WO2024054954A1 - Composés hétérobifonctionnels et méthodes de traitement de maladie - Google Patents

Composés hétérobifonctionnels et méthodes de traitement de maladie Download PDF

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WO2024054954A1
WO2024054954A1 PCT/US2023/073696 US2023073696W WO2024054954A1 WO 2024054954 A1 WO2024054954 A1 WO 2024054954A1 US 2023073696 W US2023073696 W US 2023073696W WO 2024054954 A1 WO2024054954 A1 WO 2024054954A1
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Prior art keywords
alkylene
alkyl
compound
membered
nitrogen
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PCT/US2023/073696
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English (en)
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Kyle J. Eastman
Katherine J. KAYSER-BRICKER
James John Mousseau
David E. PULEO
Kanak Shail RAINA
Nilesh K. ZAWARE
Taavi Neklesa
Samuel W. Gerritz
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Halda Therapeutics Opco, Inc.
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Publication of WO2024054954A1 publication Critical patent/WO2024054954A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Solid tumors including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population.
  • the incidence of prostate cancer increases with age, and with increasing longevity of human subjects, there continues to be a corresponding rise in the number of patients suffering from prostate cancer.
  • Breast cancer is one of the most common cancers among women and is a leading cause of death for women between ages 50-55.
  • Lung cancer is a leading cause of death among cancer patients, where over 85% of lung cancers are non-small cell lung cancer (NSCLC). Many lung cancers are attributed to tobacco smoking. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. [0004] New therapies are needed to address this unmet need in cancer therapy.
  • new therapies are needed that achieve an anti-cancer effect through a different mechanism than commonly available therapies.
  • Exemplary mechanisms for common anti-cancer therapies include (a) alkylation of DNA which limits ability of the cell to reproduce, (b) topoisomerase inhibition, in which the therapeutic agent inhibits the activity of a topoisomerases thereby limiting separation of strands of DNA, and (c) mitotic inhibition, where the therapeutic agent reduces ability of the cell to divide.
  • New therapies that achieve an anti-cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines.
  • the invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer.
  • one aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the 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, such as a compound of Formula I or II, to treat the cancer.
  • Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I or II, to cause death of the cancer cell.
  • DETAILED DESCRIPTION [0010]
  • the invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer.
  • alkyl applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that 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, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • 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 units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and 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, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: [0015]
  • Exemplary bridged bicyclics include: . [0016] The term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • 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 heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • the term “-(C 0 alkylene)-“ refers to a bond. Accordingly, the term “-(C 0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C 1-3 alkylene)- group.
  • alkenylene refers to a bivalent 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 a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • haloaryl refers to an aryl group that is substituted with at least one halogen.
  • exemplary haloaryl groups include chlorophenyl (e.g., 3-chlorophenyl, 4-chlorophenyl), fluorophenyl, and the like.
  • phenylene refers to a bivalent phenyl group.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • 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, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where 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.
  • Nonlimiting 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.
  • a heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • haloheteroaryl refers to a heteroaryl group that is substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, and the like.
  • heteroarylene refers to a bivalent heteroaryl group.
  • pyrazolylene imidazolylene
  • pyrrolylene respectively refer to bivalent pyrazolyl, imidazolyl, and pyrrolyl groups.
  • pyridinylene and pyrimidinylene”, respectively refer to bivalent pyridinyl and pyrimidinyl groups.
  • pyridazinylene pyrimidinylene
  • pyrazinylene pyrazinylene
  • pyridinylene pyrazinylene
  • pyridinylene respectively refer to bivalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl groups.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring 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.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • heterocyclylene refers to a bivalent heterocyclyl group.
  • heterocycloalkyl refers to a saturated heterocyclyl.
  • heterocycloalkylene refers to a bivalent heterocycloalkyl group.
  • 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 having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R * is C 1–6 aliphatic
  • R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or – NO 2
  • each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 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, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2, – C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , – C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 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, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an
  • the term "pharmaceutically acceptable salt” refers to those salts which are, 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 and the like, and are 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, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • 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, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C 3 -C 6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH 2 F, -CHF2, -CF3, -CH 2 CF3, -CF2CF3, and the like.
  • chloroalkyl refers to an alkyl group that is substituted with at least one chloro.
  • bromoalkyl refers to an alkyl group that is substituted with at least one bromo.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • Exemplary hydroxyalkyl groups include -CH 2 CH 2 OH, -C(H)(OH)CH 3 , -CH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • heteroalkyl refers to an alkyl group in which one or more carbon atoms has been replaced by a heteroatom (e.g., N, O, or S).
  • exemplary heteroalkyl groups include -OCH3, -CH 2 OCH3, -CH 2 CH 2 N(CH3) 2 , and -CH 2 CH 2 OH.
  • the heteroalkyl group may contain, for example, from 2-4, 2-6, or 2-8 atoms selected from the group consisting of carbon and a heteroatom (e.g., N, O, or S).
  • the phrase 3-8 membered heteroalkyl refers to a heteroalkyl group having from 3 to 8 atoms selected from the group consisting of carbon and a heteroatom.
  • the term “heteroalkylene” refers to a bivalent heteroalkyl group.
  • alkenyl and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • haloalkenyl refers to an alkenyl group that is substituted with at least one halogen.
  • fluoroalkenyl refers to an alkenyl group that is substituted with at least one fluoro.
  • nitroalkenyl refers to an alkenyl group that is substituted with at least one nitro.
  • carbocyclylene refers to a bivalent cycloaliphatic group.
  • alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • exemplary haloalkoxyl groups include - OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 , and the like.
  • amino is art-recognized and refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein R 50 , R 51 , R 52 and R 53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R 61 , or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 61 represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8.
  • R 50 and R 51 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 )m-R 61 , or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R 61 represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and
  • m is zero or an integer in the range of 1 to 8;
  • R 52 is an alkyl, an alkenyl, or -(CH 2 )m-R 61 .
  • solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • IC50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (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 administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • 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.
  • a compound of the 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) zwitterions (“inner salts”) may be formed.
  • acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • an amount of acid or base such as an equivalent amount
  • a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • Heterobifunctional Compounds One aspect of the invention provides heterobifunctional compounds.
  • the compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. Without being bound by theory, the compounds can facilitate therapeutic effects by binding to both an androgen receptor and PLK1 (polo like kinase 1).
  • R 1 is phenyl substituted by cyano, halogen, and m occurrences of R 4 ;
  • R 2 represents independently for each occurrence C 1-4 alkyl;
  • R 3 is hydrogen or C 1-4 alkyl;
  • R 4 is C 1-4 alkyl;
  • R 5 represents independently for each occurrence C 1-4 alkyl or halogen;
  • a 1 is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R 5 ;
  • R 1A represents independently for each occurrence C 1 -C 6 alkoxy, hydroxyl, or C 1 -C 6 alkyl;
  • R 2A , R 3A , R 4A , R 5A , and R 6A are independently hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • R 1 is phenyl substituted by cyano, halogen, and m occurrences of R 4 .
