Synthesis of Compound 4 [ka] To a solution of 3-[tert-butoxycarbonyl(methyl)amino]propyl 4-methylbenzenesulfonate (7.0 g, 20 μmol, 1.0 equiv.) in DMF (70 mL) was added KCO (5.6 g, 41 μmol, 2.0 equiv.) and benzyl piperazine-1-carboxylate (4.49 g, 20.4 μmol, 3.9 mL, 1.0 equiv.). The mixture was stirred at 50° C. for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 40 mm, 15 μm, mobile phase: [water (FA)-ACN]; B%: 12% to 42%, 10 min loading) to obtain the compound 4-[3-[tert-butoxycarbonyl(methyl)amino]propyl]piperazine-1-carboxylate benzyl (1.2 g, 3.1 μmol, 15% yield) as a yellow oil.

[0528] 1.3 Synthesis of Compound 5 [ka] To a solution of benzyl 4-[3-[tert-butoxycarbonyl(methyl)amino]propyl]piperazine-1-carboxylate (1.2 g, 3.1 μmol, 1.0 equiv.) in TFE (12 mL) under N was added Pd / C (300 mg, 10% purity). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 25 °C under H (15 psi) for 12 h. The reaction was filtered, and the filtrate was concentrated in vacuo to give the crude product. The compound tert-butyl N-methyl-N-(3-piperazin-1-ylpropyl)carbamate (780 mg, crude) was obtained as a white solid.

[0529] 1.4 Synthesis of Compound 7 [ka] To a solution of tert-butyl N-methyl-N-(3-piperazin-1-ylpropyl)carbamate (680 mg, 2.64 μmol, 1.2 equiv.) in DMF (20 mL) was added K2CO3 (609 mg, 4.41 μmol, 2.0 equiv.) and benzyl N-(3-bromopropyl)carbamate (600 mg, 2.20 μmol, 1.0 equiv.). The mixture was stirred at 25 °C for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 mm × 50 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 37%-67%, 11 min). The compound N-[3-[4-[3-(benzyloxycarbonylamino)propyl]piperazin-1-yl]propyl]-N-methyl-tert-butylcarbamate (680 mg, 1.52 μmol, 69% yield) was obtained as a colorless oil.

[0530] 1.5 Synthesis of Compound 8 [ka] To a solution of tert-butyl N-[3-[4-[3-(benzyloxycarbonylamino)propyl]piperazin-1-yl]propyl]-N-methyl-carbamate (680 mg, 1.52 μmol, 1.0 equiv.) in TFE (10 mL) under N was added Pd / C (1.52 μmol, 10% purity, 1.0 equiv.). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 25 °C under H (15 psi) for 1 h. The reaction was filtered, and the filtrate was concentrated in vacuo to give the crude product. The compound tert-butyl N-[3-[4-(3-aminopropyl)piperazin-1-yl]propyl]-N-methyl-carbamate (400 mg, crude) was obtained as a white solid.

[0531] 1.6 Synthesis of Compound 10 [ka] A solution of tert-butyl N-[3-[4-(3-aminopropyl)piperazin-1-yl]propyl]-N-methyl-carbamate (75 mg, 0.24 mmol, 1.0 equiv.) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0]]-methyl]carbamate (8.3.0) in DMF (2 mL) was dissolved in 10 mL of tert-butyl N-[3-[4-(3-aminopropyl)piperazin-1-yl]propyl]-N-methyl-carbamate (8.3.0) 2,6 To a solution of ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (95.61 mg, 238.5 μmol, 1.0 equiv.), HATU (181 mg, 0.477 μmol, 2 equiv.) and DIEA (154 mg, 1.19 μmol, 0.21 mL, 5.0 equiv.) were added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, dichloromethane / methyl alcohol = 30 / 1 to 3 / 1). The compound N-[3-[4-[3-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0] 2,6tert-Butyl]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]propyl]piperazin-1-yl]propyl]-N-methyl-carbamate (150 mg, 0.215 μmol, 90% yield) was obtained as a white solid.

[0532] Synthesis of compound 11 [ka] N-[3-[4-[3-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6 To a solution of tert-butyl]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]propyl]piperazin-1-yl]propyl]-N-methyl-carbamate (150 mg, 0.215 μmol, 1.0 equiv.) was added TFA (3.08 g, 27.0 μmol, 2 mL, 126 equiv.). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product. Compound 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0] 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-[4-[3-(methylamino)propyl]piperazin-1-yl]propyl]acetamide (128 mg, crude) as a white solid.

[0533] 1.7 Synthesis of I-5 [ka] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (84 mg, 0.20 μmol, 1 equiv.) in NMP (3 mL) was added K2CO3 (56 mg, 0.40 μmol, 2.0 equiv.) and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.0]. 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-[4-[3-(methylamino)propyl]piperazin-1-yl]propyl]acetamide (120 mg, 0.201 μmol, 1.0 equiv.) was added. The mixture was stirred at 50 °C for 0.5 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge C18 150 mm × 50 mm, 10 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 48%-78%, 11 min). The compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[3-[4-[3-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]propyl]piperazin-1-yl]propyl-methyl-amino]pyrimidine-5-carboxamide (36 mg, 35 μmol, 17% yield, 95% purity) was obtained as a yellow solid. 1H NMR (CD3OD ,400 MHz): δ 8.75 (s, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.49 - 7.38 (m, 4H), 7.14 (d, J = 2.4 Hz, 1H), 7.00 (m, 1H), 4.65 (m, 3H), 4.29 (s, 1H), 4.15 (s, 1H), 3.78 (t, J = 7.2 Hz, 2H), 3.46 - 3.38 (m, 1H), 3.31 - 3.27 (m, 3H), 3.24 (s, 3H), 2.71 (s, 3H), 2.64 - 2.51 (m, 4H), 2.50 - 2.41 (m, 8H), 1.92 - 1.84 (m, 2H), 1.83 - 1.75 (m, 2H), 1.72 (s, 3H), 1.30 (s, 6H), 1.23 - 1.23 (m, 1H), 1.23 (s, 6H).

