WO2024072793A1 - Composés de pyridine carboxamide et leur utilisation dans le traitement de pathologies médicales - Google Patents

Composés de pyridine carboxamide et leur utilisation dans le traitement de pathologies médicales Download PDF

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WO2024072793A1
WO2024072793A1 PCT/US2023/033707 US2023033707W WO2024072793A1 WO 2024072793 A1 WO2024072793 A1 WO 2024072793A1 US 2023033707 W US2023033707 W US 2023033707W WO 2024072793 A1 WO2024072793 A1 WO 2024072793A1
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nitrogen
oxygen
sulfur
independently selected
heteroatoms independently
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PCT/US2023/033707
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English (en)
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Todd Bosanac
Nathan Oliver Fuller
Robert Owen Hughes
Guy Bemis
Janeta Valentina POPOVICI MULLER
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Rectify Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention provides pyridine carboxamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • ATP -binding cassette (ABC) transporters are a large, phylogenetically conserved gene family with broad physiological and pathological relevance. [1,2] They are expressed throughout the body and transport a diverse range of substrates across lipid membranes. ABC transporters are transmembrane, ATP-binding proteins that use the energy released during ATP hydrolysis to move substrates from one side of a lipid membrane to the other. [2,3]
  • ABC transporters underly rare monogenic disorders with even more implicated in the predisposition to and symptomology of common and complex diseases.
  • Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery.
  • cystic fibrosis CF
  • progressive familial intrahepatic cholestasis 2 PFIC2
  • Stargardt disease STGD
  • pathogenic ABC transporter missense mutations principally their impact on protein folding leading to endoplasmic reticulum (ER) degradation (trafficking defects), or protein function, leading to decreased substrate transport (transport defects).
  • ER endoplasmic reticulum
  • transport defects leading to decreased substrate transport (transport defects).
  • small molecule compounds may enable treatment of disease symptoms not directly caused by mutations in ABC transporter genes.
  • the invention provides pyridine carboxamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • one aspect of the invention provides a collection of pyrrolo[2,3-c]pyridin-7-onyl-pyridine carboxamide 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 pyrrolo[2,3-c]pyridin-7-onyl- pyridine carboxamide 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 ABC transporter dysfunction.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the ABC transporter dysfunction, as further described in the detailed description.
  • the invention provides pyridine carboxamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry , pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry 7 , 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. Blackwell, eds.); “Current protocols in molecular biology” (F.M.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl. (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0013] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: [0014]
  • 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 C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3.4-dihydro-2H-pyrrolyl). NH (as in pyrrolidinyl) orNR + (as in N-substituted pyrrolidinyl)).
  • bivalent C 1-8 (or C 1-4 ) 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., 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 -(C 1-3 alkylene)- group.
  • alkeny lene 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
  • 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 > 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 quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl.
  • 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.
  • heterocycle As used herein, the terms “heterocycle.” “heterocyclyl.” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-2H pyrrolyl ), NH (as in pyrrolidinyl), or + NR (as in N- -substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by one or more 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.
  • oxo-heterocyclylene refers to a multivalent oxo- heterocyclyl group having the appropriate number of open valences to account for 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.
  • Each R° is independently hydrogen, C 1-6 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, -CH 2 -(5- 6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or.
  • R* is C 1-6 aliphatic
  • R* is optionally substituted with halogen, - Ro, -(haloR*), -OH, -OR*, -O(haloRo), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NRo 2 or -NO 2
  • each R* is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -1 Ph or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • R1 is C 1-6 aliphatic
  • R is optionally substituted with halogen, -Ro, -(haloR*), -OH, -OR*, - O(haloR*), -CN, -C(O)OH, -C(O)ORo, -NH 2 , -NHR’, -NR 2 , or -NO 2
  • each Ro is independently selected from Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by
  • 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 + (C 1 4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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 diastereomenc 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 5 or K configuration as defined by the ZtZFMC 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 C 1 -C 12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively.
  • exemplary' alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl.
  • 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 “Cs-Ce cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkyl groups include -CH 2 CH 2 OH, -C(H)(OH)CH 3 , -CH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkenyl and alkyny 1 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.
  • alkoxy!” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 , and the like.
  • a cyclopentane substituted with an oxo group is cyclopentanone.
  • 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 H 2 O.
  • the terms “subject” and “patient” are used interchangeable 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.
  • IC50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.
  • EC 50 is art recognized and refers to the concentration of a compound that is required to achieve a response that is 50% of the maximum target effect relative to the baseline.
  • Emax is art recognized and refers to the concentration of a compound that is require to achieve maximal target effect.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitor ⁇ ' or preventative result).
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • 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 earners, 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.
  • Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (z.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.
  • One aspect of the invention provides pyridine carboxamide 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:
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl;
  • R 1 represents independently for each occurrence halo, oxo. -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R. -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR. -C(O)NR 2 . -C(O)N(R)OR.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy;
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from - OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ;
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 ;
  • R 5 represents independently for each occurrence halo, oxo. -CN, -OR, -SR. -NR 2 , -S(O) 2 R. -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -
  • -CH 2 CH 2 R -CH 2 CH 2 OR, -NHCH 2 CH 2 OR, -NHC(O)R, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-3 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C24 hydrocarbon chain
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocynch heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; n is 0, 1, 2, or 3; and p is 0, 1. 2, 3 or 4.
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is phenyl.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or phenyl.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; or an 8-10 membered bicyclic aromatic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; or a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl. [0080] In some embodiments.
  • Ring A is selected from those depicted in Table 1. below.
  • R 1 represents independently for each occurrence halo, oxo, -CN, OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , - C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, - N(R)C(O)R.
  • -OCR C 1-4 aliphatic, C 1-4 haloaliphatic. or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence halo. In some embodiments, R 1 represents independently for each occurrence -OR. In some embodiments, R 1 represents independently for each occurrence -SR. In some embodiments, R 1 represents independently for each occurrence -NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -S(O) 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O)R. In some embodiments, R 1 represents independently for each occurrence -S(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)R.
  • R 1 represents independently for each occurrence - C(O)CR 3 . In some embodiments, R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)N(R)OR. n some embodiments, R 1 represents independently for each occurrence -OC(O)R. In some embodiments, R 1 represents independently for each occurrence -OC(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -O(CR 2 ) 3 NR 2 . In some embodiments. R 1 represents independently for each occurrence -N(R)C(O)OR.
  • R 1 represents independently for each occurrence -N(R)C(O)R. In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(NR)NR 2 . In some embodiments, R 1 represents independently for each occurrence -NR(CR 2 ) 2 OR. In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 R.
  • R 1 represents independently for each occurrence -CHR 2 . In some embodiments, R 1 represents independently for each occurrence -CR 3 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 OR.
  • R 1 represents independently for each occurrence - NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence - NHC(O)R. In some embodiments, R 1 represents independently for each occurrence -CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NH 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 represents independently for each occurrence -OCR. In some embodiments, R 1 represents independently for each occurrence C 1-4 aliphatic. In some embodiments. R 1 represents independently for each occurrence C 1-4 haloaliphatic.
  • R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence -CN, — C(O)R, -C(O)CR 3 , -C(O)OR. -C(O)NR 2 . -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -, - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 )3NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)C(NR 2 , -N(R)C(NR 2 , --
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 . -C(O)R, -C(O)CR 3 , -C(O)OR.
  • R 1 represents independently for each occurrence halo, oxo, - CN, C 1-4 aliphatic. C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or -OCR.
  • R 1 represents independently for each occurrence - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -C(O)R, -C(O)CR 3 . -C(O)OR, -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 , -CR 3 . - CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence oxo or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence -CH 3 , - CH 2 C(O)NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -NHAC, -OH, -C(O)CH 2 OH, -C(O)CH 3 , - CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , -OCH 3 ,CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, - NHCH 2 CH 2 OH.
  • R 1 represents independently for each occurrence -CH 3 , -
  • R 1 represents independently for each occurrence -CH 3 , -NHAc, -OH, (O) -OCH 3 , or in some embodiments, R 1 represents independently for each occurrence -CH 3 or (O).
  • R 1 is halo. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -NR 2 . In some embodiments, R 1 is -S(O) 2 R. In some embodiments, R 1 is -S(O)2NR 2 . In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)NR 2 . In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)CR 3 . In some embodiments, R 1 is -C(O)OR. In some embodiments, R 1 is -C(O)NR 2 .
  • R 1 is -C(O)N(R)OR. In some embodiments, R 1 is -OC(O)R. In some embodiments, R 1 is -OC(O)NR 2 . In some embodiments, R 1 is - O(CR 2 )3NR 2 . In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R 1 is -N(R)C(O)R. In some embodiments, R 1 is -N(R)C(O)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 . In some embodiments, R 1 is -NR(CR 2 ) 2 OR.
  • R 1 is -N(R)S(O)2NR 2 . In some embodiments, R 1 is -N(R)S(O) 2 R. In some embodiments, R 1 is - CR 3 . In some embodiments, R 1 is -CH 2 NR 2 . In some embodiments, R 1 is -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 is -CH 2 CH 2 C(O)OR. In some embodiments, R 1 is -CH 2 C(O)NR 2 . In some embodiments, R 1 is -CH 2 CH 2 R. In some embodiments, R 1 is -CH 2 CH 2 OR. In some embodiments, R 1 is -NHCH 2 CH 2 OR.
  • R 1 is -NHC(O)R. In some embodiments, R 1 is -CH 2 OR. In some embodiments, R 1 is -CH 2 C(O)NH 2 . In some embodiments, R 1 is -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 is -OCR. In some embodiments, R 1 is C 1-4 aliphatic. In some embodiments, R 1 is C 1-4 haloaliphatic. In some embodiments, R 1 is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 is a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is -CN, — C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is halo, oxo, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, -NHCH 2 CH 2 OR, -NHC(O)R.
  • R 1 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R
  • R 1 is halo, oxo, -CN, C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently- selected from nitrogen, oxygen, and sulfur.
  • R 1 is oxo, -OR, -OC(O)R. -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or - OCR,
  • R 1 is -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 1 is halo, oxo, -OR, -C(O)R, -C(O)CR 3 , -C(O)OR, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 , -CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 is oxo or C 1-4 aliphatic.
  • R 1 is -CH 3 , -CH 2 C(O)NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , - NHAc, -OH, -C(O)CH 2 OH, -C(O)CH 3 , -CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , - OCH 3 ,CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, -NHCH 2 CH 2 OH, -CH 2 CH 2 C(O)OCH 3 , - NHS(O) 2 CH 3 . -C(O)NH 2 .