  • R 1 is phenyl substituted by cyano, halogen, and 0 occurrences of R 4 . In certain embodiments, R 1 is phenyl substituted by cyano, chloro, and 0 occurrences of R 4 . In certain embodiments, R 1 is . In certain embodiments, R 1 is phenyl substituted by cyano, halogen, and 1 occurrence of R 4 . In certain embodiments, R 1 is phenyl substituted by cyano, halogen, and 2 occurrences of R 4 . In certain embodiments, R 1 is selected from the groups depicted in the compounds in Table 1 below. [0074] As defined generally above, R 2 represents independently for each occurrence C 1-4 alkyl.
  • R 2 is C1-2 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 1 below.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1 below.
  • R 4 is C 1-4 alkyl. In certain embodiments, R 4 is CH 3 . In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1 below.
  • R 5 represents independently for each occurrence C 1-4 alkyl or halogen. In certain embodiments, R 5 is C 1-4 alkyl. In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1 below. [0078] As defined generally above, A 1 is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R 5 . In certain embodments, A 1 is pyridazinylene substituted with n occurrences of R 5 . In certain embodiments, A 1 is .
  • a 1 is pyrimidinylene substituted with n occurrences of R 5 . In certain embodiments, A 1 is , where ** is the point of attachment to L. In certain embodiments, A 1 is , where ** is the point of attachment to L. In certain embodiments, A 1 is pyrazinylene substituted with n occurrences of R 5 . In certain embodiments, A 1 . In certain embodiments, A 1 is pyridinylene substituted with n occurrences of R 5 . In certain embodiments, A 1 is pyridinylene substituted with 0 occurrences of R 5 . In certain embodiments, A 1 is , where ** is the point of attachment to L.
  • a 1 is selected from the groups depicted in the compounds in Table 1 below.
  • a 2 is .
  • a 2 is selected from the groups depicted in the compounds in Table 1 below.
  • R 1A represents independently for each occurrence C 1 -C 6 alkoxy, hydroxyl, or C 1 -C 6 alkyl. In certain embodiments, R 1A is C 1 -C 6 alkoxy. In certain embodiments, R 1A is methoxy. In certain embodiments, R 1A is hydroxyl. In certain embodiments, R 1A is C 1 -C 6 alkyl.
  • R 1A is selected from the groups depicted in the compounds in Table 1 below.
  • R 2A is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl. In certain embodiments, R 2A is hydrogen. In certain embodiments, R 2A is C 1-4 alkyl. In certain embodiments, R 2A is C 3-4 cycloalkyl. In certain embodiments, R 2A is selected from the groups depicted in the compounds in Table 1 below.
  • R 3A is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl. In certain embodiments, R 3A is hydrogen. In certain embodiments, R 3A is C 1-4 alkyl.
  • R 3A is C 3-4 cycloalkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds in Table 1 below.
  • R 4A is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl. In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A is C 1-4 alkyl. In certain embodiments, R 4A is methyl. In certain embodiments, R 4A is C 3-4 cycloalkyl. In certain embodiments, R 4A is selected from the groups depicted in the compounds in Table 1 below.
  • R 5A is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl.
  • R 5A is hydrogen. In certain embodiments, R 5A is C 1-4 alkyl. In certain embodiments, R 5A is C 3-4 cycloalkyl. In certain embodiments, R 5A is selected from the groups depicted in the compounds in Table 1 below. [0085] As defined generally above, R 6A is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl. In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-4 alkyl. In certain embodiments, R 6A is ethyl. In certain embodiments, R 6A is C 3-4 cycloalkyl. In certain embodiments, R 6A is selected from the groups depicted in the compounds in Table 1 below.
  • R 7A is C 3-7 cycloalkyl, C 1-6 alkyl, or -(C 1-6 alkylene)-(C 3-7 cycloalkyl). In certain embodiments, R 7A is C 3-7 cycloalkyl. In certain embodiments, R 7A is cyclopentyl. In certain embodiments, R 7A is C 1-6 alkyl. In certain embodiments, R 7A is -(C 1-6 alkylene)-(C 3-7 cycloalkyl). In certain embodiments, R 7A is selected from the groups depicted in the compounds in Table 1 below. [0087] As defined generally above, k is 1, 2, 3, or 4. In certain embodiments, k is 1.
  • k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0088] As defined generally 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, 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, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof: In certain embodiments, the definition of variables R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with Formula I. [0090] In certain embodiments, the compound of Formula I is further defined by Formula Ib or a pharmaceutically acceptable salt thereof: (1b).
  • the definition of variables R 2 , R 3 , A 1 , and A 2 is one of the embodiments described above in connection with Formula I.
  • the compound of Formula I is further defined by Formula Ic or a pharmaceutically acceptable salt thereof: (1c).
  • the definition of variables variables A 1 and A 2 is one of the embodiments described above in connection with Formula I.
  • the compound of Formula I is further defined by Formula 1d or a pharmaceutically acceptable salt thereof: (1d).
  • the definition of variables A 1 and A 2 is one of the embodiments described above in connection with Formula I.
  • the compounds may be further characterized according to, for example, the identity of L.
  • the compound is a compound of Formula Ie or a pharmaceutically acceptable salt thereof:
  • L is one of the following ⁇ -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-]2-8-(C 2-6 alkylene)-N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -***, wherein *** is the point of attachment to A 2 ⁇ -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring
  • a 2 is In certain embodiments, A 2 is [0096] 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)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C 3-6 cycloalkyl)-(C 3-6 cycloalkylene)-N(H)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-(C 3-6 cycloal
  • L is -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-N(H)C(O)-***, or -(6- 10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A 2 .
  • the compound is a compound of Formula If or a pharmaceutically acceptable salt thereof: wherein A 2 is and L is one of the following ⁇ -N(C 1-3 alkyl)-[(C 2-4 alkylene)-O-]2-8-(C 2-6 alkylene)-N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 )1-10-***, wherein *** is the point of attachment to A 2 ⁇ -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from
  • a 2 is In certain embodiments, A 2 is [0099] 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)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C 3-6 cycloalkyl)-(C 3-6 cycloalkylene)-N(H)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-(C 3-6 cycloal
  • L is -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-N(H)C(O)-***, or -(6- 10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A 2 .
  • TPL is a group defined by Formula II-1 that is substituted by one occurrence of R II-1A , wherein Formula II-1 is represented by: (II-1) wherein: R II-1A is a bond to L; R 1 is phenyl substituted by cyano, halogen, and m occurrences of R 4 ; R 2 represents independently for each occurrence C 1-4 alkyl; R 3 is hydrogen or C 1-4 alkyl; R 4 is C 1-4 alkyl; R 5 represents independently for each occurrence C 1-4 alkyl or halogen; A 1 is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R 5 ; L is a linker; EPL is a moiety that binds to PLK1; k
  • variables in Formula II above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula II.