[0534] Example 5—Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((5-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)oxy)piperidin-1-yl)pyrimidine-5-carboxamide (I-22) [ka] 1.1 Synthesis of Compound 3 [ka] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.89 g, 14.4 μmol, 1.0 equiv.) in THF solution (50 mL) was added NaH (861 mg, 21.5 μmol, 60% purity, 1.5 equiv.) and 5-benzyloxypentyl 4-methylbenzenesulfonate (5.0 g, 14.4 μmol, 1.0 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1). The compound tert-butyl 4-(5-benzyloxypentoxy)piperidine-1-carboxylate (3.3 g, 8.7 μmol, yield 61%) was obtained as a white solid.

[0535] 1.2 Synthesis of Compound 4 [ka] To a solution of tert-butyl 4-(5-benzyloxypentoxy)piperidine-1-carboxylate (3.3 g, 8.7 μmol, 1.0 equiv) in TFE (30 mL) under N was added Pd / C (2.0 g, 10% purity). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at 25 °C for 2 h. The reaction was filtered, and the filtrate was concentrated in vacuo to give crude tert-butyl 4-(5-hydroxypentoxy)piperidine-1-carboxylate (2.4 g, crude) as a white solid.

[0536] 1.3 Synthesis of Compound 5 [ka] To a solution of tert-butyl 4-(5-hydroxypentoxy)piperidine-1-carboxylate (2.4 g, 8.4 μmol, 1.0 equiv.) in DCM (30 mL) was added TosCl (3.18 g, 16.7 μmol, 2.0 equiv.) and TEA (3.38 g, 33.4 μmol, 4.7 mL, 4.0 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1). tert-Butyl 4-[5-(p-tolylsulfonyloxy)pentoxy]piperidine-1-carboxylate (3.3 g, 7.5 μmol, 89% yield) was obtained as a white solid.

[0537] 1.4 Synthesis of Compound 7 [ka] To a solution of tert-butyl 4-[5-(p-tolylsulfonyloxy)pentoxy]piperidine-1-carboxylate (1.6 g, 3.6 μmol, 1.0 equiv.) in DMSO (15 mL) was added DIEA (2.34 g, 18.1 μmol, 3.16 mL, 5.0 equiv.) and N-benzyl-1-phenyl-methanamine (715 mg, 3.62 μmol, 694 μL, 1.0 equiv.). The mixture was stirred at 80 °C for 2 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). tert-Butyl 4-[5-(dibenzylamino)pentoxy]piperidine-1-carboxylate (200 mg, 429 μmol, 12% yield) was obtained as a white solid.

[0538] 1.5 Synthesis of Compound 8 [ka] To a solution of tert-butyl 4-[5-(dibenzylamino)pentoxy]piperidine-1-carboxylate (200 mg, 429 μmol, 1.0 equiv) in TFE (10 mL) under N was added Pd / C (100 mg, 10% purity). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at 25 °C for 2 h. The reaction was filtered, and the filtrate was concentrated in vacuo to give the crude product tert-butyl 4-(5-aminopentoxy)piperidine-1-carboxylate (120 mg, crude) as a white solid.

[0539] 1.6 Synthesis of Compound 10 [ka] tert-Butyl 4-(5-aminopentoxy)piperidine-1-carboxylate (80 mg, 0.28 μmol, 1.0 equiv.), 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[(8.3.0)]]. 2,6 To a solution of ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (112 mg, 279 μmol, 1.0 equiv.) was added HATU (212 mg, 559 μmol, 2.0 equiv.) and DIEA (181 mg, 1.40 μmol, 243 μL, 5.0 equiv.). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 mm × 30 mm, 3 mm; mobile phase: [water (TFA)-ACN]; B%: 65%-85%, 7 min as additive) to give 4-[5-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0] 2,6 tert-Butyl]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]pentoxy]piperidine-1-carboxylate (120 mg, 179 μmol, 64% yield) was obtained as a white solid.

[0540] 1.7 Synthesis of Compound 11 [ka] 4-[5-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6 To a solution of tert-butyl 2-[(9S)-trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]pentoxy]piperidine-1-carboxylate (60 mg, 90 μmol, 1.0 equiv.) was added TFA (1.85 g, 16.2 μmol, 1.2 mL, 181 equiv.). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give crude 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[(4,5,13-trimethylphenyl) ... 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[5-(4-piperidyloxy)pentyl]acetamide (50 mg, crude) as a white solid.

[0541] 1.8 Synthesis of I-22 [ka] To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[5-(4-piperidyloxy)pentyl]acetamide (45 mg, 79 μmol, 1.0 equiv.) in NMP (1 mL) was added KCO (55 mg, 0.40 μmol, 1.1 mL, 5.0 equiv.) and 2-chloro-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide (33 mg, 79 μmol, 1.0 equiv.). The mixture was stirred at 50° C. for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150mm x 50mm, 3mm; mobile phase: [water (FA)-ACN]; B%: 60%-90%, 10 min as additive) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[5-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0]. 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]pentoxy]-1-piperidyl]pyrimidine-5-carboxamide (35 mg, 37 μmol, 47% yield, 100% purity) was obtained as a yellow solid. 1H NMR (400 MHz, MeOD): δ 8.69-8.74 (m, 2 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.39-7.48 (m, 4 H), 7.12 (d, J = 2.4 Hz, 1 H), 6.98 (m, 1 H), 4.52-4.65 (m, 2 H), 4.23-4.35 (m, 3 H), 3.61 (m, 1 H), 3.51-3.58 (m, 4 H), 3.42 (m, 1 H), 3.26 (m, 3 H), 2.70 (s, 3 H), 2.45 (s, 3 H), 1.92 (m, 2 H), 1.70 (s, 3 H), 1.59-1.67 (m, 4 H), 1.45-1.56 (m, 4 H), 1.28 (s, 6 H), 1.21 (s, 6 H).