  • R 1 is -CH 3 . -NHAc, -OH, -C(O)CH 2 OH. -C(O)CH 3 . -
  • R 1 is -CH 3 or (O).
  • R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is halo, -OH, -CN, cyclopropyl. C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -CN, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo. -OH. -CN. C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy. In some embodiments. R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 haloalkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 2 is hydrogen, cyclopropyl, C 1-3 alkyd optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , or C 1-3 alkoxy.
  • R 2 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from - OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen or C 1-3 alkyl.
  • R 2 unsubstituted C 1-3 alkyd.
  • R 2 is C 1-3 alkyd substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen. In some embodiments, R 2 is -OH. In some embodiments, R 2 is -CN. In some embodiments, R 2 is cyclopropyl.
  • R 2 is halo. In some embodiments, R 2 is Cl, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Br.
  • R 2 is C 1-3 alkyd. In some embodiments, R 2 is methyl. In some embodiments. R 2 is ethyl. In some embodiments. R 2 is i-propyl. In some embodiments, R 2 is n- propyl. [0111] In some embodiments. R 2 is C 1-3 haloalkyl. In some embodiments, R 2 is CF 3 . In some embodiments, R 2 is CHF 2 .
  • R 2 is C 1-3 alkoxy. In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 CH 2 OCH 3 .
  • R 2 is selected from those depicted in Table 1, below.
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 . -NH(CH 3 ). and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is substituted C 1-3 alkyl as defined above and herein, wherein the substitution occurs on the terminal carbon atom.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH and OMe. In some embodiments. R 3 is hydrogen or C 1-3 alkyl.
  • R 3 is hydrogen. In some embodiments. R 3 is cyclopropyl. In some embodiments, R 3 is C 1-3 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is i-propyl. In some embodiments, R 3 is n- propyl.
  • R 3 is C 1-3 alkyd substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is C 1-3 alkyl substituted with a group selected from -OH or OMe.
  • R 3 is C 1-3 alkyl substituted with a group selected from -OMe, -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 .
  • R 3 is C 1-3 alkyl substituted with a group selected from -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 .
  • R 3 is -CH 2 OCH 3 .
  • R 3 is -CH 2 OCH 3 .
  • R 3 is -CH 2 CH 2 OCH 3 .
  • R 3 is selected from those depicted in Table 1, below.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a phenyl, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 4 is a phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 . [0127] In some embodiments.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 2- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 2-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, - N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -N(R)S(O)
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence -OR. In certain embodiments, R 5 represents independently for each occurrence -SR. In certain embodiments, R 5 represents independently for each occurrence -NR 2 . In certain embodiments, R 5 represents independently for each occurrence -S(O) 2 R. In certain embodiments, R 3 represents independently for each occurrence
  • R 5 represents independently for each occurrence -S(O)R. In certain embodiments. R 5 represents independently for each occurrence -S(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)R. In certain embodiments, R 3 represents independently for each occurrence -C(O)CR 3 . In certain embodiments, R 5 represents independently for each occurrence -C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)N(R)OR. In certain embodiments, R 3 represents independently for each occurrence -OC(O)R.
  • R 3 represents independently for each occurrence -OC(O)NR 2 .
  • R 5 represents independently for each occurrence -O(CR 2 )3NR 2 .
  • R 5 represents independently for each occurrence -N(R)C(O)OR.
  • R 3 represents independently for each occurrence -N(R)C(O)R.
  • R 3 represents independently for each occurrence -N(R)C(O)NR 2 .
  • R 5 represents independently for each occurrence -N(R)C(NR)NR 2 .
  • R 5 represents independently for each occurrence-NR(CR 2 ) 2 OR.
  • R 5 represents independently for each occurrence -N(R)S(O) 2 NR 2 .
  • R 3 represents independently for each occurrence -N(R)S(O) 2 R.
  • R 5 represents independently for each occurrence -CH 2 R.
  • R 5 represents independently for each occurrence -CHR 2 .
  • R 5 represents independently for each occurrence -CR 3 .
  • R 5 represents independently for each occurrence -CH 2 NR 2 .
  • R 5 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR.
  • R 5 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In certain embodiments.
  • R 5 represents independently for each occurrence -CH 2 C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 R, In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 OR. In certain embodiments. R 5 represents independently for each occurrence -NHCH 2 CH 2 OR. In certain embodiments. R 5 represents independently for each occurrence -NHC(O)R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 represents independently for each occurrencea C 1-3 alkyl group.
  • R 5 represents independently for each occurrence a C 1-3 haloalkyl group, In certain embodiments, R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 represents independently for each occurrence phenyl. In certain embodiments, R 5 represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments. R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 represents independently for each occurrence - CN, -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 .
  • R 5 represents independently for each occurrence N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 5 represents independently for each occurrence a C 1-3 heteroalky 1 group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 .
  • R 5 represents independently for each occurrence halo, oxo, -CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo. In certain embodiments, R 5 is -OR. In certain embodiments, R 5 is -SR. In certain embodiments, R 5 is -NR 2 . In certain embodiments, R 5 is -S(O) 2 R. In certain embodiments. R 5 is -S(O) 2 NR 2 . In certain embodiments. R 5 is -S(O)R. In certain embodiments, R 5 is -S(O)NR 2 . In certain embodiments. R 5 is -C(O)R. In certain embodiments, R 3 is -C(O)CR 3 . In certain embodiments, R 5 is -C(O)OR.
  • R 3 is -C(O)NR 2 .
  • R 5 is -C(O)N(R)OR.
  • R 5 is -OC(O)R.
  • R 5 is -OC(O)NR 2 .
  • R 5 is -O(CR 2 ) 3 NR 2 .
  • R 5 is -N(R)C(O)OR.
  • R 5 is -N(R)C(O)R.
  • R 3 is -N(R)C(O)NR 2 .
  • R 5 is -N(R)C(NR)NR 2 .
  • R 5 is-NR(CR 2 ) 2 OR. In certain embodiments, R 5 is -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 is -N(R)S(O) 2 R. In certain embodiments, R 5 is -CH 2 R. In certain embodiments, R 5 is -CHR 2 . In certain embodiments, R 5 is -CR 3 . In certain embodiments, R 5 is -CH 2 NR 2 . In certain embodiments, R 5 is - CH 2 NHCH 2 CH 2 OR. In certain embodiments. R 5 is -CH 2 CH 2 C(O)OR. In certain embodiments, R 5 is -CH 2 C(O)NR 2 .
  • R 5 is -CH 2 CH 2 R, In certain embodiments, R 5 is - CH 2 CH 2 OR. In certain embodiments, R 5 is -NHCH 2 CH 2 OR. In certain embodiments, R 5 is - NHC(O)R. In certain embodiments, R 5 is -CH 2 OR. In certain embodiments, R 5 is - CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 isa C 1-3 alkyl group. In certain embodiments, R 5 is a C 1-3 haloalkyl group. In certain embodiments, R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 is phenyl. In certain embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 is a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 is -CN, -C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -. -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 . -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 . -CH 2 NHC(O)OCR 3 .
  • R 5 is -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, - N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3
  • -CH 2 CH 2 OR - NHCH 2 CH 2 OR, -NHC(O)R, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, or a C 1-3 haloalky 1 group.
  • R 5 is halo, oxo, -CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is selected from those depicted in Table 1, below.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, , or a 5-7- membered bridged bicyclic carbocyclene: wherein when one unit of L 1 is replaced with
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is as defined above, wherein when one unit of L 1 is a gem- dimethyl unit, L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7-membered bridged bicyclic carbocyclene.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, or -C(O)NR-.
  • L 1 is a saturated straight or branched, bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent Cw hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced y ; p , 2-4 y bon chain.
  • L 1 is a saturated straight bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 2-4 hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by .
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched bivalent C 1-4 hydrocarbon chain.
  • L 1 is selected from those depicted in Table 1, below.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence optionally substituted Ci- 6 aliphatic. In certain embodiments, R represents independently for each occurrence optionally substituted phenyl. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence C 1-6 aliphatic. In certain embodiments, R represents independently for each occurrence phenyl. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic. [0165] In certain embodiments, R represents independently for each occurrence an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is halo. In certain embodiments, R is optionally substituted C 1-6 aliphatic. In certain embodiments, R is optionally substituted phenyl. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is halo. In certain embodiments, R is C 1-6 aliphatic. In certain embodiments, R is phenyl. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hy droxy l, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hy droxy l, halo, or optionally substituted C 1-6 aliphatic.
  • R is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocynch carbocyclic ring.
  • R is hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, Cl, F, -CH 2 OH.- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is selected from those depicted in Table 1. below.
  • n is 0, 1, 2, or 3.
  • n is 0, 2, or 3.
  • n is 0, 1, or 3.
  • n is 0, 1, or 2.
  • n is 2 or 3.
  • n is 0 or 1.
  • n is 0 or 3.
  • n is 0 or 2.
  • n is 1 or 2.
  • n is 1 or 3.
  • n is 0.
  • n is 1 .
  • n is 2. In certain embodiments, n is 3.
  • p is 0, 1, 2, 3 or 4. In certain embodiments, p is 1, 2, 3 or 4. In certain embodiments, p is 0, 2, 3 or 4. In certain embodiments, p is 0, 1, 3 or 4. In certain embodiments, p is 0, 1, 2, or 4. In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 2, 3 or 4. In certain embodiments, p is 0, 3 or 4. In certain embodiments, p is 0, 1, or 4. In certain embodiments, p is 0, 1. or 2. In certain embodiments, p is 1. 3 or 4. In certain embodiments, p is 1 , 2, or 4. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 0, 2 or 4.
  • p is 0, 2 or 3. In certain embodiments, p is 0, 1 or 3. In certain embodiments, p is 3 or 4. In certain embodiments, p is 0 or 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 4. In certain embodiments, p is 1 or 2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0 or 3. In certain embodiments, p is 1 or 3. In certain embodiments, p is 2 or 3. In certain embodiments, p is 2 or 4. 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 4.
  • the present invention provides a compound of Formulae I-A, I-B, or I-C:
  • the present invention provides a compound of Formulae I-D: 1-D or a pharmaceutically acceptable salt thereof, wherein each of Ring A. R 1 , R 2 . R 3 , R 4 , R 5 , L 1 , R. n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • One aspect of the invention provides a compound represented by Formula II: or a pharmaceutically acceptable salt thereof; wherein:
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring. or phenyl;
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CHj), and -N(CH 2 ) 2 , C
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from - OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ;
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 ;
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 .
  • Y represents independently for each occurrence -R. oxo, -OR, -NR 2 , -OCH 2 CHF 2 . - OCH 2 CH 2 OH. or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-3 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C 2-4 hydrocarbon chain
  • L 2 is a covalent bond, -OCH 2 -, -O-. -OCH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -NH-;
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; n is 0, 1, 2, or 3; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.