  • R 1 is phenyl substituted by cyano, halogen, and m occurrences of R 4 .
  • R 1 is phenyl substituted by cyano, halogen, and 0 occurrences of R 4 . In certain embodiments, R 1 is . In certain embodiments, R 1 is phenyl substituted by cyano, halogen, and 1 occurrences of R 4 . In certain embodiments, R 1 is phenyl substituted by cyano, halogen, and 2 occurrences of R 4 . In certain embodiments, R 1 is phenyl substituted by cyano, Cl, and 0 occurrences of R 4 . In certain embodiments, R 1 is selected from the groups depicted in the compounds in Table 1 below. [0104] As defined generally above, R 2 represents independently for each occurrence C 1-4 alkyl.
  • R 2 is C 1-2 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 1 below.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1 below. [0106] As defined generally above, A 1 is a pyridazinyl, pyrimidinyl, pyrazinyl, or pyridinyl, each of which is substituted with n occurrences of R 5 .
  • a 1 is pyridazinyl substituted with n occurrences of R 5 . In certain embodiments, A 1 is pyrimidinyl substituted with n occurrences of R 5 . In certain embodiments, A 1 is pyrazinyl substituted with n occurrences of R 5 . In certain embodiments, A 1 is pyridinyl substituted with n occurrences of R 5 . In certain embodiments, A 1 is selected from the groups depicted in the compounds in Table 1 below. [0107] As defined generally 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.
  • k is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • m and n are independently 0, 1, or 2.
  • m is 0.
  • m is 1.
  • m is 2.
  • n is 0.
  • n is 1.
  • n is 2.
  • m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • the that is substituted by one occurrence of R II-1A is substituted by one occurrence of R II-1A .
  • the EPL is defined by Formula II-2 that is substituted by one occurrence of R II-2A , wherein Formula II-2 is represented by: ; wherein R II-2A is a bond to L; R 1A represents independently for each occurrence C 1 -C 6 alkoxy, hydroxyl, or C 1 -C 6 alkyl; R 2A , R 3A , R 4A , R 5A , and R 6A are independently hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl; R 7A is C 3-7 cycloalkyl, C 1-6 alkyl, or -(C 1-6 alkylene)-(C 3-7 cycloalkyl); and p is 0, 1, or 2.
  • the R 1A represents independently for each occurrence C 1 -C 6 alkoxy, hydroxyl, or C 1 -C 6 alkyl;
  • R 2A , R 3A , R 4A , R 5A , and R 6A are independently hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
  • R 7A is C 3-7 cycloalkyl, C 1-6 alkyl, or -(C 1-6 alkylene)-(C 3-7 cycloalkyl); and p is 0, 1, or 2
  • the EPL is .
  • R 1A is C 1 -C 6 alkoxy. In certain embodiments, R 1A is methoxy. In certain embodiments, R 1A is hydroxyl. In certain embodiments, R 1A is C 1 -C 6 alkyl. In certain embodiments, R 1A is selected from the groups depicted in the compounds in Table 1 below. [0116] In certain embodiments, R 2A is hydrogen. In certain embodiments, R 2A is C 1-4 alkyl. In certain embodiments, R 2A is C 3-4 cycloalkyl. In certain embodiments, R 2A is selected from the groups depicted in the compounds in Table 1 below.
  • R 3A is hydrogen. In certain embodiments, R 3A is C 1-4 alkyl. In certain embodiments, R 3A is C 3-4 cycloalkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds in Table 1 below. [0118] As In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A is C 1-4 alkyl. In certain embodiments, R 4A is methyl. In certain embodiments, R 4A is C 3-4 cycloalkyl. In certain embodiments, R 4A is selected from the groups depicted in the compounds in Table 1 below. [0119] In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-4 alkyl.
  • R 5A is C 3-4 cycloalkyl. In certain embodiments, R 5A is selected from the groups depicted in the compounds in Table 1 below.
  • R 6A is hydrogen. In certain embodiments, R 6A is C 1-4 alkyl. In certain embodiments, R 6A is ethyl. In certain embodiments, R 6A is C 3-4 cycloalkyl. In certain embodiments, R 6A is selected from the groups depicted in the compounds in Table 1 below. [0121] In certain embodiments, R 7A is C 3-7 cycloalkyl. In certain embodiments, R 7A is cyclopentyl. In certain embodiments, R 7A is C 1-6 alkyl.
  • R 7A is -(C 1-6 alkylene)-(C 3-7 cycloalkyl). In certain embodiments, R 7A is selected from the groups depicted in the compounds in Table 1 below. [0122] 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 value in the groups depicted in the compounds in Table 1 below. [0123] In certain embodiments, the EPL is selected from the groups depicted in the compounds in Table 1 below. [0124] In certain embodiments, the EPL is defined by variable A 2 set forth above in connection with Formula I.
  • the EPL is defined by one or more of the embodiments for variable A 2 set forth in connection with Formula I.
  • the compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part C: Exemplary Further Description of Linker (L) Component of Compounds of Formula I and II [0126] Compounds of Formula I and II may be further characterized according to, for example, the identity of the linker (L) component.
  • linkers are known to one of skill in the art and may be used in the heterobifunctional compounds described herein.
  • L comprises one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof.
  • L consists of one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. In certain embodiments, L consists of one or more groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. [0127] In some embodiments, L is symmetrical. In some embodiments, L is asymmetric. In certain embodiments, L is a bond.
  • L is a covalent bond or a bivalent C 1-30 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein 1-15 methylene units of L are optionally and independently replaced by 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) 2 N(H)-, -S(O) 2 N(C 1-4 alkyl)-, -S(O) 2 N(C 3-5 cycloalkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -N(C 3-5 cycloalkyl)C(O)-,
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -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)-, -
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) 2 -, -N(R**)S(O) 2 -, - S(O) 2 N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)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, wherein R** represents independently for each occurrence hydrogen, C 1-6 alkyl, or optionally substituted 3
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -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)-, -
  • L is a bivalent, saturated, straight or branched C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -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)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is a bivalent, saturated, straight or branched C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -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 alkyl)-.
  • 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.
  • 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.
  • L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, and nitrogen.
  • L is a heteroalkylene having from 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon and oxygen.
  • the L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and about 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, between 1 and about 6 ethylene glycol units, between 2 and about 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms.
  • L is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) 2 -, -N(R**)S(O) 2 -, - S(O) 2 N(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** represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) 2 -, -N(R**)S(O) 2 -, - S(O) 2 N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R** represents independently for each occurrence hydrogen, C 1-6 alkyl, or
  • L has the formula -N(R)-(optionally substituted 3-20 membered heteroalkylene)p-CH 2 -C(O)-, wherein R is hydrogen or optionally substituted C 1 -C 6 alkyl, and p is 0 or 1.