[0542] Example 6 - Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (I-35) [ka] 1.1 Synthesis of Compound 2 [ka] To a solution of benzyl piperazine-1-carboxylate (10 g, 45.4 μmol, 1.0 equiv.) and tert-butyl 4-formylpiperidine-1-carboxylate (9.68 g, 45.4 μmol, 1.0 equiv.) in DCE (30 mL) was added AcOH (272 mg, 4.54 μmol, 0.1 equiv.). The mixture was stirred at 25 °C for 1 h, and NaBH(OAc) (28.9 g, 136 μmol, 3.0 equiv.) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1). The compound 4-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate was obtained (18 g, 95% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 - 7.31 (m, 5H), 5.15 (s, 2H), 4.19 - 4.11 (m, 2H), 3.52 (s, 4H), 2.70 (J = 11.4 Hz, 2H), 2.38 (s, 4H), 2.25 - 2.14 (m, 2H), 1.74 (J = 10.9 Hz, 2H), 1.70 - 1.62 (m, 1H), 1.48 - 1.46 (m, 9H), 1.16 - 0.98 (m, 2H).

[0543] 1.2 Synthesis of Compound 3 [ka] To a solution of benzyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (5 g, 11.97 μmol, 1.0 equiv.) in THF (150 mL) was added Pd / C (500 mg, 10% purity). The mixture was stirred under H (15 psi) at 20° C. for 1 h. The mixture was filtered and concentrated to give tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.1 g, 91% yield).

[0544] 1.3 Synthesis of Compound 4 [ka] To tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1 g, 3.53 μmol, 1 equiv.) and 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (667 mg, 3.53 μmol, 1.0 equiv.) in DCE (10 mL) was added AcOH (21 mg, 353 μmol, 0.1 equiv.). The mixture was stirred at 25 °C for 1 h, and NaBH(OAc) (2.24 g, 10.59 μmol, 3.0 equiv.) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was partitioned between HO (30 mL) and DCM (30 mL). The organic phase was separated, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give tert-butyl 4-[[4-[2-(1,3-dioxoisoindolin-2-yl)ethyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (1.6 g, yield 99%). 1 H NMR (400 MHz, CDCl3): δ 7.82 - 7.73 (m, 2H), 7.68 - 7.61 (m, 2H), 4.03 - 3.91 (m, 2H), 3.76 (t, J = 6.6 Hz, 2H), 2.70 - 2.47 (m, 8H), 2.40 (s, 3H), 2.14 (d, J = 6.8 Hz, 2H), 1.87 (s, 2H), 1.63 (d, J = 13.2 Hz, 2H), 1.38 (s, 8H), 1.12 - 0.87 (m, 2H).

[0545] 1.4 Synthesis of Compound 5 [ka] To a solution of tert-butyl 4-[[4-[2-(1,3-dioxoisoindolin-2-yl)ethyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (1.2 g, 2.63 μmol, 1.0 equiv.) in EtOH (50 mL) was added NH 4 .HO (1.34 g, 26.3 μmol, 98% purity, 10 equiv.). The mixture was stirred at 70 °C for 2 h. The mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm, 5 mm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 18% to 48%, 10 min) to afford tert-butyl 4-[[4-(2-aminoethyl)piperazin-1-yl]methyl]piperidine-1-carboxylate (480 mg, 56% yield) as a white oil. 1 H NMR (400 MHz, CDCl3): δ 4.13 (s, 4H), 2.84 (t, J = 6.1 Hz, 2H), 2.68 (t, J = 12.0 Hz, 2H), 2.55 - 2.40 (m, 8H), 2.17 (d, J = 6.8 Hz, 2H), 1.71 (d, J = 12.8 Hz, 2H), 1.66 - 1.56 (m, 1H), 1.45 (s, 9H), 1.06 (J = 4.3, 12.2 Hz, 2H).

[0546] 1.5 Synthesis of Compound 6 [ka] To a solution of tert-butyl 4-[[4-(2-aminoethyl)piperazin-1-yl]methyl]piperidine-1-carboxylate (50 mg, 153 μmol, 1.0 equiv.) in DMF (2 mL) was added DIEA (99 mg, 766 μmol, 5.0 equiv.), 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (61 mg, 153 μmol, 1.0 equiv.), and HATU (69 mg, 183 μmol, 1.2 equiv.). The mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated and purified by preparative TLC (SiO, DCM / MeOH=10 / 1) to give tert-butyl 4-[[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (40 mg, 37% yield).

[0547] 1.6 Synthesis of Compound 7 [ka] To a solution of tert-butyl 4-[[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (80 mg, 113 μmol, 1.0 equiv.) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 20° C. for 0.5 h. The crude product was used directly in the next step.

[0548] 1.7 Synthesis of I-35 [ka] To a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[4-(4-piperidylmethyl)piperazin-1-yl]ethyl]acetamide (60 mg, 98 μmol, 1.0 equiv.) in NMP (3 mL) was added KCO (136 mg, 985 μmol, 10 equiv.) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (45 mg, 108 μmol, 1.1 equiv.). The mixture was stirred at 50° C. for 2 h and concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm, 5 mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 55%-85%, 9 min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl]piperazin-1-yl]methyl]-1-piperidyl]pyrimidine-5-carboxamide (31.5 mg, 31% yield). 1H NMR (400 MHz, METHANOL-d4): δ 8.74 (s, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.59 - 7.35 (m, 4H), 7.15 (d, J = 2 Hz, 1H), 7.00 (d, J = 2.4, 8.7 Hz, 1H), 4.71 - 4.53 (m, 2H), 4.29 (s, 1H), 4.15 (s, 1H), 3.50 - 3.40 (m, 3H), 3.38 - 3.35 (m, 1H), 3.00 (t, J = 12.2 Hz, 2H), 2.72 (s, 3H), 2.64 - 2.41 (m, 12H), 2.25 (d, J = 6.8 Hz, 2H), 1.95 - 1.85 (m, 3H), 1.73 (s, 3H), 1.33 - 1.26 (m, 7H), 1.23 (s, 6H), 1.19 - 1.05 (m, 2H).

