WO2022217042A1 - Quinoline-4(1h)-ones à substitution naphtyle et composés apparentés et leur utilisation dans le traitement d'affections médicales - Google Patents

Quinoline-4(1h)-ones à substitution naphtyle et composés apparentés et leur utilisation dans le traitement d'affections médicales Download PDF

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WO2022217042A1
WO2022217042A1 PCT/US2022/024006 US2022024006W WO2022217042A1 WO 2022217042 A1 WO2022217042 A1 WO 2022217042A1 US 2022024006 W US2022024006 W US 2022024006W WO 2022217042 A1 WO2022217042 A1 WO 2022217042A1
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certain embodiments
nitrogen
substituted
occurrences
heterocyclyl
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PCT/US2022/024006
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Alfredo C. Castro
Michael J. Burke
Thomas A. Wynn
Sabine K. RUPPEL
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Ikena Oncology, Inc.
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Publication of WO2022217042A1 publication Critical patent/WO2022217042A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged 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

  • the invention provides naphthyl-substituted quinolin-4(1H)-oncs and related compounds, pharmaceutical compositions, their use for inhibiting K-Ras G12D activity, and their use in the treatment of medical disorders, such as cancer.
  • K-Ras Viral Oncogene Homolog
  • K-Ras G12D and G12C activating mutations of K-Ras
  • K-Ras G12D inhibitor compounds for treating cancer has been described in, for example, international patent application WO 2021/041671, the contents of which are herein incorporated by reference in its entirety.
  • the invention provides naphthyl-substituted quinolin-4( 1H)-oncs and related compounds, pharmaceutical compositions, their use for inhibiting K-Ras G12D activity, and their use in the treatment of medical disorders, such as cancer.
  • one aspect of the invention provides a collection of naphthyl-substituted 3,4-dihydroisoquinolin- 1 (2H)-oncs and related 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 naphthyl-substituted quinolin-4( 1H)- ones and related 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 naphthyl-substituted quinolin- 4(1 H)-oncs and related 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 naphthyl-substituted quinolin-4( 1H)- ones and related 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 naphthyl-substituted AH- pyrazino[l,2-a]pyrazin-4-ones and related compounds, such as a compound represented by Formula III: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of naphthyl-substituted AH- pyrazino[l,2-a]pyrazin-4-ones and related 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 a disorder mediated by K- Ras G12D in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or III, to a subject in need thereof to treat the disorder, as further described in the detailed description.
  • Another aspect of the invention provides a method of inhibiting K-Ras G12D activity.
  • the method comprises contacting K-Ras G12D with an effective amount of a compound described herein, such as a compound of Formula I, II, or III, to inhibit K-Ras G12D activity, as further described in the detailed description.
  • the invention provides naphthyl-substituted quinolin-4( 1H)-oncs and related compounds, pharmaceutical compositions, their use for inhibiting K-Ras G12D activity, and their use in the treatment of medical disorders, such as cancer.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C.
  • 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 C3-C6 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.
  • 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.
  • Such 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.
  • 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:
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a CIM 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 quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3 , 4 - d i h y d ro - 2 H- p y rrp l y l ) , 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 C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain
  • 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., -(CH2) 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.
  • -(Co alkylene)- refers to a bond. Accordingly, the term “-(Co-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1-3 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.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached trivalent phenyl group when it has three groups attached to it (e.g., ).
  • arylene refers to a bivalent aryl 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 p 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 hetero aromatic 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 hetero aromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7-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.
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it.
  • heteroarylene is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • pyridinylene refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridinylene is a bivalent pyridine radical when it has two
  • 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 in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- di h y dro-2H-py rro l y l ) , NH (as in pyrrolidinyl), or + NR (as in A-substitutcd 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.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by an oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • 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.
  • S(O) 2 N C(NR° 2 ) 2 ; -(CH 2 ) 0-4 S(O)R°; -N(R°)S(O) 2 NRo 2 ; -N(R°)S(O) 2 R°; -N(OR°)R°; - C(NH)NR° 2 ; -P(0) 2 R°; -P(0)R° 2 ; -0P(0)R° 2 ; -0P(0)(0R°) 2 ; SiR° 3 ; -(C1-4 straight or branched alkylene)0-N(R°) 2 ; or — (C i 4 straight or branched alkylene)C(0)0-N(R°) 2 .
  • R * is C1-6 aliphatic
  • R * is optionally substituted with halogen, - R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2
  • each R* is independently selected from Ci 4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, 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(0)R ⁇ , -C(0)0R ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , - C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C1-6 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 unsubstituted 3-12-membered saturated, partially unsaturated,
  • 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, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci 4alkyl)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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • 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.
  • a compound described herein may exist as an atropisomer (e.g., substituted biaryls)
  • all forms of such atropisomer are considered part of this invention.
  • Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • 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, C1-C10 alkyl, and C1-C6 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 “C3-C6 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 -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxy alkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • 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.
  • Carbocyclylene refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, ieri-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.
  • hydroxyalkoxyl refers to an alkoxyl group that is substituted with at least one hydroxyl.
  • hydroxyalkoxyl groups include -OCH2CH2OH, -0CH 2 C(H)(0H)CH 2 CH 2 0H, and the like.
  • alkoxylene refers to a bivalent alkoxyl group.
  • a cyclopentane susbsituted with an oxo group is cyclopentanone.
  • the chemical structure encompasses and .
  • a chemical structure containing a polycyclic fused ring when depicted with one or more substituent(s) having a bond that crosses multiple rings, the one or more substituent(s) may be independently attached to any of the rings crossed by the bond.
  • the chemical structure encompasses, for example,
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the 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. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention.
  • 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.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 mM, less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • K-Ras refers to a mammalian K-Ras protein.
  • the assignment of amino acid codon and residue positions for human K-Ras is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116.
  • K-Ras G12D refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid, instead of a glycine, at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human K-Ras is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116:
  • V ariantp Gly 12 Asp .
  • K-Ras inhibitor or “K-Ras antagonist” are defined as a compound that binds to and/or inhibits K-Ras with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • inhibitor or “K-Ras G12D inhibitor” or “K-Ras G12D antagonist” are defined as a compound that binds to and/or inhibits K-Ras G12D with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g ., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in K-Ras activity, such as K-Ras G12D activity, between a sample comprising a compound of the present invention, or composition thereof, and K-Ras, such as K-Ras G12D, and an equivalent sample comprising K-Ras, such as K-Ras G12D, in the absence of said compound, or composition thereof.
  • an 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.
  • 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.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • K-Ras-associated disease or disorder means any disease or other deleterious condition in which K-Ras, or a variant or mutant thereof, is known to play a role.
  • a non-limiting example of a K-Ras-associated disease or disorder is a K-Ras-associated cancer.
  • K-Ras G12D disorder mediated by K-Ras G12D
  • disease mediated by K-Ras G12D or “disease mediated by K-Ras G12D” or "K-Ras G12D-associated disease or disorder,” as used herein, refer to diseases or disorders associated with, or mediated by, or having a K-Ras G12D mutation.
  • a non-limiting example of a K-Ras G12D-associated disease or disorder is a K-Ras G12D-associated cancer.
  • 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.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • the invention provides naphthyl-substituted quinolin-4( 1H)-oncs and related 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.
  • One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 is naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 ;
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 ;
  • R 3 is hydrogen; or one occurrence of R 3 is hydrogen, and the other occurrence of R 3 is taken together with R 4 to form a double bond between the atoms to which R 3 and R 4 are attached; or both occurrences of R 3 are taken together to form an oxo substituent;
  • R 4 is taken together with one occurrence of R 3 to form a double bond between the atoms to which R 3 and R 4 are attached;
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, hydroxyl, Ci- 6 alkoxyl, halo, or cyano;
  • R 6 and R 7 each represent independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2;
  • R 8 and R 9 each represent independently for each occurrence hydrogen, C M alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences
  • X 1 is C(H) 2 , C(R 4 )(H), or N(R 4 );
  • X 2 is N or C(CN);
  • X 3 is N or C(H);
  • X 4 is C(O) or C(H) 2 ;
  • L is a covalent bond or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-;
  • Y 1 , Y 2 , and Y 3 represent independently a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -; and m, n, and p are each independently 0, 1, 2, or 3.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above
  • the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above
  • 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 naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl, an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is 1-naphthyl substituted with m occurrences of R 5 . In certain embodiments,
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is In certain embodiments, R 1 is
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl, isoquinolinyl, or indazolyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl substituted with m occurrences of R 5 .
  • R 1 is quinoline-4-yl substituted with m occurrences of R 5 .
  • R 1 is isoquinolinyl substituted with m occurrences of R 5 .
  • R 1 is isoquinolin-l-yl substituted with m occurrences of R 5 .
  • R 1 is indazolyl substituted with m occurrences of R 5 .
  • R 1 is phenyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is In certain embodiments, R 1 is [0089] In certain embodiments, R 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 . In certain embodiments, R 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with m occurrences of R 5 . In certain embodiments, R 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R 1 is selected from the groups depicted in the compounds in Table 1 or 1-A, below.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is phenyl or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with a single occurrence of R 6 at the 1-position.
  • R 2 is piperidinyl substituted with n occurrences of R 6 .
  • R 2 is morpholinyl substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In certain embodiments, R 2 is azetidinyl. In certain embodiments, R 2 is pyrrolidinyl. In certain embodiments, R 2 is pyrrolidin-2-yl. In certain embodiments, R 2 is l-methyl-pyrrolidin-2-yl. In certain embodiments, R 2 is piperidinyl. In certain embodiments, R 2 is morpholinyl.
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with n occurrences of R 6 .
  • R 2 is phenyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is phenyl.
  • R 2 is Ci- 6 aliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloaliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is a Ci- 6 aliphatic chain substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloalkyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is Ci- 6 alkyl substituted with n occurrences of R 6 .
  • R 2 is Ci- 6 aliphatic. In certain embodiments, R 2 is C3-6 cycloaliphatic. In certain embodiments, R 2 is a Ci- 6 aliphatic chain. In certain embodiments, R 2 is C3-6 cycloalkyl. In certain embodiments, R 2 is Ci- 6 alkyl.
  • R 2 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 1 or 1-A, below.
  • R 3 is hydrogen; or one occurrence of R 3 is hydrogen, and the other occurrence of R 3 is taken together with R 4 to form a double bond between the atoms to which R 3 and R 4 are attached; or both occurrences of R 3 are taken together to form an oxo substituent.