  • variables in Formula II above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula II.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is phenyl.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or phenyl.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; or an 8-10 membered bicyclic aromatic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; or a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is selected from those depicted in Table 1, below.
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - NR(CR 2 ) 2 OR.
  • -CH 2 NR 2 -CH 2 NHCH 2 CH 2 OR, - CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -NHCH 2 CH 2 OR, -NHC(O)R, - CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , -OCR, C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence halo. In some embodiments, R 1 represents independently for each occurrence -OR. In some embodiments, R 1 represents independently for each occurrence -SR. In some embodiments, R 1 represents independently for each occurrence -NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -S(O) 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O)R. In some embodiments, R 1 represents independently for each occurrence -S(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)R.
  • R 1 represents independently for each occurrence - C(O)CR 3 . In some embodiments, R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)N(R)OR. n some embodiments, R 1 represents independently for each occurrence -OC(O)R. In some embodiments, R 1 represents independently for each occurrence -OC(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -O(CR 2 ) 3 NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)OR.
  • R 1 represents independently for each occurrence -N(R)C(O)R. In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(NR)NR 2 . In some embodiments, R 1 represents independently for each occurrence -NR(CR 2 ) 2 OR. In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 R.
  • R 1 represents independently for each occurrence -CHR 2 . In some embodiments, R 1 represents independently for each occurrence -CR 3 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 OR.
  • R 1 represents independently for each occurrence - NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence - NHC(O)R. In some embodiments, R 1 represents independently for each occurrence -CH 2 OR. In some embodiments. R 1 represents independently for each occurrence -CH 2 C(O)NH 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 represents independently for each occurrence -OCR. In some embodiments, R 1 represents independently for each occurrence C 1-4 aliphatic. In some embodiments, R 1 represents independently for each occurrence C 1-4 haloaliphatic.
  • R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence -CN, — C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 . -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -, - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 )3NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 . -C(O)R, -C(O)CR 3 , -C(O)OR. - C(O)NR 2 , -C(O)N(R)OR. -OC(O)R, -OC(O)NR 2 , -O(CR 2 )3NR 2 .
  • R 1 represents independently for each occurrence halo, oxo, - CN, C 1-4 aliphatic. C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or -OCR,
  • R 1 represents independently for each occurrence -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -C(O)R, -C(O)CR 3 . -C(O)OR, -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 , -CR 3 , - CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence oxo or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence -CHv - CH 2 C(O)NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -NHAC, -OH, -C(O)CH 2 OH, -C(O)CH 3 , - CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , -OCH 3 ,CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, - NHCH 2 CH 2 OH, -CH 2 CH 2 C(O)OCH 3 , -NHS(O) 2 CH 3 , -C(O)NH 2 , -S(O) 2 CH 3 , -Bn, -OC(CH 3 ) 2 , -NHCH 2 CH 2 OCH 3 , -F, -Cl, -Br, (O), -CH 2 NH 2 ,
  • R 1 is halo. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -NR 2 . In some embodiments, R 1 is -S(O) 2 R. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)NR 2 . In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)CR 3 . In some embodiments, R 1 is -C(O)OR.
  • R 1 is -C(O)NR 2 . In some embodiments, R 1 is -C(O)N(R)OR. In some embodiments, R 1 is -OC(O)R. In some embodiments, R 1 is -OC(O)NR 2 . In some embodiments, R 1 is - O(CR 2 ) 3 NR 2 . In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R 1 is -N(R)C(O)R. In some embodiments, R 1 is -N(R)C(O)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 .
  • R 1 is -NR(CR 2 ) 2 OR. In some embodiments, R 1 is -N(R)S(O) 2 NR 2 . In some embodiments, R 1 is -N(R)S(O) 2 R. In some embodiments, R 1 is - CR 3 . In some embodiments. R 1 is -CH 2 NR 2 . In some embodiments, R 1 is -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 is -CH 2 CH 2 C(O)OR. In some embodiments, R 1 is -CH 2 C(O)NR 2 . In some embodiments, R 1 is -CH 2 CH 2 R. In some embodiments, R 1 is -CH 2 CH 2 OR.
  • R 1 is -NHCH 2 CH 2 OR. In some embodiments, R 1 is -NHC(O)R. In some embodiments, R 1 is -CH 2 OR. In some embodiments, R 1 is -CH 2 C(O)NH 2 . In some embodiments, R 1 is -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 is -OCR. In some embodiments, R 1 is C 1-4 aliphatic. In some embodiments, R 1 is C 1-4 haloaliphatic. In some embodiments, R 1 is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 is a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is -CN, — C(O)R, -C(O)CR 3 , -C(O)OR. - C(O)NR 2 , -C(O)N(R)OR. -CR 3 , -CH 2 NR 2 , -CH 2 NHCH 2 CH 2 OR. -CH 2 CH 2 C(O)OR.
  • R 1 is halo, oxo. -OR. -SR, -NR 2 . -S(O) 2 R, -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, - NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3
  • R 1 is halo, oxo, -CN, C 1-4 aliphatic. C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or - OCR.
  • R 1 is -N(R)C(O)OR, -N(R)C(O)R, -N-(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R. -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 1 is halo, oxo, -OR, -C(O)R, -C(O)CR 3 , -C(O)OR, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 , -CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 is oxo or C 1-4 aliphatic.
  • R 1 is -CH 3 , -CH 2 C(O)NH 2 , -CH 2 OCH 3 . -CH 2 CH 2 OCH 3 , - NHAc, -OH, -C(O)CH 2 OH, -C(O)CH 3 , -CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , - OCH 3 ,CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, -NHCH 2 CH 2 OH, -CH 2 CH 2 C(O)OCH 3 , - NHS(O) 2 CH 3 , -C(O)NH 2 , -S(O) 2 CH 3 , -Bn, -OC(CH 3 ) 2 , -NHCH 2 CH 2 OCH 3 , -F, -Cl, -Br.
  • R 1 is -CH 3 or (O).
  • R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted wi th a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -CN, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, C 1-3 alkyd, C 1-3 haloalkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 haloalky 1, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl. C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 2 is hydrogen, cyclopropy l. C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen or C 1-3 alky 1 optionally substituted with a group selected from - OH, -NH 2 , -NH(CH 3 ). and -N(CH 3 ) 2 . In some embodiments, R 2 is hydrogen or C 1-3 alky 1. In some embodiments, R 2 unsubstituted C 1-3 alkyl. In some embodiments, R 2 is C 1-3 alkyl substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen. In some embodiments. R 2 is -OH. In some embodiments, R 2 is -CN. In some embodiments, R 2 is cyclopropyl.
  • R 2 is halo. In some embodiments, R 2 is Cl, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Br.
  • R 2 is C 1-3 alkyd. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is i-propyl. In some embodiments, R 2 is n- propyl.
  • R 2 is C 1-3 haloalky 1. In some embodiments, R 2 is CF 3 . In some embodiments, R 2 is CHF 2 .
  • R 2 is C 1-3 alkoxy. In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 CH 2 OCH 3 . [0229] In some embodiments. R 2 is selected from those depicted in Table 1, below.
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, OMe, -NH 2 , -NHCCH 3 ), and -N(CH 3 ) 2 .
  • R 3 is cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is substituted C 1-3 al ky 1 as defined above and herein, wherein the substitution occurs on the terminal carbon atom.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH and OMe. In some embodiments, R 3 is hydrogen or C 1-3 alkyl.
  • R 3 is hy drogen. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is C 1-3 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is i-propyl. In some embodiments, R 3 is n- propyl.
  • R 3 is C 1-3 alkyl substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 . In some embodiments, R 3 is C 1-3 alkyd substituted with a group selected from -OH or OMe. In some embodiments, R 3 is C 1-3 alkyl substituted with a group selected from -OMe, -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 . In some embodiments, R 3 is C 1-3 alkyl substituted with a group selected from -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 . In some embodiments, R 3 is -CH 2 OCH 3 . In some embodiments, R 3 is -CH 2 OCH 3 . In some embodiments, R 3 is -CH 2 CH 2 OCH 3 .
  • R 3 is selected from those depicted in Table 1, below .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a phenyl, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5
  • R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 4 is a phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 2- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic nng having 2-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 represents independently for each occurrence halo, oxo, -CN, OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , - C(O)OR, -C(O)NR 2 , C-(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, - N(R)C(O)R.
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence -OR. In certain embodiments, R 5 represents independently for each occurrence -SR. In certain embodiments, R 5 represents independently for each occurrence -NR 2 . In certain embodiments, R 5 represents independently for each occurrence -S(O) 2 R. In certain embodiments, R 5 represents independently for each occurrence
  • R 5 represents independently for each occurrence -S(O)R. In certain embodiments. R 5 represents independently for each occurrence -S(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)R. In certain embodiments, R 3 represents independently for each occurrence -C(O)CR 3 . In certain embodiments, R 3 represents independently for each occurrence -C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)N(R)OR. In certain embodiments, R 5 represents independently for each occurrence -OC(O)R.
  • R 3 represents independently for each occurrence -OC(O)NR 2 .
  • R 5 represents independently for each occurrence -O(CR 2 )JNR 2 .
  • R 5 represents independently for each occurrence -N(R)C(O)OR.
  • R 5 represents independently for each occurrence -N(R)C(O)R.
  • R 3 represents independently for each occurrence -N(R)C(O)NR 2 .
  • R 3 represents independently for each occurrence -N(R)C(NR)NR 2 .
  • R 5 represents independently for each occurrence-NR(CR 2 ) 2 OR.
  • R 5 represents independently for each occurrence -N(R)S(O) 2 NR 2 .
  • R 3 represents independently for each occurrence -N(R)S(O)2 R .
  • R 3 represents independently for each occurrence -CH 2 R.
  • R 5 represents independently for each occurrence -CHR 2 .
  • R 5 represents independently for each occurrence -CR 3 .
  • R 5 represents independently for each occurrence -CH 2 NR 2 .
  • R 5 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR.
  • R 5 represents independently for each occurrence -CH 2 CH 2 C(O)OR.
  • R 3 represents independently for each occurrence -CH 2 C(O)NR 2 .
  • R 5 represents independently for each occurrence -CH 2 CH 2 R, In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -NHCH 2 CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -NHC(O)R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 represents independently for each occurrencea C 1-3 alkyl group.
  • R 5 represents independently for each occurrence a C 1-3 haloalkyl group, In certain embodiments, R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 represents independently for each occurrence phenyl. In certain embodiments, R 5 represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 represents independently for each occurrence - CN, -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocycl
  • R 5 represents independently for each occurrence - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, - N(R)C(O)R.