  • L has the formula -N(R)-(3-20 membered heteroalkylene) p - CH 2 -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, hydroxyl, and cyano; R is hydrogen or optionally substituted C 1 -C 6 alkyl; and p is 0 or 1.
  • L has the formula -N(R)-(3-20 membered heteroalkylene)p- CH 2 -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halogen and C 1 -C 6 haloalkyl; R is hydrogen or C 1 -C 6 alkyl; and p is 0 or 1.
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -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(H)-,
  • L is a bivalent, saturated, straight or branched C 3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -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)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -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 alkyl)-.
  • L is a bivalent, saturated or unsaturated, straight or branched C 5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced with -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)-, 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.
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -N(C 1-6 alkyl)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -C(O)N(C 1-6 alkyl)-***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -(C 1-6 alkylene)-N(H)C(O)- ***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -(C 1-6 alkylene)-C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (OCH 2 CH 2 ) 1-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)C(O)-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -(C 1-6 alkylene)-
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -N(C 1-6 alkyl)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-10 -C(O)N(C 1-6 alkyl)-***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-6 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A 2 .
  • L is -(piperidinylene)-(OCH 2 CH 2 ) 1-10 -N(H)C(O)-***, - (piperidinylene)-(OCH 2 CH 2 ) 1-10 -C(O)N(H)-***, -(piperidinylene)-(OCH 2 CH 2 ) 1-10 -N(C 1-6 alkyl)C(O)-***, or -(piperidinylene)-(OCH 2 CH 2 ) 1-10 -C(O)N(C 1-6 alkyl)-***, wherein *** is the point of attachment to A 2 .
  • L is , wherein *** is the point of attachment to A 2 . In certain embodiments, L is , wherein *** is the point of attachment to A 2 . In certain embodiments, L is , wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -N(H)C(O)-C 1-10 alkylene- ***, -(3-7 membered, monocyclic, saturated heterocyclic ring 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-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (OCH 2 CH 2 ) 1-15 -C(O)N(H)-C 1-10 alkylene-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 ) 1-15 -C(O)N(C 1-10 alkylene-***,
  • L is -piperidinylene-(OCH 2 CH 2 )1-5-N(H)C(O)-C1-5 alkylene- ***, -piperidinylene-(OCH 2 CH 2 )1-5-N(C 1-4 alkyl)C(O)-C1-5 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-***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH 2 CH 2 )1-10-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0- 10 alkylene)-O-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C 1-10 alkylene, wherein *** is the point of attachment to A 2 .
  • L is -piperidinylene-(OCH 2 CH 2 ) 1-5 -***, -piperidinylene-(C 0-5 alkylene)-O-***, or -piperidinylene-(C1-5 alkylene)-***, wherein *** is the point of attachment to A 2 .
  • L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -N(H)C(O)-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 - C(O)N(H)-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -N(C 1-4 alkyl)C(O)-***, or -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -C(O)N(C 1-4 alkyl)-***, wherein *** is the point of attachment to A 2 , and X 1 is (a) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (b
  • L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, wherein *** is the point of attachment to A 2
  • X 1 is (i) C 1-15 alkylene where 1, 2, 3, or 4 methylene groups are optionally replaced by -O-, -N(H)-, -N(C 1-4 alkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -C(O)N(H)-, or - C(O)N(C 1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.
  • L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X 1 -***, wherein *** is the point of attachment to A 2
  • X 1 is (i) C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C 1-4 alkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -C(O)N(H)-, or - C(O)N(C 1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.
  • L is -(piperidinylene)-X 1 -***, wherein *** is the point of attachment to A 2
  • X 1 is (i) C 1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C 1-4 alkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-4 alkyl)-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C1-5 alkylene)-.
  • L is , wherein *** is the point of attachment to A 2
  • X 1 is (i) C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, - N(H)-, -N(C 1-4 alkyl)-, -N(H)C(O)-, -N(C 1-4 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C 1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene)-.
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0
  • L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-8 alkylene)- N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C 0-10 alkylene where 1 or 2
  • L is L is -(C 3-6 cycloalkylene)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-N(H)C(O)-***, -(C 3-6 cycloalkylene)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, - N(H)-, or -N(C 1-4 alkyl)-)-N(C 1-4 alkyl)C(O)-***, -(C 3-6 cycloalkylene)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-C(O)N(H)-***, -(C 3-6 cycloalkylene)-(C 1-10 alkylene where 1 or 2
  • L is -(C 3-6 cycloalkylene)-(C 1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-N(H)C(O)-*** or -(C 3-6 cycloalkylene)-(C 1- 10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C 1-4 alkyl)-)-N(C 1-4 alkyl)C(O)-***, wherein *** is the point of attachment to A 2 .
  • L is -N(C 1-3 alkyl)-(C 2-7 alkylene)-N(H)C(O)-***, -N(H)-(C 2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(C 1-3 alkyl)-(C2-7 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(H)-***, -N(H)-(C 2-7 alkylene)-C(O)N(H)-***, -N(H)-(C 2-7 alkylene)-C(O)N(C 1-3 alkyl)-***, -N(C 1-3 alkyl)-(O)-C(O)-C(O)-C(O)-C(
  • L is -N(C 1-3 alkyl)-(C2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(H)C(O)-***, -N(H)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(C 1-3 alkyl)-(C 2-7 alkylene)-C(O)N(H)-***, -N(H)-(C 2-7 alkylene)-C(O)N(H)-***, -N(H)-(C2-7 alkylene)-C(O)N(C 1-3 alkyl)-***, -N(C 1-3 alkyl)-(C2-7 alkylene)-C(O)N(C 1-3 alkyl
  • L is -N(CH 3 )-(C 2-7 alkylene)-N(H)C(O)-***, -N(H)-(C 2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(CH3)C(O)-***, -N(CH3)-(C2-7 alkylene)- N(CH3)C(O)-***, -N(CH3)-(C2-7 alkylene)-C(O)N(H)-***, -N(H)-(C2-7 alkylene)-C(O)N(H)-***, - N(H)-(C 2-7 alkylene)-C(O)N(CH 3 )-***, -N(CH 3 )-(C 2-7 alkylene)-C(O)N(CH 3 )-***, -N(CH 3 )-[(C 2-4 alkylene)-O