  • R 3 is hydrogen.
  • one occurrence of R 3 is hydrogen, and the other occurrence of R 3 is taken together with R 4 to form a double bond between the atoms to which R 3 and R 4 are attached.
  • both occurrences of R 3 are taken together to form an oxo substituent.
  • R 3 is selected from the groups depicted in the compounds in Table 1, below.
  • R 4 is taken together with one occurrence of R 3 to form a double bond between the atoms to which R 3 and R 4 are attached.
  • R 4 is selected from the groups depicted in the compounds in Table 1, below.
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, hydroxyl, Ci- 6 alkoxyl, halo, or cyano.
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, C1-3 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence C2-6 alkynyl or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl or hydroxyl. In certain embodiments, one occurrence of R 5 is ethynyl. In certain embodiments, one occurrence of R 5 is hydroxyl.
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, or Ci- 6 alkyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, or C1-3 alkyl. In certain embodiments, R 5 represents independently for each occurrence hydroxyl or Ci- 6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo or cyano.
  • R 5 represents independently for each occurrence C2-6 alkynyl. In certain embodiments, R 5 is ethynyl. In certain embodiments, R 5 represents independently for each occurrence C2-6 alkenyl. In certain embodiments, R 5 is ethenyl. In certain embodiments, R 5 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 5 represents independently for each occurrence C1-3 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo.
  • R 5 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 5 is fluoro. In certain embodiments, R 5 is chloro. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1 or 1-A, below.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 6 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 6 represents independently for each occurrence halo. In certain embodiments, R 6 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is chloro. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 6 is trifluoromethoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C1-3 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 6 is -NH2. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 1 or 1-A, below.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 7 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 7 represents independently for each occurrence halo. In certain embodiments, R 7 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 7 is fluoro. In certain embodiments, R 7 is chloro. In certain embodiments, R 7 is hydroxyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 7 is methoxy. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 7 is trifluoromethoxy. In certain embodiments, R 7 represents independently for each occurrence C1-6 alkyl. In certain embodiments, R 7 represents independently for each occurrence C1-3 alkyl.
  • R 7 is methyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 7 is trifluoromethyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 7 is -NH2. In certain embodiments, R 7 is selected from the groups depicted in the compounds in Table 1, below.
  • R 8 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl. In certain embodiments, R 8 is hydrogen or C 1-4 alkyl. In certain embodiments, R 8 is hydrogen or methyl.
  • R 8 is CIM alkyl or C3-5 cycloalkyl.
  • R 8 is hydrogen. In certain embodiments, R 8 is CIM alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is C3-5 cycloalkyl. In certain embodiments, R 8 is cyclopropyl. In certain embodiments, R 8 is selected from the groups depicted in the compounds in Table 1, below.
  • R 9 represents independently for each occurrence hydrogen, Ci-4 alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 represents independently for each occurrence hydrogen, C1-4 alkyl, or C3-5 cycloalkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or methyl. In certain embodiments, R 9 represents independently for each occurrence C1-4 alkyl or C3-5 cycloalkyl.
  • two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 is hydrogen. In certain embodiments, R 9 represents independently for each occurrence C M alkyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 represents independently for each occurrence C3-5 cycloalkyl. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is selected from the groups depicted in the compounds in Table 1, below.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 ; or A 1 is , [0130] In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is or
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl substituted with p occurrences of R 7 .
  • a 1 is piperidinyl substituted with p occurrences of R 7 .
  • a 1 is piperazinyl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidinyl substituted with p occurrences of R 7 .
  • a 1 is azetidinyl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In certain embodiments, A 1 is 1,4-diazepanyl. In certain embodiments, A 1 is piperidinyl. In certain embodiments, A 1 is piperazinyl. In certain embodiments, A 1 is pyrrolidinyl. In certain embodiments, A 1 is azetidinyl.
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl substituted with p occurrences of R 7 .
  • a 1 is piperidin-4-yl substituted with p occurrences of R 7 .
  • a 1 is piperazin-l-yl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is azetidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl. In certain embodiments, A 1 is 1,4-diazepan-l-yl. In certain embodiments, A 1 is piperidin-4-yl. In certain embodiments, A 1 is piperazin-l-yl. In certain embodiments, A 1 is pyrrolidin-3-yl. In certain embodiments, A 1 is azetidin-3-yl.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms. In certain embodiments, A 1 is or In certain embodiments, A 1 is In certain embodiments, A 1 i is
  • a 1 is a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated ori/zo-fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated ori/zo-fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 7-10 membered saturated ori zo-fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl or pyrimidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl substituted with p occurrences of R 7 .
  • a 1 is pyridin-4-yl substituted with p occurrences of R 7 .
  • a 1 is pyrimidinyl substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl or pyrazolyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl substituted with p occurrences of R 7 .
  • a 1 is pyrazolyl substituted with p occurrences of R 7 .
  • a 1 is selected from the groups depicted in the compounds in Table 1, below.
  • X 1 is C(H)2, C(R 4 )(H), or N(R 4 ). In certain embodiments,
  • X 1 is C(H) 2 or C(R 4 )(H). In certain embodiments, X 1 is C(R 4 )(H) or N(R 4 ). In certain embodiments, X 1 is C(H)2. In certain embodiments, X 1 is C(R 4 )(H). In certain embodiments, X 1 is N(R 4 ). In certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 1, below. [0156] As defined generally above, X 2 is N or C(CN). In certain embodiments, X 2 is N. In certain embodiments, X 2 is C(CN). In certain embodiments, X 2 is selected from the groups depicted in the compounds in Table 1, below.
  • X 3 is N or C(H). In certain embodiments, X 3 is N. In certain embodiments, X 3 is C(H). In certain embodiments, X 3 is selected from the groups depicted in the compounds in Table 1, below.
  • X 4 is C(O) or C(H)2. In certain embodiments, X 4 is C(O).
  • X 4 is C(H)2. In certain embodiments, X 4 is selected from the groups depicted in the compounds in Table 1, below.
  • L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-. In certain embodiments, L is a covalent bond.
  • L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a C1-4 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or - C(O)-. In certain embodiments, L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -N(R 9 )-, or -C(O)-.
  • L is a C 1-4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci- 4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is -0-CH 2 -, -0-(CH 2 ) 2 -, -N(R 9 )-CH 2 -, or -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -0-CH 2 - or -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH 2 - or -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -0-CH 2 -, wherein the carbon atom of L is attached to R 2 .
  • L is -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH 2 -, wherein the carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is selected from the groups depicted in the compounds in Table 1, below.
  • Y 1 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 ) 2 - or -(CH 2 ) 3 -. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) 3 -.
  • Y 1 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH 2 ) 3 -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 )-. In certain embodiments, Y 1 is -(CH 2 ) 2 -. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH 2 ) 3 -. In certain embodiments, Y 1 is -CH 2 -0-CH 2 -. In certain embodiments, Y 1 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is selected from the groups depicted in the compounds in Table 1, below.
  • Y 2 is a C 1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 2 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C 2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 ) 2 - or -(CH 2 ) 3 -. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) 3 -.
  • Y 2 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 ) 3 -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-. In certain embodiments, Y 2 is -(CH 2 ) 2 -. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 ) 3 -. In certain embodiments, Y 2 is -CH 2 -0-CH 2 -. In certain embodiments, Y 2 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is selected from the groups depicted in the compounds in Table 1, below.
  • Y 3 is a C 1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 3 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C 1-3 bivalent saturated, straight hydrocarbon chain. [0179] In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH2-O- CH2-, or -CH2-CF2-CH2-.
  • Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH2-CF2-CH2-.
  • Y 3 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH2-CF2-CH2-. In certain embodiments, Y 3 is -(CH2)2- or -(CH2)3-. In certain embodiments, Y 3 is -CH 2 -C(H)(OH)- or -CH2-CF2-CH2-. In certain embodiments, Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH2)3-. In certain embodiments, Y 3 is -(CH2)2- or -CH2-C(H)(OH)-. In certain embodiments, Y 3 is -(CH 2 ) 3 -, -CH2-O-CH2-, or -CH2-CF2-CH2-.
  • Y 3 is -(CH2)-. In certain embodiments, Y 3 is -(CH2)2-. In certain embodiments, Y 3 is -CH2-C(H)(OH)-. In certain embodiments, Y 3 is -(CH2)3-. In certain embodiments, Y 3 is -CH2-O-CH2-. In certain embodiments, Y 3 is -CH2-CF2-CH2-. In certain embodiments, Y 3 is selected from the groups depicted in the compounds in Table 1, below.
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1 or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is selected from the values represented in the compounds in Table 1, below. [0184] As defined generally above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values represented in the compounds in Table 1, below.
  • Another aspect of the invention provides a compound represented by Formula II: or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 is naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 ;
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 ;
  • R 3 is C M alkyl
  • R 4 is hydrogen, halo, or C1-4 alkyl
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, hydroxyl, Ci- 6 alkoxyl, halo, or cyano;
  • R 6 and R 7 each represent independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2;
  • R 8 and R 9 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p
  • X 1 is C(H) or N
  • X 2 is N, C(CN), or C(R 4 );
  • L is a covalent bond or a C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-;
  • Y 1 , Y 2 , and Y 3 represent independently a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 )2-; and m, n, and p are each independently 0, 1, 2, or 3.
  • the definitions of variables in Formula II above encompass multiple chemical groups.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above
  • the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above
  • 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 naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl, an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is 1-naphthyl substituted with m occurrences of R 5 . In certain embodiments,
  • R 1 is In certain embodiments, R 1 is
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl, isoquinolinyl, or indazolyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl substituted with m occurrences of R 5 .
  • R 1 is quinoline-4-yl substituted with m occurrences of R 5 .
  • R 1 is isoquinolinyl substituted with m occurrences of R 5 .
  • R 1 is isoquinolin-l-yl substituted with m occurrences of R 5 .
  • R 1 is indazolyl substituted with m occurrences of R 5 .
  • R 1 is phenyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is In certain embodiments, R 1 is
  • R 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is selected from the groups depicted in the compounds in Table 2, below.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is phenyl or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is [0209] In certain embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with a single occurrence of R 6 at the 1-position.
  • R 2 is piperidinyl substituted with n occurrences of R 6 .