[0549] ...

Claims

1. Compounds represented by formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is cyano, halogen, and R ４ is phenyl substituted by m occurrences of R ２ is independently expressed as C １－４ represents alkyl, R ３ is hydrogen or C １－４ is alkyl, R ４ is C １－４ is alkyl, R ５ is independently expressed as C １－４ represents alkyl or halogen, or R ５ One occurrence of R ３ Together with C １－３ Forming an alkylene A １ is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R ５ is replaced by n occurrences of A ２ is one of the following: 【Chemistry 2】 R １Ａ is C １－４ Alkyl or C ３－４ is cycloalkyl, R ２Ａ is independently expressed as C １－４ Alkyl or C ３－４ represents cycloalkyl, R ３Ａ Ha, Halo, C １ -C ４ Alkyl, or C １ -C ４ phenyl substituted with 1, 2, or 3 substituents independently selected from haloalkyl; R ４Ａ is -(C １－６ alkylene)-C(O)N(R ５Ａ ) (R ６Ａ ), -(C １－６ alkylene)-N(R ５Ａ ) C(O)R ７Ａ , -(C １－６ (alkylene)-CO ２ R ８Ａ , -(C １－６ (alkylene)-OC(O)R ７Ａ , -(C １－６ alkylene)-CN, -(C １－６ alkylene)-O-(C １－６ alkyl), C １－６ Alkyl, C ３－６ cycloalkyl, or -(C ０－６ alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is C １－６ the 5- to 6-membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R ５Ａ and R ６Ａ are independently hydrogen, C １－６ Alkyl or C ３－６ cycloalkyl or R ５Ａ and R ６Ａ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom, R ７Ａ is C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ８Ａ is a halogen, C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ９Ａ is a halo, R １０Ａ is independently expressed as C １－４ Alkyl or -N(R １１Ａ ) ２ represents R １１Ａ is independently at each occurrence a halogen or C １－４ represents alkyl, R １２Ａ is -(C ０－６ alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is C １－６ the 5- to 6-membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; L is a linker, k is 1, 2, 3, or 4; m, n, p, and q are independently 0, 1, or 2; s is 1 or 2).

2. R ２ The compound of claim 1 , wherein is methyl.

3. R ３ 3. The compound of claim 1 or 2, wherein is hydrogen.

4. The compound according to any one of claims 1 to 3, wherein m is 0.

5. R １ but, 【Chemistry 3】 The compound according to any one of claims 1 to 3,

6. The compound according to any one of claims 1 to 5, wherein k is 4.

7. The compound of any one of claims 1 to 6, wherein the compound is a compound of formula I:

8. 3. The compound of claim 1 or 2, wherein the compound is a compound of formula Ia, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

9. 3. The compound of claim 1 or 2, wherein the compound is a compound of formula Ib, or a pharmaceutically acceptable salt thereof: 【Chemistry 5】

10. 2. The compound of claim 1, wherein the compound is a compound of formula Ic, or a pharmaceutically acceptable salt thereof: 【Chemistry 6】

11. 2. The compound of claim 1, wherein the compound is a compound of formula Id, or a pharmaceutically acceptable salt thereof: 【Chemistry 7】

12. A １ But, R ５ 12. The compound of any one of claims 1 to 11, which is pyridazinylene substituted with n occurrences of:

13. A １ but, 【Chemistry 8】 The compound according to any one of claims 1 to 11,

14. A １ But, R ５ 12. The compound of any one of claims 1 to 11, which is pyrimidinylene substituted with n occurrences of:

15. A １ but, 【Chemistry 9】 The compound of any one of claims 1 to 11, wherein ** is the point of attachment to L.

16. A １ but, 【Chemistry 10】 The compound of any one of claims 1 to 11, wherein ** is the point of attachment to L.

17. A １ But, R ５ The compound of any one of claims 1 to 11, which is pyrazinylene substituted with n occurrences of:

18. A １ but, 【Chemistry 11】 The compound according to any one of claims 1 to 11,

19. A １ But, R ５ The compound of any one of claims 1 to 11, which is pyridinylene substituted with n occurrences of:

20. A １ but, 【Chemistry 12】 The compound of any one of claims 1 to 11, wherein ** is the point of attachment to L.

21. 20. The compound of any one of claims 1 to 12, 14, 17, or 19, wherein n is 0.

22. A ２ but, 【Chemistry 13】 The compound according to any one of claims 1 to 21,

23. R ３Ａ The compound of any one of claims 1 to 22, wherein is phenyl substituted with halo.

24. A ２ but, 【Chemistry 14】 The compound according to any one of claims 1 to 21,

25. R ４Ａ But -(C １－６ alkylene)-C(O)N(R ５Ａ ) (R ６Ａ 25. The compound according to any one of claims 1 to 21 or 24, wherein

26. R ４Ａ But -(C １－６ (alkylene)-CO ２ R ８Ａ 25. The compound of any one of claims 1 to 21 or 24, wherein

27. R ４Ａ But -(C ０－６ 25. The compound of any one of claims 1-21 or 24, wherein the compound is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

28. R ４Ａ But -(C １－３ 25. The compound of any one of claims 1 to 21 or 24, which is a 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