  • L is -N(C 1-3 alkyl)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C 1-6 alkylene)-N(H)C(O)-***, -N(C 1-3 alkyl)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C 1-6 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(H)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C 1-6 alkylene)-N(C 1-3 alkyl)C(O)-***, -N(H)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms
  • L is -N(CH 3 )-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C 1-6 alkylene)-N(H)C(O)-***, -N(CH 3 )-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C 1-6 alkylene)- N(CH 3 )C(O)-***, -N(H)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C 1-6 alkylene)-N(CH 3 )C(O)-***, -N(H)-(C 1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C 1-6
  • L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C 0-12 alkylene)-. [0169] In certain embodimens, L is C 4-14 alkylene. [0170] In certain embodiments, L is one of the following:
  • L is one of the following:
  • 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
  • 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)-[CH 2 CH 2 -O-]2-6-(C 1-6 alkylene)-C(O)-***, - N(H)-[CH 2 CH 2 -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)-[CH 2 CH 2 -O-] 2-6 -(C 1-6 alkylene)-***, -N(H)-[CH 2 CH 2 -O-] 7-15 -(C 1-6
  • 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 1-6 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(C 1-6 alkyl)-(C 7
  • L is -N(H)-[CH 2 CH 2 -O-]2-6-(C 1-6 alkylene)-C(O)-***, -N(H)- [CH 2 CH 2 -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 1-6 alkylene)-N(H)C(O)-(C 1-6 alkylene)***, -N(H)-(C 2-6 alkylene)-***, - N(H)-(C7-15 alkylene)-***, -N(C 1-6 alkyl)-(C 2-6 alkylene)-***, -N(C 1-6 alkyl)-(C7-15 alkylene)-***, - N(H)-[CH 2 CH 2 -O-]2-6-(C
  • 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)(C 1-6 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)-***, -(C1
  • L is -[CH 2 CH 2 -O-]2-6-(C 1-6 alkylene)-***, -[CH 2 CH 2 -O-]7-15- (C 1-6 alkylene)-***, -[CH 2 CH 2 -O-] 2-6 -(C 1-6 alkylene)-N(C 1-6 alkyl)(C 1-6 alkylene)-***, -[CH 2 CH 2 - O-] 7-15 -(C 1-6 alkylene)-N(C 1-6 alkyl)(C 1-6 alkylene)-***, -[CH 2 CH 2 -O-] 2-6 -(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -[CH 2 CH 2 -O-]7-15-(C 1-6 alkylene)-N(H)(C 1-6 alkylene)-***, -(C1-9 alkylene)- C(O)N(H)-(C 1-6 alkylene)-***,
  • 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-] 2-6 -(C 1-6
  • L is -N(H)-[CH 2 CH 2 -O-] 2-6 -(C 1-6 alkylene)-N(H)-***, -N(H)- [CH 2 CH 2 -O-] 7-15 -(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH 2 CH 2 -O-] 2-6 -(C 1-6 alkylene)-N(H)- ***, -N(C 1-6 alkyl)-[CH 2 CH 2 -O-]7-15-(C 1-6 alkylene)-N(H)-***, -N(C 1-6 alkyl)-[CH 2 CH 2 -O-]2-6-(C 1-6 alkylene)-N(C 1-6 alkyl)-***, or -N(C 1-6 alkyl)-[CH 2 CH 2 -O-]7-15-(C 1-6 alkylene)-N(C 1-6 alkyl)-***, or
  • L is -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4-7 cycloalkenylene, or an optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is -CH 2 -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 C4-7 cycloalkenylene)-Y 20 -, -(optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-Y 20 -, -Y 20 -CH 2 -, -Y 20 -C(H)(R 100 )-, -Y 20 -C(R 100 ) 2 -, -Y 20 -O-, -Y 20 -N(R 101
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0185] wherein X 20 , Y 20 , and Z 20 are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, - N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, or an optionally substituted C 4-7 cycloalkenylene; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0187] wherein X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is -X 20 -Y 20 -Z 20 -, wherein X 20 , Y 20 , and Z 20 are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is -C ⁇ C-Z 20 -, wherein Z 20 is -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, or an optionally substituted C4-7 cycloalkenylene; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0192] wherein X 20 , Y 20 , and Z 20 are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, - N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following:
  • V 20 , W 20 , X 20 , Y 20 , and Z 20 are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl, and R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0196] wherein W 20 , X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0198] wherein W 20 , X 20 , Y 20 , and Z 20 are independently -C(R 100 )- or -N-; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following:
  • U, V, W, X, Y, and Z are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, - N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0202] wherein X, Y, and Z are independently -C(R 100 )- or -N-; V and W are independently - CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0204] wherein W, X, Y, and Z are independently -C(R 100 )- or -N-; V is -CH 2 -, -C(H)(R 100 )-, - C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following:
  • T, U, V, W, X, Y, and Z are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, - N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0208] wherein W, X, Y, and Z are independently -C(R 100 )- or -N-; U and V are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following: [0210] wherein X, Y, and Z are independently -C(R 100 )- or -N-; U, V, and W are independently -CH 2 -, -C(H)(R 100 )-, -C(R 100 ) 2 -, O, -N(R 101 )-, -S(O) 2 -, -C(O)-, an optionally substituted C 3-7 cycloalkylene, an optionally substituted C 4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R 100 represents independently for each occurrence hydrogen, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl; R 101 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; and a dashed bond indicates a point of attachment.
  • R 100 represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 101 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
  • L is one of the following:
  • 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.
  • L is one of the following:
  • L is one of the following:
  • L is one of the following:
  • L is one of the following:
  • L is one of the following:
  • L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C0-12 alkylene)-. In certain embodiments, L is C4-14 alkylene. In certain embodiments, L is -(CH 2 ) 6-10 -.
  • L is -CH 2 CH 2 (OCH 2 CH 2 )-***, -CH 2 CH 2 (OCH 2 CH 2 ) 2 -***, - CH 2 CH 2 (OCH 2 CH 2 )3-***, -CH 2 CH 2 (OCH 2 CH 2 )4-***, -CH 2 CH 2 (OCH 2 CH 2 )5-***, - CH 2 CH 2 (OCH 2 CH 2 ) 6 -***, -CH 2 CH 2 (OCH 2 CH 2 ) 7 -***, -CH 2 CH 2 (OCH 2 CH 2 ) 8 -***, - CH 2 CH 2 (OCH 2 CH 2 ) 9 -***, -CH 2 CH 2 (OCH 2 CH 2 ) 10 -***, -CH 2 CH 2 (OCH 2 CH 2 ) 11 -***, - CH 2 CH 2 (OCH 2 CH 2 )12-***, -CH 2 CH 2 (OCH 2 CH 2 )13-***, -CH 2
  • L is -O(CH 2 CH 2 O) 2-4 -(C 0-4 alkylene)-***, -O(CH 2 CH 2 O) 5-7 - (C 0-4 alkylene)-***, -O(CH 2 CH 2 O)8-10-(C 0-4 alkylene)-***, -O(CH 2 CH 2 O)11-13-(C 0-4 alkylene)-***, -O(CH 2 CH 2 O) 14-16 -(C 0-4 alkylene)-***, -O(CH 2 CH 2 O) 16-20 -(C 0-4 alkylene)-***, -O(CH 2 CH 2 O) 2-10 - (C 0-4 alkylene)C(O)-***, or -O(CH 2 CH 2 O) 11-20 -(C 0-4 alkylene)C(O)-***, where *** is a point of attachment to A 2 .