  • R 2 is morpholinyl substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In certain embodiments, R 2 is azetidinyl. In certain embodiments, R 2 is pyrrolidinyl. In certain embodiments, R 2 is pyrrolidin-2-yl. In certain embodiments, R 2 is l-methyl-pyrrolidin-2-yl. In certain embodiments, R 2 is piperidinyl. In certain embodiments, R 2 is morpholinyl.
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with n occurrences of R 6 .
  • R 2 is phenyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is phenyl.
  • R 2 is Ci- 6 aliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloaliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is a Ci- 6 aliphatic chain substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloalkyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is Ci- 6 alkyl substituted with n occurrences of R 6 .
  • R 2 is Ci- 6 aliphatic. In certain embodiments, R 2 is C3-6 cycloaliphatic. In certain embodiments, R 2 is a Ci- 6 aliphatic chain. In certain embodiments, R 2 is C3-6 cycloalkyl. In certain embodiments, R 2 is Ci- 6 alkyl.
  • R 2 is selected from the groups depicted in the compounds in Table 2, below.
  • R 3 is Ci-4 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 2, below.
  • R 4 is hydrogen, halo, or Ci-4 alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is fluoro or chloro. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 is chloro. In certain embodiments, R 4 is C M alkyl. In certain embodiments, R 4 is methyl. In certain embodiments,
  • R 4 is selected from the groups depicted in the compounds in Table 2, below.
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, hydroxyl, Ci- 6 alkoxyl, halo, or cyano.
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, C1-3 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence C2-6 alkynyl or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl or hydroxyl. In certain embodiments, one occurrence of R 5 is ethynyl. In certain embodiments, one occurrence of R 5 is hydroxyl.
  • R 5 represents independently for each occurrence C 2-6 alkynyl, C 2-6 alkenyl, or Ci- 6 alkyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, or C 1-3 alkyl. In certain embodiments, R 5 represents independently for each occurrence hydroxyl or Ci- 6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo or cyano.
  • R 5 represents independently for each occurrence C 2-6 alkynyl. In certain embodiments, R 5 is ethynyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 alkenyl. In certain embodiments, R 5 is ethenyl. In certain embodiments, R 5 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-3 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo.
  • R 5 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 5 is fluoro. In certain embodiments, R 5 is chloro. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 2, below.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 6 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 6 represents independently for each occurrence halo. In certain embodiments, R 6 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is chloro. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 6 is trifluoromethoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C1-3 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 6 is -NH2. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 2, below.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 7 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 7 represents independently for each occurrence halo. In certain embodiments, R 7 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 7 is fluoro. In certain embodiments, R 7 is chloro. In certain embodiments, R 7 is hydroxyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 7 is methoxy. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 7 is trifluoromethoxy. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 7 represents independently for each occurrence C1-3 alkyl.
  • R 7 is methyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 7 is trifluoromethyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 7 is -NH2. In certain embodiments, R 7 is selected from the groups depicted in the compounds in Table 2, below.
  • R 8 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl. In certain embodiments, R 8 is hydrogen or C 1-4 alkyl. In certain embodiments, R 8 is hydrogen or methyl.
  • R 8 is C IM alkyl or C3-5 cycloalkyl.
  • R 8 is hydrogen. In certain embodiments, R 8 is C IM alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is C3-5 cycloalkyl. In certain embodiments, R 8 is cyclopropyl. In certain embodiments, R 8 is selected from the groups depicted in the compounds in Table 2, below.
  • R 9 represents independently for each occurrence hydrogen, Ci-4 alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 represents independently for each occurrence hydrogen, C1-4 alkyl, or C3-5 cycloalkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or methyl. In certain embodiments, R 9 represents independently for each occurrence C1-4 alkyl or C3-5 cycloalkyl.
  • two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 is hydrogen. In certain embodiments, R 9 represents independently for each occurrence C1-4 alkyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 represents independently for each occurrence C3-5 cycloalkyl. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is selected from the groups depicted in the compounds in Table 2, below.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 ; or A 1 is , ,
  • a 1 is In certain embodiments, A 1 is i n certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is [0243] In certain embodiments, A 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is or
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl substituted with p occurrences of R 7 .
  • a 1 is piperidinyl substituted with p occurrences of R 7 .
  • a 1 is piperazinyl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidinyl substituted with p occurrences of R 7 .
  • a 1 is azetidinyl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In certain embodiments, A 1 is 1,4-diazepanyl. In certain embodiments, A 1 is piperidinyl. In certain embodiments, A 1 is piperazinyl. In certain embodiments, A 1 is pyrrolidinyl. In certain embodiments, A 1 is azetidinyl.
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl substituted with p occurrences of R 7 .
  • a 1 is piperidin-4-yl substituted with p occurrences of R 7 .
  • a 1 is piperazin-l-yl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is azetidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl. In certain embodiments, A 1 is 1,4-diazepan-l-yl. In certain embodiments, A 1 is piperidin-4-yl. In certain embodiments, A 1 is piperazin-l-yl. In certain embodiments, A 1 is pyrrolidin-3-yl. In certain embodiments, A 1 is azetidin-3-yl.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms. In certain embodiments, A 1 is or In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 7-10 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl or pyrimidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl substituted with p occurrences of R 7 .
  • a 1 is pyridin-4-yl substituted with p occurrences of R 7 .
  • a 1 is pyrimidinyl substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl or pyrazolyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl substituted with p occurrences of R 7 .
  • a 1 is pyrazolyl substituted with p occurrences of R 7 .
  • a 1 is selected from the groups depicted in the compounds in Table 2, below.
  • X 1 is C(H) or N. In certain embodiments, X 1 is C(H). In certain embodiments, X 1 is N. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 2, below.
  • X 2 is N, C(CN), or C(R 4 ). In certain embodiments, X 2 is N. In certain embodiments, X 2 is C(CN) or C(R 4 ). In certain embodiments, X 2 is C(CN) or C(H).
  • X 2 is C(CN). In certain embodiments, X 2 is C(R 4 ). In certain embodiments, X 2 is C(H). In certain embodiments, X 2 is selected from the groups depicted in the compounds in Table 2, below.
  • L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-. In certain embodiments, L is a covalent bond.
  • L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a CM bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or - C(O)-.
  • L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -N(R 9 )-, or -C(O)-.
  • L is a C1-4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci- 4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is -O-CH2-, -0-(CH 2 ) 2 -, -N(R 9 )-CH 2 -, or -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -O-CH2- or -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH2- or -N(R 9 )-(CH2)2-, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -O-CH2-, wherein the carbon atom of L is attached to R 2 .
  • L is -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH2-, wherein the carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-(CH2)2-, wherein the terminal carbon atom of L is attached to R 2 .
  • L is selected from the groups depicted in the compounds in Table 2, below.
  • Y 1 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -O-, -C(H)(R 7 )-, or -C(R 7 )2-.
  • Y 1 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -O-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 1 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - O-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -O-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 1-3 bivalent saturated, straight hydrocarbon chain. [0275] In certain embodiments, Y 1 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -O- CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH2-CF2-CH2-.
  • Y 1 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH2) 2 - or -(CH2) 3 -. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH2) 3 -.
  • Y 1 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH 2 ) 3 -, -CH2-O-CH2-, or -CH2-CF2-CH2-.
  • Y 1 is -(CH2)-. In certain embodiments, Y 1 is -(CH2) 2 -. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH2) 3 -. In certain embodiments, Y 1 is -CH 2 -O-CH 2 -. In certain embodiments, Y 1 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is selected from the groups depicted in the compounds in Table 2, below.
  • Y 2 is a C 1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2-3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 ) 2 - or -(CH 2 )3-. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) -.
  • Y 2 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 ) -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-. In certain embodiments, Y 2 is -(CH 2 ) 2 -. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 )3-. In certain embodiments, Y 2 is -CH 2 -0-CH 2 -. In certain embodiments, Y 2 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is selected from the groups depicted in the compounds in Table 2, below.
  • Y 3 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 3 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C 2 -3 bivalent saturated, straight hydrocarbon chain.
  • Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 )3-, or -CH 2 -CF 2 -CH 2 -.
  • Y 3 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 3 is -(CH 2 ) 2 - or -(CH 2 )3-. In certain embodiments, Y 3 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) 3 -.
  • Y 3 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 3 is -(CH 2 ) 3 -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 3 is -(CH 2 )-. In certain embodiments, Y 3 is -(CH 2 ) 2 -. In certain embodiments, Y 3 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 3 is -(CH 2 )3-. In certain embodiments, Y 3 is -CH 2 -0-CH 2 -. In certain embodiments, Y 3 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 3 is selected from the groups depicted in the compounds in Table 2, below.
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 2, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1 or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is selected from the values represented in the compounds in Table 2, below.
  • p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values represented in the compounds in Table 2, below.
  • Another aspect of the invention provides a compound represented by Formula III: or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 is naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 ;
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 ;
  • R 4 is hydrogen, halo, or C1-4 alkyl
  • R 5 represents independently for each occurrence C2-6 alkynyl, C2-6 alkenyl, Ci- 6 alkyl, hydroxyl, Ci- 6 alkoxyl, halo, or cyano;
  • R 6 and R 7 each represent independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2;
  • R 8 and R 9 each represent independently for each occurrence hydrogen, C1-4 alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p
  • X 2 is N, C(CN), or C(R 4 );
  • L is a covalent bond or a CM bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-;
  • Y 1 , Y 2 , and Y 3 represent independently a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 )2-; and m, n, and p are each independently 0, 1, 2, or 3.
  • the definitions of variables in Formula III above encompass multiple chemical groups.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above
  • the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above
  • 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 III.
  • R 1 is naphthyl; an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl, an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or phenyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 5 .
  • R 1 is naphthyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is 1-naphthyl substituted with m occurrences of R 5 . In certain embodiments,
  • R 1 is In certain embodiments, R 1 is
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with m occurrences of R 5 .
  • R 1 is certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is an 8-10 membered bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl, isoquinolinyl, or indazolyl; each of which is substituted with m occurrences of R 5 .
  • R 1 is quinolinyl substituted with m occurrences of R 5 .
  • R 1 is quinoline-4-yl substituted with m occurrences of R 5 .
  • R 1 is isoquinolinyl substituted with m occurrences of R 5 .
  • R 1 is isoquinolin-l-yl substituted with m occurrences of R 5 .
  • R 1 is indazolyl substituted with m occurrences of R 5 .
  • R 1 is phenyl substituted with m occurrences of R 5 . In certain embodiments, R 1 is In certain embodiments, R 1 is
  • R 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with m occurrences of R 5 .