  • R 5 represents independently for each occurrence halo, oxo, - CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo. In certain embodiments. R 5 is -OR. In certain embodiments, R 5 is -SR. In certain embodiments, R 5 is -NR 2 . In certain embodiments, R 5 is -S(O) 2 R. In certain embodiments, R 5 is -S(O) 2 NR 2 . In certain embodiments, R 5 is -S(O)R. In certain embodiments, R 5 is -S(O)NR 2 . In certain embodiments, R 5 is -C(O)R. In certain embodiments, R 5 is -C(O)CR 3 . In certain embodiments, R 5 is -C(O)OR.
  • R 5 is -C(O)NR 2 . In certain embodiments, R 5 is -C(O)N(R)OR. In certain embodiments, R 5 is -OC(O)R. In certain embodiments, R 5 is -OC(O)NR 2 . In certain embodiments, R 5 is -O(CR 2 ) 3 NR 2 . In certain embodiments, R 5 is -N(R)C(O)OR. In certain embodiments, R 5 is -N(R)C(O)R. In certain embodiments, R 3 is -N(R)C(O)NR 2 . In certain embodiments, R 5 is -N(R)C(NR)NR 2 .
  • R 5 is-NR(CR 2 ) 2 OR. In certain embodiments, R 3 is -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 is -N(R)S(O) 2 R. In certain embodiments, R 3 is -CH 2 R. In certain embodiments, R 5 is -CHR 2 . In certain embodiments, R 5 is -CR 3 . In certain embodiments, R 5 is -CH 2 NR 2 . In certain embodiments, R 5 is - CH 2 NHCH 2 CH 2 OR. In certain embodiments. R 5 is -CH 2 CH 2 C(O)OR. In certain embodiments, R 5 is -CH 2 C(O)NR 2 .
  • R 5 is -CH 2 CH 2 R, In certain embodiments, R 5 is - CH 2 CH 2 OR. In certain embodiments, R 5 is -NHCH 2 CH 2 OR. In certain embodiments, R 5 is - NHC(O)R. In certain embodiments, R 5 is -CH 2 OR. In certain embodiments, R 5 is - CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 isa C 1-3 alkyl group. In certain embodiments, R 5 is a C 1-3 haloalkyl group, In certain embodiments, R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments.
  • R 5 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 5 is phenyl.
  • R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 is -CN, -C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -, -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic
  • R 5 is -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R. -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R.
  • R 5 is halo, oxo, -CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, -OR, -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is selected from those depicted in Table 1 , below.
  • Y represents independently for each occurrence -R. In certain embodiments, Y represents independently for each occurrence -OR. In certain embodiments, Y represents independently for each occurrence -NR 2 . In certain embodiments,
  • Y represents independently for each occurrence -NHCH 2 CH 2 OR. In certain embodiments, two
  • Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence oxo, -OR, - NR 2 . -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, -OR, - NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo. - NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, - OR, -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, - OR, -NR 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, - OR, -NR 2 , -OCH 2 CHF 2 , or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, - OR, -NR 2 , -OCH 2 CHF 2 , or -OCH 2 CH 2 OH; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -R, oxo, - OR, -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR.
  • Y represents independently for each occurrence -OH, halogen, optionally substituted C 1-6 aliphatic, phenyl, oxo, -OR, -NR 2 , -OCH 2 CHF 2 , - OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -OH, halogen, methyl, ethyl, i-propyl, n-propyl, phenyl, oxo, -OCH 3 , -NR 2 , -OCH 2 CHF 2 , - OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y represents independently for each occurrence -OH, halogen, methyl, ethyl, i-propyl, n-propyl, phenyl; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R. In certain embodiments, Y is -OR. In certain embodiments, Y is -NR 2 . In certain embodiments, Y is -NHCH 2 CH 2 OR. In certain embodiments, Y is -OCH 2 CHF 2 . In certain embodiments, Y is -OCH 2 CH 2 OH. In certain embodiments, two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is oxo, -OR, -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or - NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, -OR, -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or - NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, oxo, -NR?, -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or - NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, oxo, -OR, -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or - NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R. oxo, -OR, -NR 2 , -OCH 2 CH 2 OH. or - NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, oxo, -OR, -NR 2 , -OCH 2 CHF 2 , or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, oxo, -OR, -NR?, -OCH 2 CHF 2 , or -OCH 2 CH 2 OH; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -R, oxo, -OR, -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or - NHCH 2 CH 2 OR.
  • Y is -OH, halogen, optionally substituted Ci-e aliphatic, phenyl, oxo, -OR, -NR?, -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -OH, halogen, methyl, ethyl, i-propyl, n-propyl, phenyl, oxo, -OCH 3 , -NR 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 OH, or -NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is -OH, halogen, methyl, ethyl, i-propyl, n-propyl, phenyl; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is methyl. In ceratin embodiments, Y is phenyl.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, , or a 5-7- membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with , L 1 is a C 2-4 hydrocarbon chain.
  • Y is selected from those depicted in Table 1, below.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7-membered bridged bicyclic carbocyclene
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, or -C(O)NR-.
  • L 1 is a saturated straight or branched, bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(0)-, -NRC(O)-, -C(O)NR-, , or a 5-7-membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with , L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7-membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with , L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 2-4 hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by .
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched bivalent C 1-4 hydrocarbon chain.
  • L 1 is selected from those depicted in Table 1, below.
  • L 2 is a covalent bond. -OCH 2 -, -O-, -OCH 2 CH 2 -. - NHCH 2 -, -NHCH 2 CH 2 -, or -NH-.
  • L 2 is a covalent bond. In certain embodiments, L 2 is -OCH 2 - . In certain embodiments, L 2 is -O-. In certain embodiments, L 2 is -OCH 2 CH 2 -. In certain embodiments, L 2 is -NHCH 2 -. In certain embodiments, L 2 is -NHCH 2 CH 2 -. In certain embodiments, L 2 is -NH-. [0304] In certain embodiments, L 2 is -OCH 2 -, -O-, -OCH 2 CH 2 -, -NHCH 2 -, -NHCH 2 CH 2 -, or -NH-.
  • L 2 is a covalent bond, -O-, -OCH 2 CH 2 -, -NHCH 2 -, - NHCH 2 CH 2 -, or -NH-. In certain embodiments, L 2 is a covalent bond, -OCH 2 -, -OCH 2 CH 2 -, - NHCH 2 -, -NHCH 2 CH 2 -, or -NH-. In certain embodiments, L 2 is a covalent bond, -OCH 2 -, -O-, -NHCH 2 -, -NHCH 2 CH 2 -, or -NH-. In certain embodiments, L 2 is a covalent bond, -OCH 2 -, -O-.
  • L 2 is a covalent bond, -OCH 2 -, - O-, -OCH 2 CH 2 -, -NHCH 2 -, or -NH-. In certain embodiments, L 2 is a covalent bond, -OCH 2 -, - O-, -OCH 2 CH 2 -, -NHCH 2 -, or -NHCH 2 CH 2 -.
  • L 2 is selected from those depicted in Table 1, below.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence optionally substituted C 1 - 6 aliphatic. In certain embodiments, R represents independently for each occurrence optionally substituted phenyl. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence C 1-6 aliphatic. In certain embodiments, R represents independently for each occurrence phenyl. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R represents independently for each occurrence an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocy devis carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is halo.
  • R is optionally substituted C 1-6 aliphatic.
  • R is optionally substituted phenyl.
  • R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is halo. In certain embodiments, R is Ci-e aliphatic. In certain embodiments, R is phenyl. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is selected from those depicted in Table 1, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 0, 2, or 3. In certain embodiments, n is 0, 1, or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0 or 3. In certain embodiments, n is 0 or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1 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.
  • p is 0, 1, 2, 3 or 4. In certain embodiments, p is 1, 2, 3 or 4. In certain embodiments, p is 0, 2, 3 or 4. In certain embodiments, p is 0, 1, 3 or 4. In certain embodiments, p is 0, 1, 2, or 4. In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 2, 3 or 4. In certain embodiments, p is 0, 3 or 4. In certain embodiments, p is 0, 1, or 4. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 3 or 4. In certain embodiments, p is 1, 2, or 4. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 0, 2 or 4. In certain embodiments, p is 0, 2 or 3.
  • p is 0, 1 or 3. In certain embodiments, p is 3 or 4. In certain embodiments, p is 0 or 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 4. In certain embodiments, p is 1 or 2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0 or 3. In certain embodiments, p is 1 or 3. In certain embodiments, p is 2 or 3. In certain embodiments, p is 2 or 4. 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 4. [0326]
  • One aspect of the invention provides a compound represented by Formula 111: or a pharmaceutically acceptable salt thereof; wherein:
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl;
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR. -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 .
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy;
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from - OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ;
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -
  • X is -O- or -NH-
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-3 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, , or a 5-7-membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with , L 1 is a C 2-4 hydrocarbon chain;
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; n is 0, 1, 2, or 3; and p is 0, 1, 2, 3 or 4.
  • variables in Formula III above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula III.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments. Ring A is phenyl.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or phenyl.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; or an 8-10 membered bicyclic aromatic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; or a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is selected from those depicted in Table 1, below.
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , - N(R)C(O)OR. -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)C(NR 2 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O
  • R 1 represents independently for each occurrence halo. In some embodiments, R 1 represents independently for each occurrence -OR. In some embodiments, R 1 represents independently for each occurrence -SR. In some embodiments, R 1 represents independently for each occurrence -NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -S(O)?NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O)R. In some embodiments, R 1 represents independently for each occurrence -S(O)NR 2 . In some embodiments. R 1 represents independently for each occurrence -C(O)R.
  • R 1 represents independently for each occurrence - C(O)CR 3 . In some embodiments, R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(0)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)N(R)OR. n some embodiments, R 1 represents independently for each occurrence -OC(O)R. In some embodiments, R 1 represents independently for each occurrence -OC(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -O(CR 2 )JNR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)OR.
  • R 1 represents independently for each occurrence -N(R)C(O)R. In some embodiments, R 1 represents independently for each occurrence -N(R)C(0)NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(NR)NR 2 . In some embodiments, R 1 represents independently for each occurrence -NR(CR 2 ) 2 OR. In some embodiments, R 1 represents independently for each occurrence -N(R)S(O)2NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 R.
  • R 1 represents independently for each occurrence -CHR 2 . In some embodiments, R 1 represents independently for each occurrence -CR 3 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 OR.