  • L is -(C0-20 alkylene)-(OCH 2 CH 2 )1-10-(N(C 1-4 alkyl))-***, -(C0-20 alkylene)-(OCH 2 CH 2 ) 11-20 -(N(C 1-4 alkyl))-***, -(C 0-20 alkylene)-(CH 2 CH 2 O) 1-10 -(C 2-10 alkylene)- (N(C 1-4 alkyl))-(C0-10 alkylene)-***, or -(C0-20 alkylene)-(CH 2 CH 2 O)11-20-(C2-10 alkylene)-(N(C 1-4 alkyl))-(C0-10 alkylene)-***, where *** is a point of attachment to A 2 .
  • L is selected from those depicted in the compounds in Table 1, below.
  • Exemplary Specific Compounds [0225] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-54 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-54 in Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-67 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-67 in Table 1.
  • the heterobifunctional compounds described herein provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the 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, such as a compound of Formula I, II, or other compound in Section I, to treat the cancer.
  • the compound is a compound of Formula I.
  • the particular compound of Formula I is a compound defined by one of the embodiments described above.
  • 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 carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.
  • the cancer is prostate cancer.
  • the cancer is squamous cell cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.
  • lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblast
  • 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 Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative diseases, large B cell lymphoma, or B cell Lymphoma.
  • the cancer is a solid tumor or leukemia.
  • 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, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.
  • 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.
  • 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.
  • the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.
  • the cancer is a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocar
  • the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype 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
  • the cancer is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the
  • the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (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 tumors (MPNST);
  • MPNST neurofibromat
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian epithelial cancer
  • the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • the cancer is kidney 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 carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; ana
  • 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 carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ovarian epi
  • 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 cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • 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 cancer. 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 cancer. 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 tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell 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 death of the cancer cell.
  • the particular compound of Formula I or II is a compound defined by one of the embodiments described above.
  • the cancer cell is 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 carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.
  • the cancer cell is one or more of the cancers recited in the section above entitled “Cancer.”
  • the cancer cell is a prostate cancer cell.
  • the compounds useful within the methods of the invention may be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein.
  • additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat, prevent, or reduce the symptoms, of a disease or disorder contemplated herein.
  • the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein.
  • administering the compound of the invention to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating the disease contemplated herein.
  • the compound of the invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.
  • a synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet.6:429-453), the equation of Loewe additivity (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 equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • the compound of the invention and the therapeutic agent are co- administered to the subject.
  • the compound of the invention and the therapeutic agent are coformulated and co-administered to the subject.
  • the compound is administered in combination with a second therapeutic agent having activity against cancer.
  • the second therapeutic agent is mitomycin, tretinoin, ribomustin, 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, streptozocin, nimustine, vindesine, flutamide,
  • 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).
  • the second therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro).
  • Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).
  • the second therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead).
  • Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • 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).
  • the second therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals).
  • Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).
  • the second therapeutic agent is a CDK inhibitor, such as a CDK 4/6 inhibitor.
  • CDK 4/6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis).
  • Other CDK 4/6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • the second therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor.
  • IDO inhibitors being studied which may 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).
  • 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).
  • PDGF platelet-derived growth factor
  • EGF epidermal growth factor
  • EGFR antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly).
  • Approved EGFR antagonists which may 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).
  • the second therapeutic agent is an aromatase inhibitor.
  • Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).
  • the second therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma.
  • the second therapeutic agent is a folic acid inhibitor.
  • Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).
  • the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).
  • the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH isocitrate dehydrogenase
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • the second therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • the second therapeutic agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • the second therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may 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
  • the second therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).
  • the second therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotax
  • the second therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.
  • Approved platinum-based therapeutics which may 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).
  • platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • the second therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • Approved taxane compounds which may 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 which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).
  • the second therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • the second therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).
  • the second therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 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).
  • the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF ⁇ ).
  • TGF-beta or TGF ⁇ transforming growth factor-beta
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964- 978.
  • M7824 (Merck KgaA—formerly MSB0011459X), which is a bispecific, anti-PD-L1/TGF ⁇ trap compound (NCT02699515); and (NCT02517398).
  • M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF ⁇ “trap.”
  • the second therapeutic agent is a cancer vaccine.
  • the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma.
  • sipuleucel-T Provenge®, Dendreon/Valeant Pharmaceuticals
  • talimogene laherparepvec Imlygic®, BioVex/Amgen, previously known as T-VEC
  • the additional therapeutic agent is selected from an oncolytic viral therapy 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); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCTTCT016225
  • the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist.
  • 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).
  • immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested 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; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), 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; and P
  • Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
  • AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
  • Another aspect of the invention provides for 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.
  • the medicament is for treating a disease described herein, such as cancer.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer).
  • HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn/Strep. Cells are seeded in white 384-well plates at 500 cells/well in 25 ⁇ L complete medium. Following seeding, plates are spun at 300 ⁇ g ⁇ for three minutes and cultured at 37 °C with 5% CO2 ⁇ in a humidified tissue culture incubator. After 24 hours, compounds are titrated in 100% DMSO and diluted in complete cell culture medium.
  • a 25 ⁇ L aliquot of compound/media mixture is added to cells to bring total volume in well to 50 ⁇ L.
  • DMSO alone is used as a negative control. Plates are then spun at 300 ⁇ g ⁇ for three minutes and stored at 37 °C with 5% CO 2 for three days. On Day 0 and Day 3 of compound treatment, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating microplates at room temperature for 30 minutes, 25 ⁇ L CellTiter-Glo 2.0 reagent is dispensed into each well to bring total volume to 75 ⁇ L. Plates are mixed on shaker for 2 minutes at 500rpm, followed by a 10-minute incubation at room temperature.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier.
  • therapeutically effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • 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 which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • 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.
  • 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.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin;
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which 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-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • 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
  • Dosage forms for the 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 which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper 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 either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [0301] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • 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.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0305] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • 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 of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose 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 dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. IV.
  • MEDICAL KITS [0319] Another aspect of this invention is a kit comprising (i) a compound described herein, such as a compound of Formula I, and (ii) instructions for use, such as treating cancer.
  • EXAMPLES [0320] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention.
  • General Methods [0321] All reactions were carried out under an atmosphere of dry nitrogen or argon. Glassware was oven-dried prior to use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification.
  • DIPEA N,N- Diisopropylethylamine
  • THF Tetrahydrofuran
  • CH 2 Cl 2 Dichloromethane
  • DMF dimethylformamide
  • PTLC preparatory thin layer chromatographic separation.
  • HFIP hexafluoroisopropanol
  • HEPES 4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid. Flash column chromatography was performed using silica gel 60 (230-400 mesh).