  • R 1 is selected from the groups depicted in the compounds in Table 3, below.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is phenyl or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Ci- 6 aliphatic; each of which is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is substituted with n occurrences of R 6 .
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is an 8-10 membered partially unsaturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R 2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is an 8-10 membered saturated bicyclic heterocyclyl having 1 nitrogen atom. In certain embodiments, R 2 is [0317] In certain embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein said heterocyclyl is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl; each of which is substituted with n occurrences of R 6 .
  • R 2 is azetidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidinyl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with n occurrences of R 6 .
  • R 2 is pyrrolidin-2-yl substituted with a single occurrence of R 6 at the 1-position.
  • R 2 is piperidinyl substituted with n occurrences of R 6 .
  • R 2 is morpholinyl substituted with n occurrences of R 6 .
  • R 2 is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In certain embodiments, R 2 is azetidinyl. In certain embodiments, R 2 is pyrrolidinyl. In certain embodiments, R 2 is pyrrolidin-2-yl. In certain embodiments, R 2 is l-methyl-pyrrolidin-2-yl. In certain embodiments, R 2 is piperidinyl. In certain embodiments, R 2 is morpholinyl.
  • R 2 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with n occurrences of R 6 .
  • R 2 is phenyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is phenyl.
  • R 2 is Ci- 6 aliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloaliphatic substituted with n occurrences of R 6 . In certain embodiments, R 2 is a Ci- 6 aliphatic chain substituted with n occurrences of R 6 . In certain embodiments, R 2 is C3-6 cycloalkyl substituted with n occurrences of R 6 . In certain embodiments, R 2 is Ci- 6 alkyl substituted with n occurrences of R 6 .
  • R 2 is Ci- 6 aliphatic. In certain embodiments, R 2 is C3-6 cycloaliphatic. In certain embodiments, R 2 is a Ci- 6 aliphatic chain. In certain embodiments, R 2 is C3-6 cycloalkyl. In certain embodiments, R 2 is Ci- 6 alkyl.
  • R 2 is selected from the groups depicted in the compounds in Table 3, below.
  • R 4 is hydrogen, halo, or Ci- 4 alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is fluoro or chloro. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 is chloro. In certain embodiments, R 4 is C 1-4 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments,
  • R 4 is selected from the groups depicted in the compounds in Table 3, below.
  • R 5 represents independently for each occurrence C 2-6 alkynyl, C 2-6 alkenyl, C1-6 alkyl, hydroxyl, C1-6 alkoxyl, halo, or cyano.
  • R 5 represents independently for each occurrence C 2-6 alkynyl, C 2-6 alkenyl, C1-6 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, C 1-3 alkyl, or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 alkynyl or hydroxyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl or hydroxyl. In certain embodiments, one occurrence of R 5 is ethynyl. In certain embodiments, one occurrence of R 5 is hydroxyl.
  • R 5 represents independently for each occurrence C 2-6 alkynyl, C 2-6 alkenyl, or C1-6 alkyl. In certain embodiments, R 5 represents independently for each occurrence ethynyl, ethenyl, or C 1-3 alkyl. In certain embodiments, R 5 represents independently for each occurrence hydroxyl or C1-6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo or cyano.
  • R 5 represents independently for each occurrence C 2-6 alkynyl. In certain embodiments, R 5 is ethynyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 alkenyl. In certain embodiments, R 5 is ethenyl. In certain embodiments, R 5 represents independently for each occurrence Ci-6 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-3 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 represents independently for each occurrence C1-6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence halo.
  • R 5 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 5 is fluoro. In certain embodiments, R 5 is chloro. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 3, below. [0332] As defined generally above, R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 6 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 6 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 6 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 6 represents independently for each occurrence halo. In certain embodiments, R 6 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is chloro. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 6 is trifluoromethoxy. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C1-3 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 6 is -NH2. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 3, below.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, or -N(R 9 )2.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, or Ci- 6 haloalkyl. In certain embodiments, R 7 represents independently for each occurrence halo or Ci- 6 alkyl. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or Ci- 6 alkyl.
  • R 7 represents independently for each occurrence halo, hydroxyl, Ci- 6 alkoxyl, Ci- 6 haloalkoxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, hydroxyl, or -N(R 9 )2. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkoxyl, or Ci- 6 haloalkoxyl. In certain embodiments, R 7 represents independently for each occurrence halo, Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl.
  • R 7 represents independently for each occurrence Ci- 6 alkyl, Ci- 6 haloalkyl, or Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkyl or Ci- 6 haloalkyl.
  • R 7 represents independently for each occurrence halo. In certain embodiments, R 7 represents independently for each occurrence fluoro or chloro. In certain embodiments, R 7 is fluoro. In certain embodiments, R 7 is chloro. In certain embodiments, R 7 is hydroxyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkoxyl. In certain embodiments, R 7 is methoxy. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkoxyl. In certain embodiments, R 7 is trifluoromethoxy. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 alkyl. In certain embodiments, R 7 represents independently for each occurrence C1-3 alkyl.
  • R 7 is methyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 haloalkyl. In certain embodiments, R 7 is trifluoromethyl. In certain embodiments, R 7 represents independently for each occurrence Ci- 6 hydroxyalkyl. In certain embodiments, R 7 represents independently for each occurrence -N(R 9 )2. In certain embodiments, R 7 is -NH2. In certain embodiments, R 7 is selected from the groups depicted in the compounds in Table 3, below. [0340] As defined generally above, R 8 is hydrogen, Ci alkyl, or C3-5 cycloalkyl. In certain embodiments, R 8 is hydrogen or C M alkyl. In certain embodiments, R 8 is hydrogen or methyl.
  • R 8 is C IM alkyl or C3-5 cycloalkyl.
  • R 8 is hydrogen. In certain embodiments, R 8 is C IM alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is C3-5 cycloalkyl. In certain embodiments, R 8 is cyclopropyl. In certain embodiments, R 8 is selected from the groups depicted in the compounds in Table 3, below.
  • R 9 represents independently for each occurrence hydrogen, Ci-4 alkyl, or C3-5 cycloalkyl; or two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 represents independently for each occurrence hydrogen, C1-4 alkyl, or C3-5 cycloalkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R 9 represents independently for each occurrence hydrogen or methyl. In certain embodiments, R 9 represents independently for each occurrence C1-4 alkyl or C3-5 cycloalkyl.
  • two occurrences of R 9 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 9 is hydrogen. In certain embodiments, R 9 represents independently for each occurrence C1-4 alkyl. In certain embodiments, R 9 is methyl. In certain embodiments, R 9 represents independently for each occurrence C3-5 cycloalkyl. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is selected from the groups depicted in the compounds in Table 3, below.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 ; or A 1 is
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is
  • a 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is [0350] In certain embodiments, A 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 ; or A 1 is or
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or a 5- 6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; or
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; or a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 4-7 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered saturated monocyclic heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl substituted with p occurrences of R 7 .
  • a 1 is piperidinyl substituted with p occurrences of R 7 .
  • a 1 is piperazinyl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidinyl substituted with p occurrences of R 7 .
  • a 1 is azetidinyl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepanyl, piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In certain embodiments, A 1 is 1,4-diazepanyl. In certain embodiments, A 1 is piperidinyl. In certain embodiments, A 1 is piperazinyl. In certain embodiments, A 1 is pyrrolidinyl. In certain embodiments, A 1 is azetidinyl.
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl; each of which is substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl substituted with p occurrences of R 7 .
  • a 1 is piperidin-4-yl substituted with p occurrences of R 7 .
  • a 1 is piperazin-l-yl substituted with p occurrences of R 7 .
  • a 1 is pyrrolidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is azetidin-3-yl substituted with p occurrences of R 7 .
  • a 1 is 1,4-diazepan-l-yl, piperidin-4-yl, piperazin-l-yl, pyrrolidin-3-yl, or azetidin-3-yl. In certain embodiments, A 1 is 1,4-diazepan-l-yl. In certain embodiments, A 1 is piperidin-4-yl. In certain embodiments, A 1 is piperazin-l-yl. In certain embodiments, A 1 is pyrrolidin-3-yl. In certain embodiments, A 1 is azetidin-3-yl.
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 7-10 membered saturated spirocyclic heterocyclyl having 1 or 2 nitrogen atoms. In certain embodiments, A 1 is a 6-11 membered saturated spirocyclic heterocyclyl having 2 nitrogen atoms. In certain embodiments, A 1 is or In certain embodiments, A 1 is In certain embodiments, A 1 i s
  • a 1 is a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 7-10 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms; wherein said heterocyclyl is substituted with p occurrences of R 7 .
  • a 1 is a 6-11 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 7-10 membered saturated ortho- fused heterocyclyl having 1 or 2 nitrogen atoms.
  • a 1 is a 5-6 membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl or pyrimidinyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is pyridinyl substituted with p occurrences of R 7 .
  • a 1 is pyridin-4-yl substituted with p occurrences of R 7 .
  • a 1 is pyrimidinyl substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having one nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is a 5-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms; wherein said heteroaryl is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl or pyrazolyl; each of which is substituted with p occurrences of R 7 .
  • a 1 is imidazolyl substituted with p occurrences of R 7 .
  • a 1 is pyrazolyl substituted with p occurrences of R 7 .
  • a 1 is selected from the groups depicted in the compounds in Table 3, below.
  • X 2 is N, C(CN), or C(R 4 ). In certain embodiments, X 2 is N. In certain embodiments, X 2 is C(CN) or C(R 4 ). In certain embodiments, X 2 is C(CN) or C(H).
  • X 2 is C(CN). In certain embodiments, X 2 is C(R 4 ). In certain embodiments, X 2 is C(H). In certain embodiments, X 2 is selected from the groups depicted in the compounds in Table 3, below.
  • L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-. In certain embodiments, L is a covalent bond.
  • L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a C 1-4 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -N(R 9 )-, or - C(O)-. In certain embodiments, L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -N(R 9 )-, or -C(O)-.
  • L is a C1-4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -N(R 9 )-, or -C(O)-.
  • L is a Ci-4 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -O- or -N(R 9 )-.
  • L is -0-CH 2 -, -0-(CH 2 ) 2 -, -N(R 9 )-CH 2 -, or -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -0-CH 2 - or -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH 2 - or -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -0-CH 2 -, wherein the carbon atom of L is attached to R 2 .
  • L is -0-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-CH 2 -, wherein the carbon atom of L is attached to R 2 .