  • R 1 represents independently for each occurrence - NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence - NHC(O)R. In some embodiments, R 1 represents independently for each occurrence -CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NH 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 represents independently for each occurrence -OCR. In some embodiments, R 1 represents independently for each occurrence C 1-4 aliphatic. In some embodiments, R 1 represents independently for each occurrence C 1-4 haloaliphatic.
  • R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence -CN, — C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 . -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -, - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R. -CH 2 CH 2 OR. -CH 2 OR, - CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)C(NR 2 , -N(R)C(NR 2 , --SR
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 .
  • R 1 represents independently for each occurrence halo, oxo, - CN, C 1-4 aliphatic. C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or -OCR,
  • R 1 represents independently for each occurrence - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -
  • R 1 represents independently for each occurrence halo, oxo, - OR, -C(O)R, -C(O)CR 3 , -C(O)OR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 , - CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence oxo or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence -CH 3 , -
  • R 1 represents independently for each occurrence -CH 3 or (O).
  • R 1 is halo. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -NR 2 . In some embodiments, R 1 is -S(O) 2 R. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)NR 2 . In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)CR 3 . In some embodiments, R 1 is -C(O)OR. In some embodiments.
  • R 1 is -C(O)NR 2 . In some embodiments, R 1 is -C(O)N(R)OR. In some embodiments, R 1 is -OC(O)R. In some embodiments, R 1 is -OC(O)NR 2 . In some embodiments, R 1 is - O(CR 2 )3NR 2 . In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R 1 is -N(R)C(O)R. In some embodiments, R 1 is -N(R)C(O)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 . In some embodiments, R 1 is -NR(CR 2 ) 2 OR.
  • R 1 is -N(R)S(O) 2 NR 2 . In some embodiments, R 1 is -N(R)S(O) 2 R. In some embodiments, R 1 is - CR 3 . In some embodiments, R 1 is -CH 2 NR 2 . In some embodiments, R 1 is -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 is -CH 2 CH 2 C(O)OR. In some embodiments, R 1 is -CH 2 C(O)NR 2 . In some embodiments, R 1 is -CH 2 CH 2 R. In some embodiments, R 1 is -CH 2 CH 2 OR. In some embodiments, R 1 is -NHCH 2 CH 2 OR.
  • R 1 is -NHC(O)R. In some embodiments, R 1 is -CH 2 OR. In some embodiments, R 1 is -CH 2 C(O)NH 2 . In some embodiments, R 1 is -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 is -OCR. In some embodiments, R 1 is C 1-4 aliphatic. In some embodiments, R 1 is C 1-4 haloaliphatic. In some embodiments, R 1 is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 is a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is -CN, — C(O)R, -C(O)CR 3 , -C(O)OR. - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ri is halo, oxo. -OR. -SR, -NR 2 . -S(O) 2 R. -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, - NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR. -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R.
  • -N(R)C(O)NR 2 - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, - NHCH 2 CH 2 OR, -NHC(O)R, -CH 2 OR, -CH 2 C(O)NH 2 , -H 2 NHC(O)OCR 3 , -OCR1, C 1-4 aliphatic, or C 1-4 haloaliphatic.
  • R 1 is halo, oxo, -CN, C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or - OCR, [0359] In some embodiments. R 1 is -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 1 is halo, oxo, -OR, -C(O)R, -C(O)CR 3 , -C(O)OR, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 , -CH 2 OR, -CH 2 C(O)NH 2 , or C 1-4 aliphatic.
  • R 1 is oxo or C 1-4 aliphatic.
  • R 1 is -CH 3 , -CH 2 C(O)NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , - NHAc, -OH, -C(O)CH 2 OH, -C(O)CH 3 , -CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , - OCH 3 .CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, -NHCH 2 CH 2 OH, -CH 2 CH 2 C(O)OCH 3 , - NHS(O) 2 CH 3 . -C(O)NH 2 .
  • R 1 is -CH 3 . -NHAc, -OH, -C(O)CH 2 OH. -C(O)CH 3 . - C(O)OCH 3 , -C(O)OH, -C(O)NH 2 , (O), -CH 2 NH 2 , -NH 2 , -NHC(O)CH 3 , -CH 2 CH 3 , -CH 2 OH, -
  • R 1 is -CH 3 , -NHAc, -OH, (O), -OCH 3 , or . In some embodiments, R 1 is -CH 3 or (O).
  • R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -CN, cyclopropyl, C 1-3 alkyd, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo. -OH, -CN, C 1-3 alkyl, C 1-3 haloalky 1, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 haloalkyl. or C 1-3 alkoxy. In some embodiments. R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 2 is hydrogen, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , or C 1-3 alkoxy.
  • R 2 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from - OH, -NH 2 . -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen or C 1-3 alkyl.
  • R 2 unsubstituted C 1-3 alkyl.
  • R 2 is C 1-3 alkyd substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen. In some embodiments, R 2 is -OH. In some embodiments, R 2 is -CN. In some embodiments, R 2 is cyclopropyl.
  • R 2 is halo. In some embodiments, R 2 is Cl, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Br.
  • R 2 is C 1-3 alkyd. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is i-propyl. In some embodiments, R 2 is n- propyl.
  • R 2 is C 1-3 haloalkyl. In some embodiments, R 2 is CF 3 . In some embodiments, R 2 is CHF 2 .
  • R 2 is C 1-3 alkoxy. In some embodiments. R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 CH 2 OCH 3 .
  • R 2 is selected from those depicted in Table 1, below.
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ). and -N(CH 3 ) 2 .
  • R 3 is cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CHj), and -N(CH 3 ) 2 .
  • R 3 is substituted C 1-3 alkyl as defined above and herein, wherein the substitution occurs on the terminal carbon atom.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH and OMe. In some embodiments, R 3 is hydrogen or C 1-3 alkyl.
  • R 3 is hydrogen. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is C 1-3 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments. R 3 is i-propyl. In some embodiments, R 3 is n- propyl.
  • R 3 is C 1-3 alkyd substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is C 1-3 alkyl substituted with a group selected from -OH or OMe.
  • R 3 is C 1-3 alkyl substituted with a group selected from -OMe, -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 .
  • R 3 is C 1-3 alkyl substituted with a group selected from -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 .
  • R 3 is -CH 2 OCH 3 .
  • R 3 is -CH 2 OCH 3 .
  • R 3 is -CH 2 CH 2 OCH 3 .
  • R 3 is selected from those depicted in Table 1, below.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocy devis ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a phenyl, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 4 is a phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclic hetero aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 2- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 2-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R.
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence -OR. In certain embodiments, R 3 represents independently for each occurrence -SR. In certain embodiments, R 5 represents independently for each occurrence -NR 2 . In certain embodiments, R 5 represents independently for each occurrence -S(O) 2 R. In certain embodiments. R 5 represents independently for each occurrence -S(O) 2 NR 2 . In certain embodiments, R 5 represents independently for each occurrence -S(O)R. In certain embodiments, R 5 represents independently for each occurrence -S(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)R.
  • R 5 represents independently for each occurrence -C(O)CR 3 . In certain embodiments, R 5 represents independently for each occurrence -C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)N(R)OR. In certain embodiments, R 5 represents independently for each occurrence -OC(O)R. In certain embodiments, R 5 represents independently for each occurrence -OC(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -O(CR 2 )3NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)C(O)OR.
  • R 5 represents independently for each occurrence -N(R)C(O)R. In certain embodiments, R 5 represents independently for each occurrence -N(R)C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)C(NR)NR 2 . In certain embodiments, R 5 represents independently for each occurrence-NR(CR 2 ) 2 OR. In certain embodiments, R 5 represents independently for each occurrence -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)S(O) 2 R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 R.
  • R 5 represents independently for each occurrence -CHR 2 . In certain embodiments, R 5 represents independently for each occurrence -CR 3 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 NR 2 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 R, In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 OR. In certain embodiments.
  • R 5 represents independently for each occurrence -NHCH 2 CH 2 OR. In certain embodiments. R 5 represents independently for each occurrence -NHC(O)R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 represents independently for each occurrencea C 1-3 alkyl group. In certain embodiments, R 5 represents independently for each occurrence a C 1-3 haloalkyl group. In certain embodiments, R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 represents independently for each occurrence phenyl. In certain embodiments, R 5 represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments. R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 represents independently for each occurrence - CN, -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 .
  • R 5 represents independently for each occurrence N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, - CN, -OR. -SR, -NR 2 . -S(O) 2 R. -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R.
  • R 5 represents independently for each occurrence halo, oxo, - CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo. In certain embodiments, R 5 is -OR. In certain embodiments, R 5 is -SR. In certain embodiments. R 5 is -NR 2 . In certain embodiments. R 5 is -S(O) 2 R. In certain embodiments, R 5 is
  • R 5 is -S(O)R. In certain embodiments, R 5 is -S(O)NR 2 . In certain embodiments, R 5 is -C(O)R. In certain embodiments, R 5 is -C(O)CR 3 . In certain embodiments, R 5 is -C(O)OR. In certain embodiments. R 5 is -C(O)NR 2 . In certain embodiments, R 5 is -C(O)N(R)OR. In certain embodiments, R 5 is -OC(O)R. In certain embodiments, R 5 is -OC(O)NR 2 . In certain embodiments, R 5 is -O(CR 2 )3NR 2 .
  • R 5 is -N(R)C(O)OR. In certain embodiments, R 5 is -N(R)C(O)R. In certain embodiments, R 5 is -N(R)C(O)NR 2 . In certain embodiments. R 5 is -N(R)C(NR)NR 2 . In certain embodiments, R 5 is-NR(CR 2 ) 2 OR. In certain embodiments, R 5 is -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 is -N(R)S(O) 2 R. In certain embodiments, R 5 is -CH 2 R. In certain embodiments, R 5 is -CHR 2 . In certain embodiments, R 5 is -CR 3 .
  • R 5 is - CH 2 NR 2 . In certain embodiments, R 5 is -CH 2 NHCH 2 CH 2 OR. In certain embodiments, R 5 is - CH 2 CH 2 C(O)OR. In certain embodiments, R 5 is -CH 2 C(O)NR 2 . In certain embodiments, R 5 is - CH 2 CH 2 R, In certain embodiments, R 5 is -CH 2 CH 2 OR. In certain embodiments, R 5 is - NHCH 2 CH 2 OR. In certain embodiments, R 5 is -NHC(O)R. In certain embodiments, R 5 is - CH 2 OR. In certain embodiments, R 5 is -CH 2 NHC(O)OCR 3 .
  • R 5 is a C 1-3 alkyl group. In certain embodiments, R 5 is a C 1-3 haloalkyl group, In certain embodiments, R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 is a 3-6 membered saturated or partially unsaturated monocyclic carbocy devis ring. In certain embodiments, R 5 is phenyl. In certain embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 is a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 is -CN, -C(O)R, -C(O)CR 3 , -C(O)OR, C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -. -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 . -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 . -CH 2 NHC(O)OCR 3 .