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 ⁇ m;mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-70%, 8min) to give the tert-butyl N-[2-[[4-[(8- cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzoyl]amino] ethyl]-N-methyl- carbamate (113 mg, 194 ⁇ mol, 82% yield) as a yellow gum.
  • reaction mixture was concentrated under reduced pressure to give a residue and was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm 10 ⁇ m; mobile phase: [water(NH 4 HCO 3 )-ACN];B%: 54%-84%,11min) to give the N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[4-[(8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]ethyl-methyl-amino]pyrimidine-5-carboxamide (30 mg, 136 ⁇ mol, 21% yield, 98% purity) as a yellow liquid.
  • reaction mixture was concentrated under reduced pressure to give a residue and was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 ⁇ m; mobile phase: [water (NH4HCO3)-ACN];B%: %- %,11min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[2-[2-[2-[2- [[4-[[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethyl-methyl-amino]pyrimidine-5-carboxamide (20 mg, 83 ⁇ mol, 79% yield) as a yellow oil.
  • the reaction mixture was stirred at 50 °C for 12 h.
  • the reaction mixture was filtered.
  • the crude product was purified by reversed-phase HPLC(0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 ⁇ m; mobile phase: [water(FA)-ACN];B%: 44%-74%,7min).
  • reaction mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was quenched by addition water 5 mL, and then diluted with water 10 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by reversed-phase HPLC (0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 ⁇ m; mobile phase: [water(FA)-ACN];B%: 38%- 68%,7min).
  • the reaction mixture was stirred at 50 °C for 12 h.
  • the reaction mixture was filtered.
  • the crude product was purified by reversed-phase HPLC (0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 ⁇ m; mobile phase: [water(FA)-ACN];B%: 45%-75%,7min).
  • the mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um;mobile phase: [water(NH4HCO3)-ACN];B%: 30%-60%,10min) to give tert-butyl 4-(7-aminoheptoxy) piperidine- 1-carboxylate (1.2 g, 74% yield) as a light-yellow oil.
  • the mixture was by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 10min) to give tert-butyl 4-(8-aminooctoxy) piperidine-1-carboxylate (500 mg, 40% yield) as a yellow oil.
  • the reaction mixture was concentrated in vacuo to give the crude product.
  • the crude product 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[5-(4-piperidyloxy)pentoxy]ethyl]benzamide (110 mg, crude) was Yellow Oil used into the next step without further purification.
  • the mixture was stirred at 25 °C for 0.5 h.
  • the mixture was diluted with water (2 mL) and extracted with Ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-N-(4-piperidyl)benzamide.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-1-piperidyl]pyrimidine-5-carboxamide (I-55).
  • Step 1 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carboxamide.
  • reaction mixture was filtered and purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 29%-59%,7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carboxamide (85 mg, 57 % yield).
  • Step 2 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-(4-piperidylmethyl)benzamide.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carboxamide (I-56).
  • Step 1 Preparation of tert-butyl 4-[[3-(benzyloxycarbonylamino)azetidin-1- yl]methyl]piperidine-1-carboxylate.
  • tert-butyl 4-formylpiperidine-1-carboxylate 450 mg, 2.11 mmol, 1 equiv
  • benzyl N-(azetidin-3-yl)carbamate 512 mg, 2.11 mmol, 1 equiv, HCl
  • NaOAc 346 mg, 4.22 mmol, 2 equiv
  • NaBH(OAc) 3 (1.34 g, 6.33 mmol, 3 equiv).
  • Step 3 Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]azetidin-1-yl]methyl]piperidine-1- carboxylate.
  • Step 4 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[1-(4-piperidylmethyl)azetidin-3-yl]benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]azetidin-1-yl]methyl]-1-piperidyl]pyrimidine-5-carboxamide (I- 57).
  • Step 2 Preparation of (7R)-8-cyclopentyl-2-[4-(2,6-diazaspiro[3.3]heptane-2- carbonyl)-2-methoxy-anilino]-7-ethyl-5-methyl-7H-pteridin-6-one.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]pyrimidine-5-carboxamide (I-58).
  • Step 2 Preparation of (7R)-2-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carbonyl)-2-methoxy-anilino]-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[5-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]pyrimidine-5- carboxamide (I-59).
  • Step 3 Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl] amino] -3-methoxy-benzoyl]amino]cyclobutyl]amino]piperidine-1- carboxylate.
  • Step 4 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidylamino)cyclobutyl]benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]amino]-1-piperidyl]pyrimidine-5-carboxamide (I-60).
  • Step 2 Preparation of (7R)-8-cyclopentyl-7-ethyl-2-[2-methoxy-4-[3-(4- piperidyl)azetidine-1-carbonyl]anilino]-5-methyl-7H-pteridin-6-one.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]azetidin-3-yl]-1-piperidyl]pyrimidine-5-carboxamide (I-61).
  • Step 2 Preparation of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzamide.
  • Step 3 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (I-62).
  • Step 2 Preparation of tert-butyl 2-(2-aminoethyl)-1,3,3a,4,6,6a-hexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate.
  • Step 3 Preparation of tert-butyl 2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate.
  • Step 4 Preparation of N-[2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5- yl)ethyl]-4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy- benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl] amino]- 3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl]pyrimidine-5-carboxamide (I-63).
  • Step 2 Preparation of tert-butyl 4-[(3-aminocyclobutyl)-cyclopropyl- amino]piperidine-1-carboxylate.
  • tert-butyl 4-[[3-(benzyloxycarbonylamino) cyclobutyl]-cyclopropyl-amino]piperidine-1-carboxylate 40 mg, 90 umol, 1.0 equiv
  • Pd/C 20 mg, 10% purity
  • Step 3 Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]amino]cyclobutyl]-cyclopropyl- amino]piperidine-1-carboxylate.
  • Step 4 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-N-[3-[cyclopropyl(4-piperidyl)amino]cyclobutyl]-3-methoxy-benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]-cyclopropyl-amino]-1-piperidyl] pyrimidine-5- carboxamide (I-64).
  • Step 1 Preparation of 2-trimethylsilylethyl 4-[3-(tert-butoxycarbonylamino) cyclobutoxy] piperidine-1-carboxylate.
  • tert-butyl N-[3-(4-piperidyloxy) cyclobutyl] carbamate 2.5 g, 9.2 mmol, 1.0 equiv
  • Et 3 N 2. g, 27.7 mmol, 3.9 mL, 3.0 equiv
  • (2, 5-dioxopyrrolidin-1-yl) 2-trimethylsilylethyl carbonate 4.8 g, 18.5 mmol, 2.0 equiv).
  • Step 2 Preparation of 2-trimethylsilylethyl 4-(3-aminocyclobutoxy) piperidine-1- carboxylate.