  • L is -N(R 9 )-(CH 2 ) 2 -, wherein the terminal carbon atom of L is attached to R 2 .
  • L is selected from the groups depicted in the compounds in Table 3, below.
  • Y 1 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 1 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 1 is a C2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 )3-, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 ) 2 - or -(CH 2 )3-. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) 3 -.
  • Y 1 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH 2 ) 3 -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 1 is -(CH 2 )-. In certain embodiments, Y 1 is -(CH 2 ) 2 -. In certain embodiments, Y 1 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 1 is -(CH 2 )3-. In certain embodiments, Y 1 is -CH 2 -0-CH 2 -. In certain embodiments, Y 1 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 1 is selected from the groups depicted in the compounds in Table 3, below.
  • Y 2 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 2 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 2 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C1-3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 2 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 2 is a C 2 -3 bivalent saturated, straight hydrocarbon chain.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH 2 -0- CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 ) 2 - or -(CH 2 )3-. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)- or -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH 2 ) 3 -.
  • Y 2 is -(CH 2 ) 2 - or -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 ) 3 -, -CH 2 -0-CH 2 -, or -CH 2 -CF 2 -CH 2 -.
  • Y 2 is -(CH 2 )-. In certain embodiments, Y 2 is -(CH 2 ) 2 -. In certain embodiments, Y 2 is -CH 2 -C(H)(OH)-. In certain embodiments, Y 2 is -(CH 2 )3-. In certain embodiments, Y 2 is -CH 2 -0-CH 2 -. In certain embodiments, Y 2 is -CH 2 -CF 2 -CH 2 -. In certain embodiments, Y 2 is selected from the groups depicted in the compounds in Table 3, below.
  • Y 3 is a C1-3 bivalent saturated or unsaturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C 2 -3 bivalent unsaturated, straight hydrocarbon chain.
  • Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C1-3 bivalent saturated, straight hydrocarbon chain. [0393] In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by - 0-, -C(H)(R 7 )-, or -C(R 7 ) 2 -.
  • Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -0-, - C(H)(R 7 )-, or -C(R 7 ) 2 -. In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -0-, -C(H)(R 7 )-, or - C(R 7 ) 2 -. In certain embodiments, Y 3 is a C2-3 bivalent saturated, straight hydrocarbon chain.
  • Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, -CH2-O- CH2-, or -CH2-CF2-CH2-.
  • Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, - (CH 2 ) 3 -, or -CH2-CF2-CH2-.
  • Y 3 is -(CH 2 ) 2 -, -CH 2 -C(H)(OH)-, -(CH 2 ) 3 -, or -CH2-CF2-CH2-. In certain embodiments, Y 3 is -(CH2)2- or -(CH2)3-. In certain embodiments, Y 3 is -CH 2 -C(H)(OH)- or -CH2-CF2-CH2-. In certain embodiments, Y 3 is -(CH 2 )-, -(CH 2 ) 2 -, or - (CH2)3-. In certain embodiments, Y 3 is -(CH2)2- or -CH2-C(H)(OH)-. In certain embodiments, Y 3 is -(CH 2 ) 3 -, -CH2-O-CH2-, or -CH2-CF2-CH2-.
  • Y 3 is -(CH2)-. In certain embodiments, Y 3 is -(CH2)2-. In certain embodiments, Y 3 is -CH2-C(H)(OH)-. In certain embodiments, Y 3 is -(CH2)3-. In certain embodiments, Y 3 is -CH2-O-CH2-. In certain embodiments, Y 3 is -CH2-CF2-CH2-. In certain embodiments, Y 3 is selected from the groups depicted in the compounds in Table 3, below.
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Table 3, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1 or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is selected from the values represented in the compounds in Table 3, below. [0398] As defined generally above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values represented in the compounds in Table 3, below.
  • the compound is a compound in Table 1, 1-A, 2, or 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 1-A, 2, or 3 below. In certain embodiments, the compound is a compound in Table 1, 2, or 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, or 3 below. In certain embodiments, the compound is a compound in Table 1 or 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 2 below. In certain embodiments, the compound is a compound in Table 1 or 1-A below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 1-A below.
  • the compound is a compound in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 below. In certain embodiments, the compound is a compound in Table 1-A below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1-A below. In certain embodiments, the compound is a compound in Table 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2 below. In certain embodiments, the compound is a compound in Table 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3 below. TABLE 1.
  • Schemes 4 and 5 depict methods that may be used for preparing specific compounds described herein, based on methods described in Schemes 1-3 above, and in the Examples below.
  • Scheme 4 depicts methods that may be used to prepare compounds 1-5 and 1-8.
  • compound 1-26 may be prepared according to the methods depicted for compound 1-8, but using tert - butyl azetidin-3-ylcarbamate instead of tert -butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate in the first step.
  • compound 1-23 may be prepared according to the methods depicted for compound 1-5, but using 4-bromo-2-(methoxymethoxy)quinoline instead of the substituted naphthyl triflate in the Pd coupling step.
  • Scheme 5 depicts methods that may be used to prepare compounds II-3 and II-4.
  • compounds II-9 and II- 10 may be prepared according to the methods depicted for compounds II-3 and II-4, respectively, but using tert-butyl 1,4-diazepane-l-carboxylate or tert- butyl azetidin-3-ylcarbamate instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate in the first step.
  • SCHEME 5 tert-butyl 1,4-diazepane-l-carboxylate or tert- butyl azetidin-3-ylcarbamate instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate in the first step.
  • one aspect of the invention provides a method of treating a disorder mediated by K- Ras in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or III, to a subject in need thereof to treat the disorder.
  • Another aspect of the invention provides a method of treating a disorder mediated by K-Ras G12D in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or III, to a subject in need thereof to treat the disorder.
  • a compound described herein such as a compound of Formula I, II, or III
  • the compound is a compound of Formula I, II, or III defined by one of the embodiments described above.
  • K-Ras Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP-bound active
  • cellular proliferation e.g ., see Alamgeer et al., (2013) Current Opin Pharmcol.13:394-401).
  • K-Ras The role of activated K-Ras in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of K-Ras has been reported to account for up to 20% of all cancers, and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras and downstream signaling have been reported in 25 - 30% of lung adenocarcinomas (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928- 942 doi: 10.1038/nrd428).
  • K-Ras G12D mutation has been reported to be present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non- small cell lung carcinoma patients, and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset Version 4).
  • the provided compounds are inhibitors of K-Ras and are therefore useful for treating one or more disorders associated with activity of K-Ras.
  • the present invention provides a method for treating a K-Ras -mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • K-Ras-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which K-Ras, or a variant or mutant thereof, is known to play a role.
  • another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which K-Ras is known to play a role.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, of a disease or disorder characterized by or associated with increased K- Ras expression and/or increased K-Ras activity, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of K-Ras activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a K-Ras inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • the cellular proliferative disorder is cancer.
  • the cancer is characterized by increased K-Ras expression and/or increased K-Ras activity, i.e., “increased activated K-Ras.”
  • the K-Ras is a mutant K-Ras. In some embodiments, the K- Ras is an activated mutant K-Ras. In some embodiments, the K-Ras is a G12 mutant K-Ras. In some embodiments, the K-Ras is K-Ras G12D, K-Ras G12V, or K-Ras G12C. In some embodiments, the K-Ras is K-Ras G12D. In some embodiments, the K-Ras is K-Ras G12V. In some embodiments, the K-Ras is K-Ras G12C.
  • the provided compounds are inhibitors of K-Ras G12D and are therefore useful for treating one or more disorders associated with activity of K-Ras G12D.
  • the present invention provides a method for treating a K-Ras G12D-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • K-Ras G12D-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which K-Ras G12D is known to play a role.
  • another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which K-Ras G12D is known to play a role.
  • kits for treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, of a disease or disorder characterized by or associated with increased K- Ras G12D expression and/or increased K-Ras G12D activity comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of K-Ras G12D activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, an K-Ras G12D inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • the cellular proliferative disorder is cancer.
  • the cancer is characterized by increased K-Ras G12D expression and/or increased K-Ras G12D activity, i.e., “increased activated K-Ras G12D.”
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3- fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10- fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms "increased expression” and/or “increased activity" of a substance, such as K-Ras G12D, in a sample or cancer or patient refers to an increase in the amount of the substance, such as K-Ras G12D, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of the substance, such as K-Ras G12D, in a control sample or control samples, such as an individual or
  • a subject can also be determined to have an "increased expression” or “increased activity” of a substance, such as K-Ras G12D, if the expression and/or activity of the substance, such as K-Ras G12D, is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of the substance, such as K-Ras G12D, in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location ( e.g ., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis, as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • the disorder is cancer.
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor.
  • a cancer is treated by inhibiting or reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
  • the cancer is selected from is non-small cell lung cancer (NSCLC), small cell lung cancer, colorectal cancer, rectal cancer, and pancreatic cancer. In some embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer. In some embodiments, the cancer is selected from non-small cell lung cancer (NSCLC) and pancreatic cancer.
  • the cancer is a solid tumor. In certain embodiments, the cancer is a melanoma, carcinoma, or blastoma. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is an adenocarcinoma. In certain embodiments, the cancer is a blastoma.
  • the cancer is lung cancer, pancreatic cancer, colorectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, or nervous system cancer.
  • the cancer is lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is breast cancer.
  • the cancer is cervical cancer.
  • the cancer is prostate cancer.
  • the cancer is gastric cancer.
  • the cancer is skin cancer.
  • the cancer is liver cancer.
  • the cancer is bile duct cancer.
  • the cancer is nervous system cancer.
  • the cancer is breast adenocarcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, prostate adenocarcinoma, gastric adenocarcinoma, melanoma, lung squamous cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, or neuroblastoma.
  • the cancer is breast adenocarcinoma.
  • the cancer is lung adenocarcinoma.
  • the cancer is pancreatic adenocarcinoma.
  • the cancer is cervical adenocarcinoma.
  • the cancer is prostate adenocarcinoma.
  • the cancer is gastric adenocarcinoma.
  • the cancer is melanoma.
  • the cancer is lung squamous cell carcinoma, hepatocellular carcinoma, or cholangiocarcinoma. In certain embodiments, the cancer is lung squamous cell carcinoma. In certain embodiments, the cancer is hepatocellular carcinoma. In certain embodiments, the cancer is cholangiocarcinoma.