  • R 5 is -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R.
  • R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR. -OC(O)R, -OC(O)NR 2 , -O(CR 2 )3NR 2 , -N(R)C(O)OR, -N(R)C(O)R.
  • -N(R)C(O)NR 2 - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , — N(R)S(O) 2 R, -CR 3 , -CH 2 NR 2 -, - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, - NHCH 2 CH 2 OR, -NHC(O)R, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, or a C 1-3 haloalkyl group.
  • R 5 is halo, oxo, -CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is selected from those depicted in Table 1, below.
  • X is -O- or -NH-. In certain embodiments, X is -O-. In certain embodiments, X is -NH-.
  • X is selected from those depicted in Table 1. below.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, , or a 5-7- membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7-membered bridged bicyclic carbocyclene.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, or -C(O)NR-.
  • L 1 is a saturated straight or branched, bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -0-, -NR-, -C(0)-, -NRC(O)-, -C(O)NR-, , or a 5-7-membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with , L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-. -NRC(O)-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 2-4 hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by .
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched bivalent C 1-4 hydrocarbon chain.
  • L 1 is selected from those depicted in Table 1, below.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence optionally substituted Ci- 6 aliphatic. In certain embodiments, R represents independently for each occurrence optionally- substituted phenyl. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence C 1-6 aliphatic. In certain embodiments, R represents independently for each occurrence phenyl. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R represents independently for each occurrence an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is halo. In certain embodiments, R is optionally substituted C 1-6 aliphatic. In certain embodiments, R is optionally substituted phenyl. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is halo. In certain embodiments, R is C 1-6 aliphatic. In certain embodiments, R is phenyl. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently- selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is selected from those depicted in Table 1, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 0, 2, or 3. In certain embodiments, n is 0, 1, or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0 or 3. In certain embodiments, n is 0 or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1 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.
  • p is 0, 1 , 2, 3 or 4. In certain embodiments, p is 1 , 2, 3 or 4. In certain embodiments, p is 0, 2, 3 or 4. In certain embodiments, p is 0, 1, 3 or 4. In certain embodiments, p is 0, 1, 2, or 4. In certain embodiments, p is 0, 1. 2, or 3. In certain embodiments, p is 2, 3 or 4. In certain embodiments, p is 0, 3 or 4. In certain embodiments, p is 0, 1. or 4. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 3 or 4. In certain embodiments, p is 1, 2, or 4. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 0, 2 or 4.
  • p is 0, 2 or 3. In certain embodiments, p is 0, 1 or 3. In certain embodiments, p is 3 or 4. In certain embodiments, p is 0 or 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 4. In certain embodiments, p is 1 or 2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0 or 3. In certain embodiments, p is 1 or 3. In certain embodiments, p is 2 or 3. In certain embodiments, p is 2 or 4. 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 4.
  • One aspect of the invention provides a compound represented by Formula IV : or a pharmaceutically acceptable salt thereof; wherein:
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl;
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C1-5 haloalkyl, or C 1-3 alkoxy;
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from - OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ;
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 ;
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-3 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C24 hydrocarbon chain
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocynch heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; n is 0, 1, 2, or 3; and p is 0, 1. 2, 3 or 4.
  • variables in Formula IV above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula IV.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments. Ring A is phenyl.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic aromatic carbocyclic ring; or phenyl.
  • Ring A a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or phenyl.
  • Ring A is a 6-1 1 membered saturated or partially unsaturated bicyclic carbocyclic ring; or an 8-10 membered bicyclic aromatic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; or a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from oxygen, and sulfur; a 6-1 1 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and suflur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl.
  • Ring A is selected from those depicted in Table 1, below.
  • R 1 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R
  • R 1 represents independently for each occurrence halo.
  • R 1 represents independently for each occurrence -OR. In some embodiments, R 1 represents independently for each occurrence -SR. In some embodiments, R 1 represents independently for each occurrence -NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -S(O)2NR 2 . In some embodiments, R 1 represents independently for each occurrence -S(O)R. In some embodiments, R 1 represents independently for each occurrence -S(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)R. In some embodiments, R 1 represents independently for each occurrence - C(O)CR 3 .
  • R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -C(O)N(R)OR. n some embodiments, R 1 represents independently for each occurrence -OC(O)R. In some embodiments, R 1 represents independently for each occurrence -OC(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -O(CR 2 )3NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)OR. In some embodiments, R 1 represents independently for each occurrence -N(R)C(O)R.
  • R 1 represents independently for each occurrence -N(R)C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)C(NR)NR 2 . In some embodiments, R 1 represents independently for each occurrence -NR(CR 2 ) 2 OR. In some embodiments, R 1 represents independently for each occurrence -N(R)S(O)2NR 2 . In some embodiments, R 1 represents independently for each occurrence -N(R)S(O) 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 R. In some embodiments, R 1 represents independently for each occurrence -CHR 2 . In some embodiments, R 1 represents independently for each occurrence -CR 3 .
  • R 1 represents independently for each occurrence -CH 2 NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 C(O)OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NR 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 R. In some embodiments, R 1 represents independently for each occurrence -CH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence - NHCH 2 CH 2 OR. In some embodiments, R 1 represents independently for each occurrence - NHC(O)R.
  • R 1 represents independently for each occurrence -CH 2 OR. In some embodiments, R 1 represents independently for each occurrence -CH 2 C(O)NH 2 . In some embodiments, R 1 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 represents independently for each occurrence -OCR. In some embodiments, R 1 represents independently for each occurrence C 1-4 aliphatic. In some embodiments, R 1 represents independently for each occurrence C 1-4 haloaliphatic. In some embodiments, R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 represents independently for each occurrence a 3-8 membered saturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence -CN, — C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -, - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR. -CH 2 OR, - CH 2 C(O)NH 2 . -CH 2 NHC(O)OCR 3 .
  • Ri represents independently for each occurrence halo, oxo, - OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 . -N(R)C(O)OR, -N(R)C(O)R. -N(R)C(O)NR 2 . -N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR. - N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, -NHC(O)R, or -OCR.
  • R 1 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 . -C(O)R, -C(O)CR 3 , -C(O)OR. - C(O)NR 2 , -C(O)N(R)OR. -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 .
  • R 1 represents independently for each occurrence halo, oxo, - CN, C 1-4 aliphatic. C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or -OCR, [0463] In some embodiments, R 1 represents independently for each occurrence -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 1 represents independently for each occurrence halo, oxo, - OR, -C(O)R, -C(O)CR 3 , -C(O)OR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 , - CH 2 OR, -CH 2 C(O)NH 2 . or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence oxo or C 1-4 aliphatic.
  • R 1 represents independently for each occurrence -CH 3 , - CH 2 C(O)NH 2 . -CH 2 OCH 3 . -CH 2 CH 2 OCH 3 . -NHAC, -OH, -C(O)CH 2 OH, -C(O)CH 3 . - CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , -OCH 3 ,CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, -
  • R 1 represents independently for each occurrence -CH 3 , - NHAc, -OH, -C(O)CH 2 OH, -C(O)CH 3 , -C(O)OCH 3 , -C(O)OH, -C(O)NH 2 , (O), -CH 2 NH 2 , -
  • R 1 represents independently for each occurrence -CH 3 , -NHAc, -OH, (O) -OCH 3 , or in some embodiments, R 1 represents independently for each occurrence -CH 3 or (O).
  • R 1 is halo. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -NR 2 . In some embodiments, R 1 is -S(O) 2 R. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O)R. In some embodiments. R 1 is -S(O)NR 2 . In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)CR 3 . In some embodiments, R 1 is -C(O)OR.
  • R 1 is -C(O)NR 2 . In some embodiments, R 1 is -C(O)N(R)OR. In some embodiments, R 1 is -OC(O)R. In some embodiments, R 1 is -OC(O)NR 2 . In some embodiments, R 1 is - O(CR 2 ) 3 NR 2 . In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R 1 is -N(R)C(O)R. In some embodiments, R 1 is -N(R)C(O)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 . In some embodiments, R 1 is -N(R)C(NR)NR 2 .
  • R 1 is -NR(CR 2 ) 2 OR. In some embodiments, R 1 is -N(R)S(O)2NR 2 . In some embodiments, R 1 is -N(R)S(O) 2 R. In some embodiments, R 1 is - CR 3 . In some embodiments. R 1 is -CH 2 NR 2 . In some embodiments, R 1 is -CH 2 NHCH 2 CH 2 OR. In some embodiments, R 1 is -CH 2 CH 2 C(O)OR. In some embodiments, R 1 is -CH 2 C(O)NR 2 . In some embodiments, R 1 is -CH 2 CH 2 R. In some embodiments, R 1 is -CH 2 CH 2 OR.
  • R 1 is -NHCH 2 CH 2 OR. In some embodiments, R 1 is -NHC(O)R. In some embodiments, R 1 is -CH 2 OR. In some embodiments, R 1 is -CH 2 C(O)NH 2 . In some embodiments, R 1 is -CH 2 NHC(O)OCR 3 . In some embodiments, R 1 is -OCR. In some embodiments, R 1 is C 1-4 aliphatic. In some embodiments, R 1 is C 1-4 haloaliphatic. In some embodiments, R 1 is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R 1 is a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is -CN, — C(O)R, -C(O)CR 3 , -C(O)OR. - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , -CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, - CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is halo, oxo. -OR. -SR, -NR 2 . -S(O) 2 R.
  • R 1 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , -N(R)C(O)OR, -N(R)C(O)R.
  • -N(R)C(O)NR 2 - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, - NHCH 2 CH 2 OR, -NHC(O)R, -CH 2 OR, -CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , -OCR, C 1-4 aliphatic, or C 1-4 haloaliphatic.
  • R 1 is halo, oxo, -CN, C 1-4 aliphatic, C 1-4 haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring and a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , or - OCR,
  • R 1 is -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R
  • R 1 is halo, oxo, -OR, -C(O)R, -C(O)CR 3 , -C(O)OR, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -CR 3 .
  • R 1 is oxo or C 1-4 aliphatic.
  • R 1 is -CH 3 , -CH 2 C(O)NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , - NHAc, -OH, -C(O)CH 2 OH, -C(O)CH 3 , -CH 2 NHCH 2 CH 2 OH, -CH 2 C(O)NH 2 , - OCH 3 .CH 2 OCH 3 , -C(O)OCH 3 , -C(O)OH, -NHCH 2 CH 2 OH, -CH 2 CH 2 C(O)OCH 3 .