29. R ４Ａ But -(C １－３ 25. The compound of any one of claims 1 to 21 or 24, which is a (alkylene)-(oxazolyl).

30. R １Ａ But C １－４ The compound of any one of claims 1 to 29, which is alkyl.

31. R １Ａ The compound according to any one of claims 1 to 29, wherein is methyl.

32. R ２Ａ But C １－４ The compound of any one of claims 1 to 31, which is alkyl.

33. R ２Ａ The compound according to any one of claims 1 to 31, wherein is methyl.

34. The compound of any one of claims 1 to 33, wherein p is 2.

35. A ２ but, 【Chemistry 15】 The compound according to any one of claims 1 to 21,

36. A ２ but, 【Chemistry 16】 The compound according to any one of claims 1 to 21,

37. A ２ but, 【Chemistry 17】 The compound according to any one of claims 1 to 21,

38. A ２ but, 【Chemistry 18】 The compound according to any one of claims 1 to 21,

39. A ２ but, 【Chemistry 19】 The compound according to any one of claims 1 to 21,

40. A ２ but, 【Chemistry 20】 The compound according to any one of claims 1 to 21,

41. A ２ but, 【Chemical 21】 22. The compound according to any one of claims 1 to 21, wherein q is 1.

42. A ２ but, 【Chemical 22】 The compound according to any one of claims 1 to 21,

43. A ２ but, 【Chemical 23】 The compound according to any one of claims 1 to 21,

44. A ２ but, 【Chemistry 24】 The compound according to any one of claims 1 to 21,

45. A ２ is one of the following: 【Chemistry 25】

46. Compounds represented by formula I*: 【Chemical 26】 or a pharmaceutically acceptable salt thereof, wherein R １ is cyano, halogen, and R ４ is phenyl substituted by m occurrences of R ２ is independently expressed as C １－４ represents alkyl, R ３ is hydrogen or C １－４ is alkyl, R ４ is C １－４ is alkyl, R ５ is independently expressed as C １－４ represents alkyl or halogen, or R ５ One occurrence of R ３ Together with C １－３ Forming an alkylene A １ is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R ５ is replaced by n occurrences of A ２ teeth, 【Chemical 27】 and R １Ａ is C １－４ Alkyl or C ３－４ is cycloalkyl, R ２Ａ is independently expressed as C １－４ Alkyl or C ３－４ represents cycloalkyl, R ３Ａ Ha, Halo, C １ -C ４ Alkyl, or C １ -C ４ phenyl substituted with 1, 2, or 3 substituents independently selected from haloalkyl; R ４Ａ is C １－６ Hydroxyalkyl, C １－４ Haloalkyl, -(C １－６ alkylene)-C(O)N(R ５Ａ ) (R ６Ａ ), -(C １－６ alkylene)-N(R ５Ａ ) C(O)R ７Ａ , -(C １－６ (alkylene)-CO ２ R ８Ａ , -(C １－６ (alkylene)-OC(O)R ７Ａ , -(C １－６ alkylene)-CN, -(C １－６ alkylene)-O-(C １－６ alkyl), C １－６ Alkyl, C ３－６ cycloalkyl, or -(C ０－６ alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is C １－６ the 5- to 6-membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R ５Ａ and R ６Ａ are independently hydrogen, C １－６ Alkyl or C ３－６ cycloalkyl or R ５Ａ and R ６Ａ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom, R ７Ａ is C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ８Ａ is a halogen, C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ９Ａ is a halo, R １０Ａ is hydrogen or C １－４ alkyl or R ４Ａ and R １０Ａ together with the carbon atoms to which they are attached form a 3- to 5-membered saturated carbocyclic ring, L is a linker, k is 1, 2, 3, or 4; m, n, p, and q are independently 0, 1, or 2.

47. A ２ is one of the following: 【Chemical Formula 28】

48. L is a divalent saturated or unsaturated, linear or branched C １－６０ a hydrocarbon chain, wherein 0 to 20 methylene units of said hydrocarbon are independently —O—, —S—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(H)S(O) ２ -, -N(C １－６ alkyl)S(O) ２ -, -S(O) ２ N(H)-, -S(O) ２ N (C １－６ alkyl)-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C １－６ alkyl)-, —OC(O)N(H)-, —OC(O)N(C １－６ alkyl)-, -N(H)C(O)O-, -N(C １－６ alkyl)C(O)O-, -N(C ３－７ cycloalkyl)-, an optionally substituted 3- to 10-membered carbocyclyl, or an optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

49. L is a divalent saturated linear or branched C ３－３０ a hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently —O—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the aryl group is substituted with aryl, ...

50. L is a divalent saturated linear or branched C ３－３０ a hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently —O—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)—, —C(O)N(H)—, or —C(O)N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is substituted with (alkyl)-.

51. L is a divalent saturated or unsaturated, linear or branched C ５－４０ a hydrocarbon chain, wherein 1 to 20 methylene units of said hydrocarbon are independently —O—, —N(H)—, —N(C １－６ alkyl)-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the aryl group is substituted by an optionally substituted 3- to 10-membered carbocyclyl, or an optionally substituted 3- to 10-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

52. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１５ -O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

53. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－５ -O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

54. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) ６－１０ -O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

55. L is -piperidinylene-(OCH ２ CH ２ ) １－１５ -O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

56. L, 【Chemical 29】 wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

57. L, 【Chemistry 30】 wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

58. L, 【Chemical 31】 wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

59. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１５ -N(H)C(O)-C １－１０ alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１５ -N(C １－４ alkyl)C(O)-C １－１０ alkylene-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１５ -C(O)N(H)-C １－１０ alkylene-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１５ -C(O)N(C １－４ alkyl)-C １－１０ alkylene-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

60. L is -piperidinylene-(OCH ２ CH ２ ) １－５ -N(H)C(O)-C １－５ Alkylene-***, -piperidinylene-(OCH ２ CH ２ ) １－５ -N(C １－４ alkyl)C(O)-C １－５ Alkylene-***, -piperidinylene-(OCH ２ CH ２ ) １－５ -C(O)N(H)-C １－５ Alkylene-***, or -piperidinylene-(OCH ２ CH ２ ) １－５ -C(O)N(C １－４ alkyl)-C １－５ alkylene-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

61. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ２ CH ２ ) １－１０ -***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－１０ alkylene)-O-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-C １－１０ alkylene, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

62. L is -piperidinylene-(OCH ２ CH ２ ) １－５ -***, -piperidinylene-(C ０－５ alkylene)-O-***, or -piperidinylene-(C １－５ alkylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

63. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X １ -***, where *** is A ２ is the point of attachment to X １ (i) one or two methylene groups are —O—, —N(H)—, or —N(C １－４ C optionally replaced by alkyl)- １－１０ alkylene, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C １－１０ 48. The compound of any one of claims 1 to 47, wherein:

64. L is -(piperidinylene)-X １ -***, where *** is A ２ is the point of attachment to X １ (i) one or two methylene groups are —O—, —N(H)—, or —N(C １－４ C optionally replaced by alkyl)- １－５ alkylene, (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C １－５ 48. The compound of any one of claims 1 to 47, wherein:

65. L, 【Chemical 32】 wherein *** is A ２ is the point of attachment to X １ (i) one or two methylene groups are —O—, —N(H)—, or —N(C １－４ C optionally replaced by alkyl)- １－１０ alkylene, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C １－１０ 48. The compound of any one of claims 1 to 47, wherein:

66. L is -(piperazinylene)-X １ -***, where *** is A ２ is the point of attachment to X １ (i) C in which one or two methylene groups are optionally replaced by —O— １－５ alkylene, (ii) a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen, or (iii) -(a 3- to 4-membered monocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-(C １－５ 48. The compound of any one of claims 1 to 47, wherein:

67. L, 【Chemical 33】 wherein *** is A ２ is the point of attachment to X １ (i) C in which one or two methylene groups are optionally replaced by —O— １－１０ alkylene, (ii) a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C １－１０ 48. The compound of any one of claims 1 to 47, wherein:

68. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ２ -(C １－１０ alkylene)-***, wherein *** is A ２ is the point of attachment to X ２ is —O—, —N(H)—, or —N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is (alkyl)-.

69. L is -(piperidinylene)-X ２ -(C １－１０ alkylene)-***, wherein *** is A ２ is the point of attachment to X ２ is —O—, —N(H)—, or —N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is (alkyl)-.

70. L is -(piperidinylene)-X ２ -(3-7 membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-***, wherein *** is A ２ is the point of attachment to X ２ is —O—, —N(H)—, or —N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is (alkyl)-.

71. L, 【Chemical 34】 wherein *** is A ２ is the point of attachment to X ２ is —O—, —N(H)—, or —N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is (alkyl)-.

72. L, 【Chemistry 35】 wherein *** is A ２ is the point of attachment to X ２ is —O—, —N(H)—, or —N(C １－６ 48. The compound of any one of claims 1 to 47, wherein the compound is (alkyl)-.

73. X ２ The compound according to any one of claims 68 to 72, wherein is -O-.

74. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X １ -***, where *** is A ２ is the point of attachment to X １ But one CH ２ The group is -C(H)(C ３－６ -(OCH) optionally substituted with -cycloalkyl ２ CH ２ ) １－１０ The compound according to any one of claims 1 to 47,

75. 48. The compound of any one of claims 1 to 47, wherein L is a 7-11 membered spirocyclic or fused bicyclic saturated heterocycle containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen.

76. 48. The compound of any one of claims 1 to 47, wherein L is a 7-8 membered spirocyclic or fused bicyclic saturated heterocycle containing two heteroatoms selected from nitrogen.

77. L is -(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

78. L is -(9-membered spirocyclic saturated heterocycle containing one heteroatom selected from nitrogen)-O-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

79. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(a 3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-, wherein X ３ But C １－１０ Alkylene, —O—, —N(H)—, —N(C １－４ 48. The compound of any one of claims 1 to 47, wherein the aryl group is aryl, aryl, aryl(alkyl), ...

80. L is -(piperidinylene)-(C １－５ alkylene)-(piperazinylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

81. L is -(piperazinylene)-(azetidinylene)-*** or (azetidinylene)-(piperazinylene)-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

82. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C ２－６ alkylene)-N(C １－６ alkyl)C(O)-(C １－６ alkylene)-***, and L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C ２－６ alkylene)-C(O)N(H)-(C １－６ alkylene)-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-(C ２－６ alkylene)-C(O)N(C １－６ alkyl)-(C １－６ alkylene)-***, wherein X ３ But C １－１０ Alkylene, —O—, —N(H)—, —N(C １－４ 48. The compound of any one of claims 1 to 47, wherein the aryl group is aryl, aryl, aryl(alkyl), ...

83. L is -(piperidinylene)-(C １－５ alkylene)-(piperazinylene)-(C ２－５ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

84. L is -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(C ３－６ cycloalkylene)-O-***, -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(C ３－６ cycloalkylene)-N(H)-***, or -(3- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-X ３ -(C ３－６ cycloalkylene)-N(C １－４ alkyl)-***, wherein *** is A ２ is the point of attachment to X ３ But C １－１０ Alkylene, —O—, —N(H)—, —N(C １－４ 48. The compound of any one of claims 1 to 47, wherein the aryl group is aryl, aryl, aryl(alkyl), ...

85. L is -(piperidinylene)-X ３ -(C ３－６ Cycloalkylene)-O-***, -(piperidinylene)-X ３ -(C ３－６ -(cycloalkylene)-N(H)-***, or -(piperidinylene)-X ３ -(C ３－６ cycloalkylene)-***, wherein *** is A ２ is the point of attachment to X ３ But C １－１０ Alkylene, —O—, —N(H)—, —N(C １－４ 48. The compound of any one of claims 1 to 47, wherein the aryl group is aryl, aryl, aryl(alkyl), ...