  • the cancer is glioblastoma or neuroblastoma. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma. [0429] In certain embodiments, the cancer is lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer.
  • the cancer has elevated K-Ras activity. In certain embodiments, the cancer overexpresses K-Ras. In some embodiments, a subject having a disorder associated with or mediated by K-Ras has been identified or diagnosed as having a cancer having a K-Ras mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a K-Ras mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject who has one or more tumor that is positive for a K-Ras mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumor(s) have a K-Ras mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a K-Ras gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a K-Ras mutation (and, for example, the clinical record indicates that the subject should be treated with any of the compounds or compositions provided herein).
  • an assay is used to determine whether the patient has a K-Ras mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a K-Ras-associated cancer, a patient having one or more symptoms of a K- Ras-associated cancer, and/or a patient that has an increased risk of developing a K-Ras- associated cancer).
  • a sample e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a K-Ras-associated cancer, a patient having one or more symptoms of a K- Ras-associated cancer, and/or a patient that has an increased risk of developing a K-Ras- associated cancer).
  • Non-limiting examples of such assays that can be used to determine whether a patient or subject has a K-Ras mutation include next generation sequencing (NGS), immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • NGS next generation sequencing
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • the K-Ras mutation is a G12 mutation. In some embodiments, the K-Ras mutation is G12D, G12V, or G12C. In some embodiments, the K-Ras mutation is G12D. In some embodiments, the K-Ras mutation is G12V. In some embodiments, the K-Ras mutation is G12C.
  • the cancer has elevated K-Ras G12D activity. In certain embodiments, the cancer overexpresses K-Ras G12D.
  • a subject having a disorder associated with or mediated by K-Ras G12D has been identified or diagnosed as having a cancer having a K-Ras G12D mutation (e.g ., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a K-Ras G12D mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject who has one or more tumor that is positive for a K-Ras G12D mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject can be a subject whose tumor(s) have a K-Ras G12D mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a K-Ras G12D gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a K-Ras G12D mutation (and, for example, the clinical record indicates that the subject should be treated with any of the compounds or compositions provided herein).
  • an assay is used to determine whether the patient has a K-Ras G12D mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a K-Ras G12D-associated cancer, a patient having one or more symptoms of a K-Ras G12D-associated cancer, and/or a patient that has an increased risk of developing a K-Ras G12D-associated cancer).
  • a sample e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a K-Ras G12D-associated cancer, a patient having one or more symptoms of a K-Ras G12D-associated cancer, and/or a patient that has an increased risk of developing a K-Ras G12D-
  • Non-limiting examples of such assays that can be used to determine whether a patient or subject has a K-Ras G12D mutation include next generation sequencing (NGS), immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR- based amplification (e.g ., RT-PCR and quantitative real-time RT-PCR).
  • NGS next generation sequencing
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • the cancer is a leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, or a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma
  • a leukemia
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • the cancer is acoustic neuroma, astrocytoma ( e.g .
  • Grade I Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • GBM Glioblastoma
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the cancer is mesothelioma, hepatobilliary (hepatic and billiary duct), 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, lymphoc
  • the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, 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, 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 selected from renal cell carcinoma, or 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; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct
  • 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
  • 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
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer.
  • 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. 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.
  • UPSC papillary serous carcinoma
  • 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. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, II, or III, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (for example, cancer).
  • a compound described herein such as a compound of Formula I, II, or III, or other compounds in Section I
  • a medical disorder such as a medical disorder described herein (for example, cancer).
  • the compounds described herein can inhibit K-Ras activity.
  • another aspect of the invention provides a method of inhibiting K-Ras activity. The method comprises contacting K-Ras with an effective amount of a naphthyl-substituted quinolin-4( 1H)- one or related compound described herein, such as a compound of Formula I, II, or III, or other compounds in Section I, to inhibit K-Ras activity.
  • the compound is a compound of Formula I, II, or III defined by one of the embodiments described above.
  • the K-Ras is a mutant K-Ras. In some embodiments, the K-Ras is an activated mutant K-Ras. In some embodiments, the K-Ras is a G 12 mutant K-Ras. In some embodiments, the K-Ras is K-Ras G12D, K-Ras G12V, or K-Ras G12C. In some embodiments, the K-Ras is K-Ras G12D. In some embodiments, the K-Ras is K-Ras G12V. In some embodiments, the K-Ras is K-Ras G12C.
  • the compounds described herein can inhibit K-Ras G12D activity.
  • another aspect of the invention provides a method of inhibiting K-Ras G12D activity.
  • the method comprises contacting K-Ras G12D with an effective amount of a naphthyl- substituted quinolin-4( 1H)-onc or related compound described herein, such as a compound of Formula I, II, or III, or other compounds in Section I, to inhibit K-Ras G12D activity.
  • the compound is a compound of Formula I, II, or III defined by one of the embodiments described above.
  • Compounds may be tested for ability to bind to and/or inhibit K-Ras activity according to any of various assays known in the art, including, for example, surface plasmon resonance binding assays, TR-FRET displacement binding assays, TR-FRET assays that detect Ras-Raf interaction, and cell-based phosphorylation inhibition assays.
  • Compounds may be tested for ability to bind to and/or inhibit K-Ras G12D activity according to any of various assays known in the art, including, for example, surface plasmon resonance binding assays, TR-FRET displacement binding assays, TR-FRET assays that detect Ras-Raf interaction, and cell-based phosphorylation inhibition assays.
  • Naphthyl-substituted quinolin-4( l//)-onc or related compounds described herein e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • additional therapeutic agents to treat medical disorders, such as a cancer.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • One or more other therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent and a compound or composition of the invention are administerd as a multiple dosage regimen more than 24 hours aparts.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions which comprise an additional therapeutic agent, such as a second anti-cancer agent, as described above varies depending upon the host treated and the particular mode of administration.
  • a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • compositions which comprise one or more other therapeutic agent(s) can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this invention is preferably no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase "normally administered” means the amount an FDA- approved therapeutic agent is approved for dosing per the FDA label insert.
  • another aspect of the invention provides a method of treating cancer in a patient.
  • the method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a naphthyl-substituted quinolin-4( l /7)-onc or related compound described herein and (ii) a second anti-cancer agent, in order to treat the cancer.
  • the second anti-cancer agent is an EGFR inhibitor, a FAK inhibitor, a RAF/ERK/MAPK inhibitor, a mTOR Inhibitor, a MEK Inhibitor, or a Phosphoinositide 3-Kinase Inhibitor.
  • the second anti-cancer agent is an ALK Inhibitor, an ATR Inhibitor, an A2A Antagonist, a Base Excision Repair Inhibitor, a Bcr-Abl Tyrosine Kinase Inhibitor, a Bruton's Tyrosine Kinase Inhibitor, a CDC7 Inhibitor, a CHK1 Inhibitor, a Cyclin-Dependent Kinase Inhibitor, a DNA-PK Inhibitor, an Inhibitor of both DNA-PK and mTOR, a DNMT1 Inhibitor, a DNMT1 Inhibitor plus 2-chloro-deoxy adenosine, an HD AC Inhibitor, a Hedgehog Signaling Pathway Inhibitor, an IDO Inhibitor, a JAK Inhibitor, a mTOR Inhibitor, a MEK Inhibitor, a MELK Inhibitor, a
  • the second anti-cancer agent is an ALK Inhibitor. In certain embodiments, the second anti-cancer agent is an ALK Inhibitor comprisng ceritinib or crizotinib. In certain embodiments, the second anti-cancer agent is an ATR Inhibitor. In certain embodiments, the second anti-cancer agent is an ATR Inhibitor comprising AZD6738 or VX- 970. In certain embodiments, the second anti-cancer agent is an A2A Antagonist. In certain embodiments, the second anti-cancer agent is a Base Excision Repair Inhibitor comprising methoxyamine.
  • the second anti-cancer agent is a Base Excision Repair Inhibitor, such as methoxyamine.
  • the second anti-cancer agent is a Bcr- Abl Tyrosine Kinase Inhibitor.
  • the second anti-cancer agent is a Bcr- Abl Tyrosine Kinase Inhibitor comprising dasatinib or nilotinib.
  • the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor.
  • the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor comprising ibrutinib.
  • the second anti-cancer agent is a CDC7 Inhibitor.
  • the second anti-cancer agent is a CDC7 Inhibitor comprising RXDX-103 or AS- 141.
  • the second anti-cancer agent is a CHK1 Inhibitor. In certain embodiments, the second anti-cancer agent is a CHK1 Inhibitor comprising MK-8776, ARRY- 575, or SAR-020106. In certain embodiments, the second anti-cancer agent is a Cyclin- Dependent Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Cyclin- Dependent Kinase Inhibitor comprising palbociclib. In certain embodiments, the second anti cancer agent is a DNA-PK Inhibitor. In certain embodiments, the second anti-cancer agent is a DNA-PK Inhibitor comprising MSC2490484A. In certain embodiments, the second anti-cancer agent is Inhibitor of both DNA-PK and mTOR. In certain embodiments, the second anti-cancer agent comprises CC-115.
  • the second anti-cancer agent is a DNMT1 Inhibitor.
  • the second anti-cancer agent is a DNMT1 Inhibitor comprising decitabine, RX- 3117, guadecitabine, NUC-8000, or azacytidine.
  • the second anti-cancer agent comprises a DNMT1 Inhibitor and 2-chloro-deoxyadenosine.
  • the second anti-cancer agent comprises ASTX-727.
  • the second anti-cancer agent is a HD AC Inhibitor.
  • the second anti-cancer agent is a HDAC Inhibitor comprising OBP-801, CHR- 3996, etinostate, resminostate, pracinostat, CG-200745, panobinostat, romidepsin, mocetinostat, belinostat, AR-42, ricolinostat, KA-3000, or ACY-241.
  • the second anti-cancer agent is a Hedgehog Signaling Pathway Inhibitor. In certain embodiments, the second anti-cancer agent is a Hedgehog Signaling Pathway Inhibitor comprising sonidegib or vismodegib. In certain embodiments, the second anti-cancer agent is an IDO Inhibitor. In certain embodiments, the second anti-cancer agent is an IDO Inhibitor comprising INCB024360. In certain embodiments, the second anti-cancer agent is a JAK Inhibitor. In certain embodiments, the second anti-cancer agent is a JAK Inhibitor comprising ruxolitinib or tofacitinib.