  • R 1 is selected from those depicted in Table 1, below.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-4 haloalkyl, or C 1-4 alkoxy.
  • R 2 is halo, -OH, -CN, cyclopropyl, C 1-4 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-4 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 )y C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, -OH, -CN, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 . -NH(CH 3 ), and -N(CH 3 ) 2 , C 1-3 haloalkyl. or C 1-3 alkoxy.
  • R 2 is hydrogen, halo. -CN. cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, cyclopropyl, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • R 2 is hydrogen, halo, -OH, -CN, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 haloalkyl. or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, R 2 is hydrogen, halo, -OH, -CN, cyclopropyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 2 is hydrogen, cyclopropyl, C 1-3 alkyl optionally substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 , or C 1-3 alkoxy.
  • R 2 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from - OH, -NH 2 . -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen or C 1-3 alkyl.
  • R 2 unsubstituted C 1-3 alkyl.
  • R 2 is C 1-3 alkyl substituted with a group selected from -OH, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 2 is hydrogen. In some embodiments, R 2 is -OH. In some embodiments, R 2 is -CN. In some embodiments, R 2 is cyclopropyl.
  • R 2 is halo. In some embodiments, R 2 is C1, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Br.
  • R 2 is C 1-3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is i-propyl. In some embodiments, R 2 is n- propyl.
  • R 2 is C 1-3 haloalkyl. In some embodiments, R 2 is CF 3 . In some embodiments. R 2 is CHF 2 .
  • R 2 is C 1-3 alkoxy. In some embodiments. R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 OCH 3 . In some embodiments, R 2 is -CH 2 CH 2 OCH 3 .
  • R 2 is selected from those depicted in Table 1, below.
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ). and -N(CH 3 ) 2 .
  • R 3 is cyclopropyl, or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 3 is hydrogen, cyclopropyl, or C 1-3 alkyl substituted with a group selected from -OH, -OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • R J is substituted C 1-3 alkyd as defined above and herein, wherein the substitution occurs on the terminal carbon atom.
  • R 3 is hydrogen or C 1-3 alkyl optionally substituted with a group selected from -OH and OMe. In some embodiments, R 3 is hydrogen or C 1-3 alkyl.
  • R 3 is hy drogen. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is C 1-3 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is i-propyl. In some embodiments, R 3 is n- propyl.
  • R 3 is C 1-3 alkyd substituted with a group selected from -OH, OMe, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 . In some embodiments, R 3 is C 1-3 alkyd substituted with a group selected from -OH or OMe. In some embodiments, R 3 is C 1-3 alkyd substituted w ith a group selected from -OMe, -NH 2 , -NH(CH 3 ). or -N(CH 3 ) 2 .
  • R 3 is C 1-3 alkyl substituted with a group selected from -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 . In some embodiments, R 3 is -CH 2 OCH 3 . In some embodiments, R 3 is -CH 2 OCH 3 . In some embodiments, R 3 is -CH 2 CH 2 OCH 3 .
  • R 3 is selected from those depicted in Table 1, below .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein R 4 is substituted with p instances of R ⁇ In some embodiments, R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is a phenyl, wherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 4 is a phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ringwherein R 4 is substituted with p instances of R 5 . In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R ⁇
  • R 4 is a cyclic group selected from a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is a cyclic group selected from a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 8-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 2- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 2-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4 is substituted with p instances of R 5 .
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 represents independently for each occurrence halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, - C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R. -OC(O)NR 2 , -O(CR 2 ) 3 NR 2 , - N(R)C(O)OR.
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence -OR. In certain embodiments, R 5 represents independently for each occurrence -SR. In certain embodiments, R 5 represents independently for each occurrence -NR?. In certain embodiments, R 5 represents independently for each occurrence -S(O) 2 R. In certain embodiments, R 5 represents independently for each occurrence
  • R 5 represents independently for each occurrence -S(O)R. In certain embodiments, R 5 represents independently for each occurrence -S(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)R. In certain embodiments, R 5 represents independently for each occurrence -C(O)CR 3 . In certain embodiments, R 5 represents independently for each occurrence -C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -C(O)N(R)OR. In certain embodiments, R 5 represents independently for each occurrence -OC(O)R.
  • R 5 represents independently for each occurrence -OC(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -O(CR 2 )3NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)C(O)OR. In certain embodiments, R 5 represents independently for each occurrence -N(R)C(O)R. In certain embodiments, R 5 represents independently for each occurrence -N(R)C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)C(NR)NR 2 . In certain embodiments, R 5 represents independently for each occurrence-NR(CR 2 ) 2 OR.
  • R 5 represents independently for each occurrence -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 represents independently for each occurrence -N(R)S(O) 2 R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 R. In certain embodiments, R 5 represents independently for each occurrence -CHR 2 . In certain embodiments, R 5 represents independently for each occurrence -CR 3 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 NR 2 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHCH 2 CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 C(O)OR.
  • R 5 represents independently for each occurrence -CH 2 C(O)NR 2 . In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 R, In certain embodiments, R 5 represents independently for each occurrence -CH 2 CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -NHCH 2 CH 2 OR. In certain embodiments. R 5 represents independently for each occurrence -NHC(O)R. In certain embodiments, R 5 represents independently for each occurrence -CH 2 OR. In certain embodiments, R 5 represents independently for each occurrence -CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 represents independently for each occurrencea C 1-3 alkyl group.
  • R 5 represents independently for each occurrence a C 1-3 haloalkyl group, In certain embodiments, R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 represents independently for each occurrence phenyl. In certain embodiments, R 5 represents independently for each occurrence a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 represents independently for each occurrence a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence oxo, - OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 ) 3 NR 2 .
  • R 5 represents independently for each occurrence - CN, -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 , - CH 2 NHCH 2 CH 2 OR, -CH 2 CH 2 C(O)OR, -CH 2 C(O)NR 2 , -CH 2 CH 2 R, -CH 2 CH 2 OR, -CH 2 OR, - CH 2 C(O)NH 2 , -CH 2 NHC(O)OCR 3 , a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocycl
  • R 5 represents independently for each occurrence N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -
  • NR(CR 2 ) 2 OR -N(R)S(O) 2 NR 2 , N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or -NHC(O)R.
  • R 5 represents independently for each occurrence a C 1-3 heteroalkyl group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, - CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR,
  • R 5 represents independently for each occurrence halo, oxo, - CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyd group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo. In certain embodiments. R 5 is -OR. In certain embodiments, R 5 is -SR. In certain embodiments, R 5 is -NR 2 . In certain embodiments, R 5 is -S(O) 2 R. In certain embodiments, R 5 is -S(O) 2 NR 2 . In certain embodiments, R 5 is -S(O)R. In certain embodiments, R 5 is -S(O)NR 2 . In certain embodiments, R 5 is -C(O)R. In certain embodiments, R 5 is -C(O)CR 3 . In certain embodiments, R 5 is -C(O)OR.
  • R 5 is -C(O)NR 2 . In certain embodiments, R 5 is -C(O)N(R)OR. In certain embodiments, R 5 is -OC(O)R. In certain embodiments, R 5 is -OC(O)NR 2 . In certain embodiments, R 5 is -O(CR 2 ) 3 NR 2 . In certain embodiments, R 5 is -N(R)C(O)OR. In certain embodiments, R 5 is -N(R)C(O)R. In certain embodiments, R 5 is -N(R)C(O)NR 2 . In certain embodiments, R 5 is -N(R)C(NR)NR 2 . In certain embodiments. In certain embodiments.
  • R 5 is-NR(CR 2 ) 2 OR. In certain embodiments, R 5 is -N(R)S(O) 2 NR 2 . In certain embodiments, R 5 is -N(R)S(O) 2 R. In certain embodiments, R 5 is -CH 2 R. In certain embodiments, R 5 is -CHR 2 . In certain embodiments, R 5 is -CR 3 . In certain embodiments, R 5 is -CH 2 NR 2 . In certain embodiments, R 5 is - CH 2 NHCH 2 CH 2 OR. In certain embodiments. R 5 is -CH 2 CH 2 C(O)OR. In certain embodiments, R 5 is -CH 2 C(O)NR 2 .
  • R 5 is -CH 2 CH 2 R, In certain embodiments, R 5 is - CH 2 CH 2 OR. In certain embodiments, R 5 is -NHCH 2 CH 2 OR. In certain embodiments, R 5 is - NHC(O)R. In certain embodiments, R 5 is -CH 2 OR. In certain embodiments, R 5 is - CH 2 NHC(O)OCR 3 . In certain embodiments, R 5 isa C 1-3 alkyl group. In certain embodiments, R 5 is a C 1-3 haloalkyl group, In certain embodiments, R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R 5 is phenyl. In certain embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 5 is a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is oxo, -OR, -OC(O)R, -OC(O)NR 2 , or -O(CR 2 )3NR 2 .
  • R 5 is -CN, -C(O)R, -C(O)CR 3 , -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -CR 3 , -CH 2 NR 2 -.
  • R 5 is -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 - N(R)C(NR)NR 2 , -NR(CR 2 ) 2 OR, -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -NHCH 2 CH 2 OR, or - NHC(O)R
  • R 5 is a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, -CN, -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)CR 3 , -C(O)OR, -C(O)NR 2 . -C(O)N(R)OR.
  • R 5 is halo, oxo, -CN, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 heteroalkyd group having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is halo, oxo, a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 1-3 heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 is selected from those depicted in Table 1, below.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7- membered bridged bicyclic carbocyclene; wherein when one unit of L 1 is replaced with
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, -C(O)NR-, or a 5-7-membered bridged bicyclic carbocyclene.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-, or -C(O)NR-.
  • L 1 is a saturated straight or branched, bivalent C 1-4 hydrocarbon chain, wherein 0-2 methylene units of L 1 are independently replaced by -O-, -NR-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced y p , y bon chain.
  • L 1 is a saturated straight bivalent C 1-4 hydrocarbon chain, wherein 1-2 methylene units of L 1 are independently replaced by -O-, -NR-, -C(O)-, -NRC(O)-,
  • L 1 is a C 2-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 2-4 hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by .
  • L 1 is a saturated straight or branched, optionally substituted bivalent C 1-4 hydrocarbon chain.
  • L 1 is a saturated straight or branched bivalent C 1-4 hydrocarbon chain.