  • 2-trimethylsilylethyl 4-[3-(tert-butoxycarbonylamino)cyclo- butoxy]piperidine-1-carboxylate 1.5 g, 3.6 mmol, 1.0 equiv
  • MeOH 10 mL
  • Step 3 Preparation of 2-trimethylsilylethyl 4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy benzoyl]amino] cyclobutoxy] piperidine-1- carboxylate.
  • Step 4 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidyloxy)cyclobutyl]benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutoxy]-1-piperidyl]pyrimidine-5-carboxamide (I-65).
  • Step 1 Preparation of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoate.
  • Step 2 Preparation of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7- dihydropteridin-2-yl)amino]-3-methoxy-benzoate.
  • methyl 4-[(8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzoate 1.0 g, 2.2 mmol, 1.0 equiv
  • BH 3 ⁇ THF (1 M, 22.7 mL, 10.0 equiv) in THF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere.
  • Step 3 Preparation of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-benzoic acid.
  • a solution of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl- 6,7-dihydropteridin-2-yl)amino]-3-methoxy-benzoate (475 mg, 1.1 mmol, 1.0 equiv), LiOH ⁇ H2O (234 mg, 5.5 mmol, 5.0 equiv) in THF (6.0 mL), H 2 O (3.0 mL), MeOH (6.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere.
  • reaction mixture was adjusted pH to 5 with HCl (1N). Then the reaction mixture was concentrated under reduced pressure to remove organic solvent. Then the mixture was filtered and the filter cake was dried to give 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-benzoic acid (266 mg, 646 umol, 57% yield) as a white solid.
  • Step 4 Preparation of tert-butyl 4-[4-[4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7- dihydropteridin-2-yl)amino]-3-methoxy-phenyl]-4-oxo-butoxy]piperidine-1-carboxylate.
  • Step 5 Preparation of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide.
  • Step 6 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidine-5-carboxamide (I-66).
  • Step 2 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]-methyl-amino]-3-methoxy-benzoic acid.
  • Step 3 Preparation of tert-butyl 4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]-methyl-amino]-3-methoxy-benzoyl]amino]ethoxy]piperidine-1- carboxylate.
  • Step 4 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]-methyl-amino]-3-methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide.
  • Step 5 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)-methyl- amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidine-5-carboxamide (I-67).
  • the reaction mixture was quenched by addition saturated NH4Cl solution (15 mL), and then extracted with CH 2 Cl 2 (8 mL*3). The combined water layers were concentrated in vacuo.
  • the crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(FA)-ACN];gradient:5%-35% B over 15 min) to afford tert-butyl 2-(methylamino)-7-azaspiro[3.5]nonane-7-carboxylate (260 mg, 1.02 mmol, 49% yield) as a colorless solid.
  • Step 2 Preparation of tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonane-7- carboxylate.
  • Step 3 Preparation of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-methyl-benzamide.
  • Step 4 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (I- 68).
  • Step 1 Preparation of tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] azetidine-1-carboxylate.
  • a mixture of tert-butyl 3-allylazetidine-1-carboxylate (2.00 g, 10.1 mmol, 1 equiv) and Zn (8.62 g, 132 mmol, 13 equiv) in dioxane (28 mL) was added a solution of 2,2,2-trichloroacetyl chloride (5.53 g, 30.4 mmol, 3.39 mL, 3 equiv) and 1,2-dimethoxyethane (2.74 g, 30.4 mmol, 3.16 mL, 3 equiv) in dioxane (10 mL) in dropwise at 0°C for 0.5 h under N2.
  • the resulting mixture was stirred at 25 °C for 23.5 h.
  • the reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (30 mL).
  • the mixture was filtered and the mixture was extracted with ethyl acetate (15 mL*3).
  • the combined organic phase was washed with brine (15 mL*4), dried with anhydrous Na2SO4, filtered and concentrated in vacuo.
  • Step 2 Preparation of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1- carboxylate.
  • Step 3 Preparation of tert-butyl 3-[[3-(methylamino)cyclobutyl]methyl] azetidine- 1-carboxylate.
  • the reaction mixture was quenched by addition saturated NH 4 Cl solution (10 mL), and the mixture was extracted with CH 2 Cl 2 (8 mL*3). The water phase was concentrated in vacuo.
  • the crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)- ACN];gradient:0%-30% B over 9 min) to afford tert-butyl 3-[[3- (methylamino)cyclobutyl]methyl]azetidine-1-carboxylate (126 mg, 0.50 mmol, 59% yield) as a colorless oil.
  • Step 4 Preparation of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl] azetidine-1-carboxylate.
  • Step 5 Preparation of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-methyl- benzamide.
  • Step 6 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl]azetidin-1-yl]pyrimidine-5- carboxamide (I-69).
  • Step 1 Preparation of tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] piperidine-1-carboxylate.
  • a solution of tert-butyl 4-allylpiperidine-1-carboxylate (6.60 g, 29.0 mmol, 1 equiv) and Zn (19.0 g, 291 mmol, 10 equiv) in dioxane (50 mL) was slowly dropwise added a solution of 1,2-dimethoxyethane (8.00 g, 88.0 mmol, 3 equiv) and 2,2,2-trichloroacetyl chloride (16.0 g, 88.0 mmol, 3 equiv) in dioxane (50 mL) over a period of 0.5 h under N 2 at 0 °C.
  • Step 3 Preparation of tert-butyl 4-[(3-hydroxyiminocyclobutyl)methyl] piperidine- 1-carboxylate.
  • Step 4 Preparation of tert-butyl 4-[(3-aminocyclobutyl)methyl]piperidine-1- carboxylate.
  • Step 5 Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]amino]cyclobutyl]methyl]piperidine-1- carboxylate.
  • Step 6 Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidylmethyl)cyclobutyl]benzamide.
  • Step 7 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]-1-piperidyl]pyrimidine-5-carboxamide (I-70).
  • the resulting mixture was stirred at 25 °C for 23.5 h.
  • the reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (30 mL).
  • the mixture was filtered and the mixture was extracted with ethyl acetate (15 mL*3).
  • the combined organic phase was washed with brine (15 mL*4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 2 Preparation of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1- carboxylate.
  • Step 3 Preparation of tert-butyl 3-[(3-hydroxyiminocyclobutyl)methyl]azetidine-1- carboxylate.
  • Step 5 Preparation of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]cyclobutyl]methyl]azetidine-1- carboxylate.
  • Step 6 Preparation of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzamide.
  • Step 7 Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]azetidin-1-yl]pyrimidine-5-carboxamide (I-71).
  • Step 2 Preparation of tert-butyl 4-[2-(4-nitrophenoxy)ethoxy]piperidine-1- carboxylate.

Abstract

L'invention concerne des composés hétérobifonctionnels, des compositions pharmaceutiques et leur utilisation dans le traitement de maladies, telles que le cancer.
PCT/US2023/073696 2022-09-08 2023-09-08 Composés hétérobifonctionnels et méthodes de traitement de maladie WO2024054954A1 (fr)

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