  • the second anti-cancer agent is a mTOR Inhibitor. In certain embodiments, the second anti-cancer agent is a mTOR Inhibitor comprising everolimus or temsirolimus. In certain embodiments, the second anti-cancer agent is a MEK Inhibitor. In certain embodiments, the second anti-cancer agent is a MEK Inhibitor comprising cobimetinib or trametinib. In certain embodiments, the second anti-cancer agent is a MELK Inhibitor. In certain embodiments, the second anti-cancer agent is a MELK Inhibitor comprising ARN-7016, APTO-500, or OTS-167.
  • the second anti cancer agent is a MTH1 Inhibitor. In certain embodiments, the second anti-cancer agent is a MTH1 Inhibitor comprising (S)-crizotinib, TH287, or TH588.
  • the second anti-cancer agent is a PARP Inhibitor.
  • the second anti-cancer agent is a PARP Inhibitor comprising MP-124, olaparib, BGB-290, talazoparib, veliparib, niraparib, E7449, rucaparb, or ABT-767.
  • the second anti-cancer agent is a Phosphoinositide 3-Kinase Inhibitor.
  • the second anti-cancer agent is a Phosphoinositide 3-Kinase Inhibitor comprising idelalisib.
  • the second anti-cancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly ADP ribose polymerase 1 and dihydroorotate dehydrogenase).
  • the second anti-cancer agent is a Proteasome Inhibitor. In certain embodiments, the second anti-cancer agent is a Proteasome Inhibitor comprising bortezomib or carfilzomib. In certain embodiments, the second anti-cancer agent is a Topoisomerase-II Inhibitor. In certain embodiments, the second anti-cancer agent is a Topoisomerase-II Inhibitor comprising vosaroxin.
  • the second anti-cancer agent is a Tyrosine Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Tyrosine Kinase Inhibitor comprising bosutinib, cabozantinib, imatinib or ponatinib. In certain embodiments, the second anti-cancer agent is a VEGFR Inhibitor. In certain embodiments, the second anti-cancer agent is a VEGFR Inhibitor comprising regorafenib. In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor. In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor comprising AZD1775.
  • the second anti-cancer agent is a compound targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or
  • the second anti-cancer agent is an agonist of 0X40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS.
  • the second anti cancer agent is an agonist of 0X40, CD137, CD40, or GITR.
  • the second anti-cancer agent is an agonist of CD27, HVEM, TNFRSF25, or ICOS.
  • the second anti-cancer agent is a therapeutic antibody.
  • the therapeutic antibody targets one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, a mucin, TAG-72, CAIX, PSMA, a folate-binding protein, a ganglioside, Le, VEGF, VEGFR, VEGFR2, integrin aVp3, integrin a5b1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin- 1 beta, B4GALNT1, interleukin- 6, and interleukin-6 receptor.
  • the second anti-cancer agent is a therapeutic antibody selected from the group consisting of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregovomab, minetumomab, cG250, J591, Movl8, farletuzumab, 3F8, chl4.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramuci
  • the second anti-cancer agent is a cytokine.
  • the cytokine is IL-12, IL-15, GM-CSF, or G-CSF.
  • the second anti-cancer agent is sipuleucel-T, aldesleukin (a human recombinant interleukin-2 product having the chemical name des-alanyl-1, serine- 125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N- ⁇ 3-[5-(2- aminopyri midi n-4-yl)-2-ter t -butyl- 1 ,3-thiazol-4-yl] -2- fluorophenyl ⁇ -2,6- difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane- 1- sulfonic acid ⁇ 3-[5-(4-ch)
  • the second anti-cancer agent is a placental growth factor, an antibody-drug conjugate, an oncolytic vims, or an anti-cancer vaccine.
  • the second anti-cancer agent is a placental growth factor.
  • the second anti-cancer agent is a placental growth factor comprising ziv-aflibercept.
  • the second anti-cancer agent is an antibody-drug conjugate.
  • the second anti-cancer agent is an antibody-drug conjugate selected from the group consisting of brentoxumab vedotin and trastuzumab emtransine.
  • the second anti-cancer agent is an oncolytic virus. In certain embodiments, the second anti-cancer agent is the oncolytic vims talimogene laherparepvec. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine selected from the group consistint of a GM-CSF tumor vaccine, a STING/GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anti-cancer agent is a cytokine selected from IL-12, IL-15, GM- CSF, and G-CSF.
  • the second anti-cancer agent is an immune checkpoint inhibitor (also referred to as immune checkpoint blockers).
  • Immune checkpoint inhibitors are a class of therapeutic agents that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol. 12, pages 252-264.
  • the immune checkpoint inhibitor is an agent that inhibits one or more of (i) cytotoxic T- lymphocyte- associated antigen 4 (CTLA4), (ii) programmed cell death protein 1 (PD1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4, and (vii) TIM3.
  • CTLA4 cytotoxic T- lymphocyte- associated antigen 4
  • PD1 programmed cell death protein 1
  • PDL1 programmed cell death protein 1
  • PDL1 programmed cell death protein 1
  • PDL1 programmed cell death protein 1
  • PD1 programmed cell death protein 1
  • PDL1 programmed cell death protein 1
  • PD1 programmed cell death
  • the immune checkpoint inhibitor is pembrolizumab.
  • the second anti-cancer agent is a monoclonal antibody that targets a non-checkpoint target (e.g., herceptin).
  • the second anti-cancer agent is a non-cytoxic agent (e.g., a tyrosine -kinase inhibitor).
  • the second anti-cancer agent is selected from mitomycin, ribomustin, vincristine, tretinoin, etoposide, cladribine, gemcitabine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunombicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, cytarabine, bicalutamide, vinorelbine, vesnarin
  • the second anti-cancer agent is radiation therapy.
  • the second anti-cancer agent is a MEK Inhibitor.
  • the second anti-cancer agent is binimetinib, cobimetinib, refametinib, selumetinib, trametinib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • the second anti-cancer agent is trametinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is trametinib or a pharmaceutically acceptable solvate thereof. In certain embodiments, the second anti-cancer agent is trametinib dimethylsulfoxide. In certain embodiments, the second anti cancer agent is trametinib.
  • the second anti-cancer agent is binimetinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is cobimetinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is refametinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is selumetinib or a pharmaceutically acceptable salt and/or solvate thereof.
  • the second anti-cancer agent is binimetinib. In certain embodiments, the second anti-cancer agent is cobimetinib. In certain embodiments, the second anti-cancer agent is refametinib. In certain embodiments, the second anti-cancer agent is selumetinib.
  • the second anti-cancer agent is a TEAD inhibitor.
  • the TEAD inhibitor is selected from those described in WO 2020/243415, the contents of which are herein incorporated by reference in their entirety.
  • the TEAD inhibitor is selected from those described in WO 2020/243423, the contents of which are herein incorporated by reference in their entirety.
  • the TEAD inhibitor is selected from those described in US Patent No. 11,274,082, the contents of which are herein incorporated by reference in their entirety.
  • the second anti-cancer agent is an ERK5 inhibitor.
  • the ERK5 inhibitor is selected from those described in WO 2022/051567, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051565, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051569, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051568, the contents of which are herein incorporated by reference in their entirety.
  • the method further comprises administering to the subject a third anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fourth anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fifth anti-cancer agent.
  • the third anti-cancer agent is one of the second anti-cancer agents described above.
  • the fourth anti-cancer agent is one of the second anti-cancer agents described above.
  • the fifth anti-cancer agent is one of the second anti-cancer agents described above.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the naphthyl-substituted quinolin-4( 1H)-onc or related compound described herein e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • the additional therapeutic agent(s) e.g. the second, third, or fourth, or fifth anti-cancer agent, described above
  • the naphthyl-substituted quinolin-4( 1 H)-onc or related compound described herein e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • the additional therapeutic agent(s) e.g. the second, third, or fourth, or fifth anti-cancer agent, described above
  • the naphthyl-substituted quinolin-4( 1H)-onc or related compound described herein e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • the additional therapeutic agent(s) e.g. the second, third, or fourth, or fifth anti-cancer agent, described above
  • the naphthyl-substituted quinolin-4( 1 H)-onc or related compound described herein e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • the additional therapeutic agent(s) e.g. the second, third, or fourth, or fifth anticancer agent, described above
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • Another aspect of this invention is a kit comprising a therapeutically effective amount of the naphthyl-substituted quinolin-4( 1 H)-onc or related compound described herein (e.g., a compound of Formula I, II, or III, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • a pharmaceutically acceptable carrier e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • vehicle or diluent e.g., a compound of Formula I, II, or III, or other compounds in Section I
  • the invention provides pharmaceutical 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.
  • the pharmaceutical 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
  • a 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.
  • a therapeutically effective amount is an amount sufficient for inhibition of K-Ras G12D.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease, such as cancer.
  • 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. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • 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 poly anhydrides; 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.
  • 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; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such
  • 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 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. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions 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.
  • 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.
  • 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 appropriate.
  • 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.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • 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.
  • Ophthalmic formulations 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.
  • 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.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • 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.
  • biodegradable polymers such as polylactide-polyglycolide.
  • 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 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, parenterahy, topically, or rectahy. 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. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterahy” as used herein 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 intrastemal 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.
  • 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.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • 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 naphthyl-substituted quinolin-4( 1H)-onc or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.
  • a unit dosage form such as a tablet or capsule
  • a naphthyl-substituted quinolin-4( 1H)-onc or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.
  • Step 1 Benzyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate
  • Step 2 Benzyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2- fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate
  • Step 3 tert- Butyl 3-[2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 tert -Butyl 3-[2-[[(2/?,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- [3-(methoxymethoxy)-8-methyl-l-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 4-[4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl- naphthalen-2-ol (1-31)
  • the assay quantifies the inhibition of SOSl-mediated nucleotide exchange of K-Ras (G12D, G12V, G12C, or wild-type).
  • K-Ras K-Ras
  • Tb-streptavidin Tb-streptavidin
  • the K-Ras complex was allowed to incubate with varied concentrations of test compounds before the addition of the mixture of SOS1 and fluorescently- labeled GTP (BODIPY-GTP) to initiate the reaction.
  • BODIPY-GTP fluorescently- labeled GTP
  • the TR-FRET signal was monitored after 30 min.
  • the TR-FRET signal was generated by Tb and BODIPY-GTP, that displaced unlabeled GDP.
  • Biotinylated K-Ras enzyme G12D, G12V, G12C, and wild-type
  • SOS1 were purchased from GenScript.