  • L 1 is selected from those depicted in Table 1, below.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence optionally substituted Ci- 6 aliphatic. In certain embodiments, R represents independently for each occurrence optionally substituted phenyl. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence halo. In certain embodiments, R represents independently for each occurrence C 1-6 aliphatic. In certain embodiments, R represents independently for each occurrence phenyl. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R represents independently for each occurrence 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R represents independently for each occurrence an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R represents independently for each occurrence hy drogen, hydroxyl, C1, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is halo. In certain embodiments, R is optionally substituted C 1-6 aliphatic. In certain embodiments, R is optionally substituted phenyl. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is halo. In certain embodiments, R is C 1-6 aliphatic. In certain embodiments, R is phenyl. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or a group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or optionally substituted C 1-6 aliphatic.
  • R is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydroxyl, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R is hydrogen, hydroxyl, Cl, F, -CH 2 OH,- CH 2 CH 2 OH, methyl, ethyl, i-propyl, n-propyl, cyclopropyl, or phenyl.
  • R is selected from those depicted in Table 1, below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 0, 2, or 3. In certain embodiments, n is 0, 1, or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0 or 3. In certain embodiments, n is 0 or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1 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.
  • p is 0, 1, 2, 3 or 4. In certain embodiments, p is 1, 2, 3 or 4. In certain embodiments, p is 0, 2, 3 or 4. In certain embodiments, p is 0, 1, 3 or 4. In certain embodiments, p is 0, 1, 2, or 4. In certain embodiments, p is 0, 1. 2, or 3. In certain embodiments, p is 2, 3 or 4. In certain embodiments, p is 0, 3 or 4. In certain embodiments, p is 0, 1, or 4. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 3 or 4. In certain embodiments, p is 1. 2, or 4. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is 0, 2 or 4. In certain embodiments, p is 0, 2 or 3.
  • p is 0, 1 or 3. In certain embodiments, p is 3 or 4. In certain embodiments, p is 0 or 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 4. In certain embodiments, p is 1 or 2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0 or 3. In certain embodiments, p is 1 or 3. In certain embodiments, p is 2 or 3. In certain embodiments, p is 2 or 4. 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 4.
  • the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1.
  • the present invention provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.
  • the present invention provides a compound set forth in Table
  • the present invention provides a compound set forth in Table 1, above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a method of treating a disorder in which enhanced ABC transporter function is of clinical benefit.
  • a disorder is one in which ABC transporter dysfunction is etiological for disease.
  • correction of one or more underlying mutations associated with ABC transporter dysfunction is rationalized.
  • methods of the present invention provide enhancement of one or more non-mutated forms of an ABC transporter.
  • the invention provides a method of treating a disorder in which enhanced ABC transporter function is of clinical benefit, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder in which enhanced ABC transporter function is of clinical benefit.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula 1 is a compound defined by one of the embodiments described in Section I, above.
  • the invention provides a method of treating a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.
  • the present invention provides a method of alleviating one or more symptoms of a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.
  • the disorder associated with ABC transporter dysfunction is characterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3. ABCA4. ABCA5, ABCA7, ABCA12, ABCB2. ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6 ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4 , ABCG5, ABCG8, ABCG1, and ABCG4.
  • the present invention provides methods of treating a disorder selected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3.
  • ARCI autosomal recessive Ichthyosis congenital 4A
  • Bare lymphocyte syndrome type I Bare lymphocyte syndrome type I due to TAP2 deficiency
  • X-linked sideroblastic anemia with ataxia Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy, Biliary atresia, Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD/NASH, Alzheimer's disease, Huntington's disease, Multiple sclerosis, Parkinson's disease, Hirschsprung disease, Zellweger syndrome, Type 2 diabetes, Obesity, Type 1 diabetes.
  • Atherosclerosis Dyslipidemia, Generalized arterial calcification of infancy, Calciphylaxis, Autosomal recessive cone-rod dystrophy. Gout, PF1C1, Myo5B deficiency cholestasis, PFIC4, and Low phospholipid associated cholelithiasis.
  • the disorder associated with ABC transporter dysfunction is cystic fibrosis (CF).
  • the present invention provides a method of treating cystic fibrosis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I. In some such embodiments, the method further comprises administering one or more additional therapeutic agents, described further below and herein.
  • the disorder associated with ABC transporter dysfunction is cholestasis.
  • the present invention provides a method of treating cholestasis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I.
  • a compound described herein such as a compound of Formula I.
  • the cholestasis is intrahepatic.
  • the cholestasis is extrahepatic.
  • the cholestasis is any of those described above and herein. Subjects
  • the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as a disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.
  • Another aspect of the invention provides for combination therapy.
  • Compounds described herein such as a compound of Formula I, or other compounds in Section I
  • additional therapeutic agents such as an autoimmune disorder, cancer, etc.
  • 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 coadministering 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 agent 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. If administered as a multiple dosage regime, 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. 19. 20. 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.
  • the present invention provides a method of treating cystic fibrosis (CF) comprising administering a compound of the present invention with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a cystic fibrosis transmembrane conductance (CFTR) modulator, a nutritional agent, or any agent known to treat CF.
  • the one or more additional therapeutic agents is an S- nitrosoglutathione reductase (GSNOR) inhibitor.
  • GSNOR S- nitrosoglutathione reductase
  • the GSNOR inhibitor is selected from a GSNOR inhibitor disclosed in W02010/019903, U.S. Pat. No. 8,470,857, U.S. Pat. No.8, 642,628, W02010/019910, U.S. Pat. No.8,586,624, WO2011/100433, U.S. Pat. No.US 8,481,590, WO2012/048181, WO2012/083165, W02012/083171, or WO 2012/170371.
  • the one or more additional therapeutic agents is an ileal bile transport (IBAT) inhibitor.
  • the IBAT inhibitor is selected from an IBAT inhibitor disclosed in AU2011326873, US2020/0330545, WO2012/064266, WO2020/167964, or Front. Pharmacol. 2018; 9: 931 (Al-Dury et al., published online August 21, 2018).
  • IBAT inhibitors include, but are not limited to odevixibat, elobixivat, maralixibat, linerixibat, GSK2330672, SHP626 (volixibat), A4250, etc.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically.
  • 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.
  • kits comprising a therapeutically effective amount of the compound described herein (such as a compound of Formula I, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • 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
  • terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colonng 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 polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • 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), surfaceactive 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, com, 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
  • 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 know n 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 7 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, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository', etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” 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, intracistemally 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 know n to those of skill in the art.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • 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 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
  • UV 220nm (or 215nm, 254 nm)
  • ABCB11 E297G an assay for measuring the expression of the E297G variant of human ABCB11 (henceforth referred to as ABCB11 E297G) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCB11 E297G.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCB11 E297G by calculating an Emax and EC 50 value.
  • HEK-293 cells stably expressing E297G (HEK-293/E297G cells) were used for this assay and were maintained at 37°C (5% CO2, humidified) in Eagle's Minimum Essential Medium supplemented with 10% fetal bovine serum and 1 % Glutamine .
  • the HEK-293/E297G cells were seeded in black/transparent- bottom 384-well plates at 20,000 cells/well in 22.5 ⁇ l Opti-MEM (Thermofisher, product # 11058021) media supplemented with 2.7% of fetal bovine serum (Gibco, product # 16000044) and allowed to settle for 4 hours at 37°C (5% CO2, humidified).
  • Compound serial dilutions are prepared in Opti-MEM as four times (4x) the final concentration and using a dilution factor of 2.15. After the four h incubation period, 7.5 ⁇ l of the 4x dilutions are transferred to the assay plate.
  • Dose response curves include eight doses with the top final concentration at 25 ⁇ M in 0.75% DMSO.
  • Liquid handling is performed in a robotic device equipped with a 384-tip head (Analytik Jena - CyBio Vario). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO2, humidified). After the 24-hour treatment, plates are allowed to equilibrate for 30 minutes at room temperature. Using the Analytik Jena - CyBio Vario instrument, the volume of each well is reduced to 15 pl and 15 ⁇ l of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer's instructions, is added back to each well. The plates are incubated at room temperature for additional 30 minutes and luminescent signal is acquired using a Hamamatsu FDSS 7000 EX plate-reader (20 reads, exposure time 0.2 seconds, gain 200).
  • Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment. Sci Rep 11, 19810. 10.1038/S41598-021-99184-1
  • ABCA1 is the cAMP -inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem 275, 34508-34511.
  • Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 13, 340-347. 10.1038/nml546

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Abstract

L'invention concerne des composés de pyridine carboxamide, des compositions pharmaceutiques et leur utilisation dans le traitement de pathologies médicales.
PCT/US2023/033707 2022-09-26 2023-09-26 Composés de pyridine carboxamide et leur utilisation dans le traitement de pathologies médicales WO2024072793A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) * 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP
US20080286204A1 (en) * 2007-05-09 2008-11-20 Hadida-Ruah Sara S Modulators of cftr
WO2008141119A2 (fr) * 2007-05-09 2008-11-20 Vertex Pharmaceuticals Incorporated Modulateurs de cftr
WO2009036412A1 (fr) * 2007-09-14 2009-03-19 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de la conductance transmembranaire de la mucoviscidose
WO2009108657A2 (fr) * 2008-02-28 2009-09-03 Vertex Pharmaceuticals Incorporated Dérivés hétéroaryles convenant comme modulateurs du cftr
WO2009123896A1 (fr) * 2008-03-31 2009-10-08 Vertex Pharmaceuticals Incorporated Dérivés de pyridyle en tant que modulateur du cftr
WO2014186704A2 (fr) * 2013-05-17 2014-11-20 N30 Pharmaceuticals, Inc. Nouveaux composés permettant le traitement de la fibrose kystique
CN107812003A (zh) * 2017-11-23 2018-03-20 南京市儿童医院 Vx‑809在制备治疗进行性家族性肝内胆汁淤积症药物中的应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) * 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP
US20080286204A1 (en) * 2007-05-09 2008-11-20 Hadida-Ruah Sara S Modulators of cftr
WO2008141119A2 (fr) * 2007-05-09 2008-11-20 Vertex Pharmaceuticals Incorporated Modulateurs de cftr
WO2009036412A1 (fr) * 2007-09-14 2009-03-19 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de la conductance transmembranaire de la mucoviscidose
WO2009108657A2 (fr) * 2008-02-28 2009-09-03 Vertex Pharmaceuticals Incorporated Dérivés hétéroaryles convenant comme modulateurs du cftr
WO2009123896A1 (fr) * 2008-03-31 2009-10-08 Vertex Pharmaceuticals Incorporated Dérivés de pyridyle en tant que modulateur du cftr
WO2014186704A2 (fr) * 2013-05-17 2014-11-20 N30 Pharmaceuticals, Inc. Nouveaux composés permettant le traitement de la fibrose kystique
CN107812003A (zh) * 2017-11-23 2018-03-20 南京市儿童医院 Vx‑809在制备治疗进行性家族性肝内胆汁淤积症药物中的应用

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