86. L is -N(C １－３ alkyl)-(C ２－７ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, -N(C １－３ alkyl)-(C ２－７ alkylene)-N(C １－３ alkyl)C(O)-(C １－６ alkylene)-***, -N(H)-(C ２－７ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, -N(H)-(C ２－７ alkylene)-N(C １－３ alkyl)C(O)-(C １－６ alkylene)-***, -N(C １－３ alkyl)-(C ２－７ alkylene)-C(O)N(H)-(C １－６ alkylene)-***, -N(C １－３ alkyl)-(C ２－７ alkylene)-C(O)N(C １－３ alkyl)-(C １－６ alkylene)-***, -N(H)-(C ２－７ alkylene)-C(O)N(H)-(C １－６ alkylene)-***, or -N(H)-(C ２－７ alkylene)-C(O)N(C １－３ alkyl)-(C １－６ alkylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

87. L is -N(C １－３ alkyl)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-, -N(C １－３ alkyl)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-N(C １－３ alkyl)C(O)-(C １－６ alkylene)-, -N(H)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-, -N(H)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-N(C １－３ alkyl)C(O)-(C １－６ alkylene)-, -N(C １－３ alkyl)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-C(O)N(H)-(C １－６ alkylene)-, -N(C １－３ alkyl)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-C(O)N(C １－３ alkyl)-(C １－６ alkylene)-, or -N(H)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-C(O)N(H)-(C １－６ alkylene)-, -N(H)-[(C ２－４ alkylene)-O-] ２－８ -(C ２－６ alkylene)-C(O)N(C １－３ alkyl)-(C １－６ alkylene)-, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

88. L is -N(CH ３ )-[(CH ２ CH ２ )-O-] ２－８ -(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, -N(CH ３ )-[(CH ２ CH ２ )-O-] ２－８ -(C ２－６ alkylene)-N(CH ３ )C(O)-(C １－６ alkylene)-***, -N(H)-[(CH ２ CH ２ )-O-] ２－８ -(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, or -N(H)-[(CH ２ CH ２ )-O-] ２－８ -(C ２－６ alkylene)-N(H)C(O)-(C １－６ alkylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

89. L is a group represented by the formula -(C ０－１２ alkylene)-(optionally substituted 3- to 40-membered heteroalkylene)-(C ０－１２ The compound of any one of claims 1 to 47, having a substituted or unsubstituted alkylene group.

90. The compound of any one of claims 1 to 47, wherein L is one of the following: 【Chemical Formula 36】 (Wherein, *** represents A ２ (This is the attachment point to the

91. The compound of any one of claims 1 to 47, wherein L is one of the following: 【Chemical 37】 (Wherein, *** represents A ２ (This is the attachment point to the

92. L, 【Chemical 38】 wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

93. L, 【Chemical 39】 wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

94. L is -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ３－４ cycloalkylene)-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O)-(C １－４ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(3- to 5-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-(C ０－４ alkylene)-O-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-C(O))-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-O-(C ０－６ alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C １－６ alkylene)-O-(C ０－６ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-C(O)N(H)-(C ０－６ alkylene)-***, -(N(C １－６ alkyl)-(C ０－６ alkylene)-C(O)N(H)-(C ０－６ alkylene)-***, -(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ２－４ alkynylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C １－６ alkyl)-(3- to 5-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen)-C(O)N(H)-(C ０－６ alkylene)-N(H))-***, -(C(O)N(H)-(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-N(C １－６ alkyl)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-O-***, -C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen)-C(O)-***, -(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C ０－６ alkylene)***, —C(O)—(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C １－６ alkylene)-***, -(C(O)N(H)-(C １－６ alkylene)-C(O)N(H)-(C ０－６ alkylene)-***, or -(8- to 11-membered fused bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C １－４ alkylene)-***, where *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

95. L is -N(C １－６ alkyl)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(C ０－６ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－４ alkylene)-O-***, -(C ０－６ alkylene)-N(H)C(O)N(H)-(C ０－６ alkylene)-***, -N(H)-(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-***, -(C ０－６ alkylene)-C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-***, -(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)N(C １－６ )-(C ０－６ alkylene)-***, -(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-N(C １－６ alkyl)-(3- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-O-(5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-(5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-O-***, -(4- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-(5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen)-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen and substituted with 1 or 2 fluoro)-(C １－４ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－４ alkylene)-(C ３－６ cycloalkylene)-(C ０－４ alkylene)-O-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－４ alkylene)-(C ３－６ cycloalkylene)-(C ０－４ alkylene)-***, -(C ０－４ alkylene)-(8-12 membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-***, -(C ０－４ alkylene)-(C ３－６ cycloalkylene)-(C ２－４ alkynylene)-***, -(C ０－４ alkylene)-(8-10 membered fused bicyclic heterocyclyl substituted with 1 or 2 fluoro groups containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－４ alkylene)-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-O-***, -(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-***, -(C ０－４ alkylene)-(4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with trifluoromethyl)-(C ０－４ alkylene)-N(H)-***, or -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-***, -(C ３－６ cycloalkylene)-C(O)N(C １－６ alkyl) (C ０－６ alkylene)-***, -(5-6 membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(phenylene substituted with 0 or 1 occurrence of methyl or halo)-(C ０－６ alkylene)-***, -(5- to 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-(5- to 6-membered saturated monocyclic oxo-substituted heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen)-(C ０－６ alkylene)-***, -(8-12 membered spirocyclic C containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen １－４ alkyl-substituted heterocyclyl)-(C ０－６ alkylene)-(O) ０－１ ***, -(C ２－４ alkynylene)-(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, -(C ０－４ alkylene)-(C ３－７ cycloalkylene)-(C ２－４ alkynylene)-***, -(C １－４ alkylene)-(8- to 12-membered spirocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, -(C １－４ alkylene)-(5- to 7-membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, -(C ０－４ alkylene)-(5- to 7-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C ２－４ alkenylene)-***, or -(C ０－４ alkylene)-(6-8 membered saturated heterocyclyl substituted with 1 or 2 fluoro groups containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C ０－４ alkylene)-***, wherein *** is A ２ 48. The compound of any one of claims 1 to 47, wherein:

96. 2. The compound of claim 1, wherein the compound is a compound of formula Ie, or a pharmaceutically acceptable salt thereof: 【Chemistry 40】 wherein L is (i) Ψ-(an 8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie, or (ii) a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen, said heterocycle being selected from C １－４ substituted with 0 or 1 occurrence of alkyl).

97. 97. The compound of claim 96, wherein L is Ψ-(8-10 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie.

98. 97. The compound of claim 96, wherein L is Ψ-(9-membered spirocyclic saturated heterocycle containing 1 heteroatom selected from nitrogen)-O-, where Ψ is the point of attachment to the pyrimidinylene of formula Ie.