  • Other materials were: Tb-streptavidin (Cisbio-610SATLB), BODIPY FL GTP (Thermo-G12411), and white 384-well ProxiPlus Assay Plates (Perkin-Elmer- 6008289).
  • the assay buffer was 20 mM HEPES pH 7.5, 50 mM NaCl, 10 mM MgCl2, 0.01% Tween-20, 1 mM DTT.
  • Total assay volume was 15 ⁇ L, and final assay concentrations were biotinylated K-Ras enzyme (G12D, G12V, or wild-type; 1.0 nM), SOS1 (200 nM), Tb-streptavidin (1 nM), and BODIPY-GTP (100 nM).
  • the assay was conducted at 23 °C. Controls included all the reagents, but replaced test compound solution with DMSO (0% inhibition control) or 100 mM GDP (100% inhibition control).
  • Test compound was dissolved and diluted in DMSO (100 mM top concentration, 3-fold dilution, 11 doses), then transferred to the assay plate using Echo. The final DMSO concentration was 1.5%.
  • the mixture of 1.5x K-Ras enzyme (G12D, G12V, G12C, or wild-type) and Streptavidin-Tb in assay buffer was prepared, and then pre-incubated at 23°C for 1 hour. The enzyme mixture was then dispensed into the assay plate (10 ⁇ L/weII). The plate was allowed to react with enzyme and compound for 30 minutes. A mixture of 3x SOS1 and BODIPY-GTP in assay buffer was added (5 ⁇ L/well).
  • the plate was spun at 1000 rpm for 30 seconds and then sealed. After incubating for 30 min, the assay signal was detected with Envision plate reader. The TR-FRET ratios were used to calculate percent inhibition values for each concentration of compound, using the no inhibition and 100% inhibition controls. IC50 values were calculated by Xlfit from the percent inhibition values using the 4-parameter logistical equation. Part II - Results
  • An exemplary compound was tested for its ability to inhibit phosphorylation of ERK downstream of K-Ras G12D using a homogeneous time-resolved fluorescence assay. Assay procedures and results are described below.
  • the culture/assay medium was RPMI-1640 +10% FBS. Cells were seeded at 6,000 cells/well, 50 mE/well. Compound treatment time was 4 hours. Controls replaced test compound solution with 0.8% DMSO (max control) or 0.2 mM trametinib (min control).
  • Procedure Cells were harvested from T150 growthflask using 0.05% trypsin/EDTA solution. Medium (10 mL) was added to stop trypsinizing. The cells were pipetted into a conical-bottomed, 50-mL centrifuge tube and centrifuged for 5 minutes at 1,000 rpm. The cell pellet was resuspended in medium, and cell count was determined (ViCell counter). Cell density was adjusted using fresh medium, then 384-well poly-D-lysine coated plates were seeded with 50 ⁇ L/well of the cell suspension. The cell plate was incubated overnight in a 37 °C, 5% CO2 incubator.
  • Test compounds were dissolved and diluted in DMSO (20 mM top concentration, 3-fold dilution, 10 doses) using Tecan. Compounds were added to the cell plate. The final DMSO concentration was 0.8%. The cell plate was incubated for 4 hours in the incubator.
  • Detection was conducted using a CisBio pERK kit. Kit-supplied lysis buffer was prepared and kept on ice. Concentrated (4x) lysis buffer was diluted with 3 volumes of deionized water, then lOOx of the blocking agent was added. Media was removed from the cell plate. Lysis buffer (35 mE/well) was added, and then the plate was placed on a plate agitator and shaken at 300 rpm, 4 °C for 40 minutes. Upon completion, the resulting lysate plate was centrifuged for 3 minutes at 1500 rpm.
  • Assay plates were prepared containing the HTRF antibody buffer. For each assay plate, 50 ⁇ L of d2-conjugate antibody was mixed with 950 ⁇ L of detection buffer. For each assay plate, 50 ⁇ L of cryptate antibody was mixed with 950 ⁇ L of detection buffer. The two diluted antibodies were then mixed together, and 3.4 ⁇ L of the resulting antibody buffer was dispensed to wells of an empty 384-well white Proxi plate. The plate was sealed and centrifuged 30 minutes at 1,000 rpm.
  • An exemplary compound was tested for its ability to inhibit the binding of GMPPNP- bound KRas (G12D or WT) to the Ras binding domain of RAF.
  • KRas protein was biotinylated and RAF protein was FLAG-tagged. Compounds were incubated with KRas-GMPPNP for 30 minutes at room temperature, followed by addition of RAF protein, Tb-anti-FLAG and SA-XL665 HTRF reagents. Fluorescence detection was carried out after 1.5 hours of incubation. IC50 values were calculated using a four-parameter fit.
  • GMPPNP-loaded KRAS-G12D Biotinylated GMPPNP-loaded KRAS-G12D, GMPPNP-loaded KRAS-WT and FLAG-tagged-Raf-RBD were purchased from GenScript. GMPPNP was obtained from Sigma. Perkin Elmer and Cisbio provided the Tb-anti-FLAG and streptavidin XL665 reagents and the white 384W ProxiPlus assay plates.
  • the assay buffer was 20 mM HEPES, pH 7.5, 150 mM NaCl,
  • HTRF ratios were used to calculate percent inhibition values for each concentration of compound, using the no inhibition and 100% inhibition controls.
  • IC50 values were calculated by Xlfit from the percent inhibition values using the 4-parameter logistical equation.
  • EXAMPLE 5 Assay for Inhibition of K-Ras G12D-mediated Phosphorylation of ERK
  • Compounds may be tested for ability to inhibit phosphorylation of ERK downstream of K-Ras G12D according to the following experimental procedure.
  • AGS cells (ATCC CRL-1739) expressing G12D are grown in DMEM medium supplemented with 10% fetal bovine serum, 10 mM HEPES, and Penicillin/Streptomycin. Cells are plated in tissue culture treated 96 well plates at a density of 40,000 cells/well and allowed to attach for 12-14 hours. Diluted test compound is then added in a final concentration of 0.5% DMSO. After 3 hours, the medium is removed, 150 pL of 4.0% formaldehyde is added and the plates incubated at room temperature for 20 minutes. Then, the plates are washed with PBS, and permeabilized with 150 pL of ice cold 100% methanol for 10 minutes. Non-specific antibody binding to the plates is blocked using 100 pL Licor blocking buffer (Li-Cor Biotechnology, Lincoln NE) for 1 hour at room temperature.
  • Licor blocking buffer Li-Cor Biotechnology, Lincoln NE
  • the amount of phospho-ERK is determined using an antibody specific for the phosphorylated form of ERK and compared to the amount of GAPDH. Primary antibodies used for the detection are added as follows: Phospho-ERK (Cell Signaling cs-9101) diluted 1:500 and GAPDH(Millipore MAB374) diluted 1:5000 in Licor block + 0.05%Tween 20. The plates are incubated for 2 hours at room temperature. Then, the plates are washed with PBS + 0.05%
  • Secondary antibodies used to visualize primary antibodies are added as follows: Anti- rabbit-680 diluted 1 : 1000 and Anti-mouse-800 diluted 1 : 1000 both in Licor block +0.05% TweeN20, and are incubated for 1 hour at room temperature. Then, the plates are washed with PBS + 0.05% Tween 20. A 100 pL aliquot of PBS is added to each well and the plates are read on a Li-Cor Odyssey CLX plate reader.
  • the phospho-ERK Thr202/Tyr204 signal is normalized to the GAPDH signal for each well and percent of DMSO control values are calculated. IC50 values are generated using a 4- parameter fit of the dose response curve
  • EXAMPLE 6 Biological Assay for Inhibiting 3D Cancer Cell Cultures Using Combination Therapy
  • Exemplary compounds having K-Ras G12D inhibitory activity may be tested for ability to inhibit 3D cancer cell cultures of pancreatic cancer and lung cancer. Assay procedures are described below.
  • cells are seeded in 231 soft agar in 96-well, low-attachment tissue-culture plates. After 24 hours, cells are treated with a concentration range of one or more K-Ras G12D inhibitors. At the time of treatment, assay plates that did not receive treatment are collected and cell viability is measured using alamarBlue reagent to establish baseline cell viability. Treated plates are incubated for 7 days, and alamarBlue readout is then collected.
  • EXAMPLE 7 Biological Assay for Inhibiting Mouse Xenograft Tumor Growth
  • Exemplary compounds having K-Ras G12D inhibitory activity may be tested, alone or in combination with other agents, such as trametinib, for ability to inhibit tumor growth in patient- derived mouse xenograft models of pancreatic cancer and lung cancer. Assay procedures are described below.
  • mice (6-8 weeks old) are inoculated subcutaneously in the right flank with a primary human tumor xenograft model tumor fragment (2-3 mm 3 in diameter) for tumor development.
  • mice are inoculated with a human lung adenocarcinoma tumor model (MSCLC, ADC model LU6424) that harbors a BRAF mutation (LU6424);
  • mice are inoculated with a human pancreatic tumor model (adenosquamous carcinoma model PA6258) with a K-Ras G12D mutation (PA6258).
  • mean tumor volume reaches approximately 150-200 mm 3 , animals are randomly allocated to appropriate treatment groups.
  • mice are treated with one of the following: (l)Vehicle control, (2) Exemplary K-Ras G12D inhibitor alone, (3) Second anti-cancer agent alone, or (4) Combination of K-Ras G12D inhibitor and second anti-cancer agent. Tumors are measured twice per week using calipers.

Abstract

L'invention concerne des quinolin-4(1H)-ones à substitution naphtyle et des composés apparentés, des compositions pharmaceutiques, leur utilisation pour inhiber l'activité de K-Ras G12D et leur utilisation dans le traitement d'affections médicales, telles que le cancer.
PCT/US2022/024006 2021-04-09 2022-04-08 Quinoline-4(1h)-ones à substitution naphtyle et composés apparentés et leur utilisation dans le traitement d'affections médicales WO2022217042A1 (fr)

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WO2023198191A1 (fr) * 2022-04-15 2023-10-19 杭州多域生物技术有限公司 Composé à six et six chaînons, procédé de préparation, composition pharmaceutique et application
CN116120315A (zh) * 2023-04-19 2023-05-16 山东绿叶制药有限公司 一种kras g12c抑制剂及其应用
CN116120315B (zh) * 2023-04-19 2023-06-09 山东绿叶制药有限公司 一种kras g12c抑制剂及其应用

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