99. 97. The compound of claim 96, wherein L is a 9-11 membered spirocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen.

100. 97. The compound of claim 96, wherein L is a 10-membered spirocyclic saturated heterocycle containing one heteroatom selected from nitrogen.

101. 2. The compound of claim 1, wherein the compound is a compound of formula If, or a pharmaceutically acceptable salt thereof: 【Chemistry 41】

102. 2. The compound of claim 1, wherein the compound is a compound of formula Ig, or a pharmaceutically acceptable salt thereof: 【Chemistry 42】

103. Compounds represented by formula II: 【Chemistry 43】 or a pharmaceutically acceptable salt thereof, wherein TPL is R ＩＩ－１Ａ is a group defined by formula II-1 substituted by one occurrence of 【Chemical 44】 wherein: R ＩＩ－１Ａ is the bond to L, R １ is cyano, halogen, and R ４ is phenyl substituted by m occurrences of R ２ is independently expressed as C １－４ represents alkyl, R ３ is hydrogen or C １－４ is alkyl, R ４ is C １－４ is alkyl, R ５ is independently expressed as C １－４ represents alkyl or halogen, or R ５ One occurrence of R ３ Together with C １－３ Forming an alkylene A １ is pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is R ５ is replaced by n occurrences of L is a linker, EPL is the moiety that binds to BRD4, k is 1, 2, 3, or 4; m and n are independently 0, 1, or 2.

104. The TPL is R ＩＩ－１Ａ is replaced by one occurrence of 【Chemistry 45】 104. The compound of claim 103, wherein:

105. The TPL is 【Chemistry 46】 104. The compound of claim 103, wherein:

106. The EPL is ＩＩ－２Ａ wherein formula II-2 is defined by formula II-2, which is substituted by one occurrence of 【Chemistry 47】 wherein: R ＩＩ－２Ａ is the bond to L, R １Ａ But C １－４ Alkyl or C ３－４ is cycloalkyl, R ２Ａ But for each occurrence, C １－４ Alkyl or C ３－４ represents cycloalkyl, R ３Ａ But, Halo, C １ -C ４ Alkyl, or C １ -C ４ phenyl substituted with 1, 2, or 3 substituents independently selected from haloalkyl; R ４Ａ But -(C １－６ alkylene)-C(O)N(R ５Ａ ) (R ６Ａ ), -(C １－６ alkylene)-N(R ５Ａ ) C(O)R ７Ａ , -(C １－６ (alkylene)-CO ２ R ８Ａ , -(C １－６ (alkylene)-OC(O)R ７Ａ , -(C １－６ alkylene)-CN, -(C １－６ alkylene)-O-(C １－６ alkyl), C １－６ Alkyl, C ３－６ cycloalkyl, or -(C ０－６ alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is C １－６ the 5- to 6-membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; R ５Ａ and R ６Ａ are independently hydrogen, C １－６ Alkyl or C ３－６ cycloalkyl or R ５Ａ and R ６Ａ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing one nitrogen atom, R ７Ａ But C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ８Ａ But halogen, C １－６ Alkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or C ３－６ is cycloalkyl, R ９Ａ But it's a halo, R １０Ａ But for each occurrence, C １－４ Alkyl or -N(R １１Ａ ) ２ represents R １１Ａ may independently represent at each occurrence a halogen or C １－４ represents alkyl, R １２Ａ But -(C ０－６ alkylene)-(5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is C １－６ the 5- to 6-membered heteroaryl substituted with 0, 1, or 2 occurrences of alkyl; p and q are independently 0, 1, or 2; The compound according to any one of claims 103 to 105, wherein s is 1 or 2.

107. The EPL is 【Chemistry 48】 and each of these is R ＩＩ－２Ａ is replaced by one occurrence of R ＩＩ－２Ａ is a bond to L.

108. The EPL is 【Chemistry 49】 The compound according to any one of claims 103 to 105,

109. The EPL is 【Chemistry 50】 The compound according to any one of claims 103 to 105,

110. L is a divalent saturated or unsaturated, linear or branched C １－６０ a hydrocarbon chain, wherein 0 to 20 methylene units of said hydrocarbon are independently —O—, —S—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ２ -, -N(H)S(O) ２ -, -N(C １－６ alkyl)S(O) ２ -, -S(O) ２ N(H)-, -S(O) ２ N (C １－６ alkyl)-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C １－６ alkyl)-, —OC(O)N(H)-, —OC(O)N(C １－６ alkyl)-, -N(H)C(O)O-, -N(C １－６ 110. The compound of any one of claims 103 to 109, wherein the aryl group is substituted by (a)-( ...

111. L is a divalent saturated linear or branched C ３－３０ a hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently —O—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C １－６ 110. The compound of any one of claims 103 to 109, wherein the aryl group is substituted by a 3- to 10-membered alkyl)-, a 3- to 10-membered carbocyclyl, or a 3- to 10-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

112. L is a divalent saturated linear or branched C ３－３０ a hydrocarbon chain, wherein 0 to 15 methylene units of said hydrocarbon are independently —O—, —N(H)—, —N(C １－６ alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C １－６ alkyl)C(O)—, —C(O)N(H)—, or —C(O)N(C １－６ 110. The compound of any one of claims 103 to 109, wherein the compound is substituted with (alkyl)-.

113. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

114. A pharmaceutical composition comprising a compound according to any one of claims 1 to 113 and a pharmaceutically acceptable carrier.

115. 114. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 113, thereby treating said cancer.

116. 116. The method of claim 115, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

117. 116. The method of claim 115, wherein the cancer is prostate cancer.

118. 114. A method of causing death of a cancer cell, comprising contacting the cancer cell with an effective amount of a compound of any one of claims 1 to 113, thereby causing death of the cancer cell.

119. 119. The method of claim 118, wherein the cancer cells are selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland cancer, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cells.

120. 119. The method of claim 118, wherein the cancer cells are prostate cancer cells.

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