WO2022051568A1 - 4-pipéridinyl-pyrrolo[2,3-b]pyridines substituées et composés apparentés et leur utilisation dans le traitement d'états médicaux - Google Patents

4-pipéridinyl-pyrrolo[2,3-b]pyridines substituées et composés apparentés et leur utilisation dans le traitement d'états médicaux Download PDF

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WO2022051568A1
WO2022051568A1 PCT/US2021/048973 US2021048973W WO2022051568A1 WO 2022051568 A1 WO2022051568 A1 WO 2022051568A1 US 2021048973 W US2021048973 W US 2021048973W WO 2022051568 A1 WO2022051568 A1 WO 2022051568A1
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certain embodiments
alkyl
independently selected
haloalkyl
occurrence
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PCT/US2021/048973
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Dominic James REYNOLDS
Andrew Richard NOVAK
Louise Michelle BIRCH
Allan Michael Jordan
Craig Alex AVERY
Michael J. Burke
Alfredo C. Castro
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Ikena Oncology, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—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 substituted 4-piperidinyl-pyrrolo [2,3 -b]pyridines and related compounds, pharmaceutical compositions, their use for inhibiting ERK5 activity, and their use in the treatment of medical disorders, such as cancer.
  • Extracellular-signal-regulated kinase 5 also known as mitogen-activated protein kinase 7 (MAPK7) and Big MAPK1 (BMK1)
  • MAPK7 mitogen-activated protein kinase 7
  • BMK1 Big MAPK1
  • New compounds having inhibitory activity toward ERK5 are therefore needed as therapeutic agents for the treatment of medical disorders, such as cancer.
  • the present invention addresses the foregoing needs and provides other related advantages.
  • the invention provides substituted 4-piperidinyl-pyrrolo[2,3-b]pyridines and related compounds, pharmaceutical compositions, their use for inhibiting ERK5 activity, and their use in the treatment of medical disorders, such as cancer.
  • one aspect of the invention provides a collection of substituted 4-piperidinyl-pyrrolo[2,3-b]pyridines and related compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted 4-piperidinyl- pyrrolo[2,3-b]pyridines and related compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating a disorder mediated by ERK5 in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder, as further described in the detailed description.
  • Another aspect of the invention provides a method of inhibiting ERK5 activity.
  • the method comprises contacting ERK5 with an effective amount of a compound described herein, such as a compound of Formula I, to inhibit ERK5 activity, as further described in the detailed description.
  • Figure 1 depicts results of the 3D cancer cell culture assay described in Example 32.
  • Figure 2 depicts results of the mouse xenograft tumor growth assay with a pancreatic cancer cell line, as described in Example 33.
  • Figure 3 depicts results of the mouse xenograft tumor growth assay with a lung cancer cell line, as described in Example 33.
  • the invention provides substituted 4-piperidinyl-pyrrolo[2,3-b]pyridines and related compounds, pharmaceutical compositions, their use for inhibiting ERK5 activity, and their use in the treatment of medical disorders, such as cancer.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms, In some embodiments, “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.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a 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) or NR + (as in N-substituted pyrrolidinyl)).
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • the term “-(C 0 alkylene)-” refers to a bond. Accordingly, the term “-(C 0-3 alkylene)-” encompasses a bond (i.e., C 0 ) and a -(C 1-3 alkylene)- group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached to it (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g., The term
  • 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 quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a hetero aromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the hetero aromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H -quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “hetero aryl 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 hetero aryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • pyridinylene refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridinylene is a bivalent pyridine radical when it has two groups attached to it (e.g., “pyridinylene” is a trivalent pyridine radical when it has three groups attached to it (e.g.,
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihy dro-2H -pyrroly 1) , NH (as in pyrrolidinyl), or + NR (as in /V-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 an oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R * is C 1-6 aliphatic
  • R * is optionally substituted with halogen
  • each R ⁇ is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently -R ⁇ , -NR ⁇ 2 ,
  • each R ⁇ is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R ⁇ is C 1 6 aliphatic, R ⁇ is optionally substituted with halogen, -R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , - O(haloR ⁇ ), -CN, -C(O)OH
  • 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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as a 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, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3- methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2-methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1- butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl- 1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C 3 -C 6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH 2 F, -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 alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • Carbocyclylene refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, 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.
  • hydroxy alkoxyl refers to an alkoxyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkoxyl groups include -OCH 2 CH 2 OH, -OCH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkoxy lene refers to a bivalent alkoxyl group.
  • a cyclopentane susb situ ted with an oxo group is cyclopentanone.
  • the substituent may be attached at any available position on the ring.
  • the chemical structure encompasses and
  • the one or more substituent(s) may be independently attached to any of the rings crossed by the bond.
  • the chemical structure encompasses, for example,
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, includes humans.
  • mammals e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like
  • IC 50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. The potency of an inhibitor is usually defined by its IC 50 value. The lower the IC 50 value the greater the potency of the antagonist and the lower the concentration that is required to inhibit the maximum biological response.
  • an inhibitor has an IC 50 and/or binding constant of less than about 100 ⁇ , less than about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • inhibitor or “ERK5 inhibitor” or “ERK5 antagonist” are defined as a compound that binds to and/or inhibits ERK5 with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in ERK5 activity between a sample comprising a compound of the present invention, or composition thereof, and ERK5, and an equivalent sample comprising ERK5, in the absence of said compound, or composition thereof.
  • an effective amount refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result).
  • An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • treating includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g ., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed.
  • acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e ., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • the invention provides substituted 4-piperidinyl-pyrrolo [2,3 -b]pyridines and related compounds.
  • the compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds.
  • One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 0 - 3 alkylene group connecting said carbon atoms; or two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond; R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, C 1-4
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -C(O)N(R 7 )(R 8 ), or C 3-6 cycloalkyl; wherein said heterocyclyls and cycloalkyl is each substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-( C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-( C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, cyano, -S-(C 1-6 haloalkyl), -S-(C 1-6 alkyl), -S(O) 2 -(C 1-6 alkyl), - S(O) 2 N(R 4 )(R 5 ), -C(O)N(R 4 )(R 5 ), -N(R 4 )C(O)-( C 1-6 aliphatic), -N(R 4 )C(O)-(C 1-6 alkoxy), - N(R 4 )-( C
  • X is -C(O)-, -S(O)-, or -S(O) 2 -;
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic saturated heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 ; n is 1 or 2; m, q, and p are each independently 0, 1, 2, or 3; and t is 0 or 1.
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 0 - 3 alkylene group connecting said carbon atoms; or two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; or two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 0-3 alkylene group connecting said carbon atoms.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ).
  • two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, or -(C 1-4 alkoxylene)-N(R 4 )(R 5 ). In certain embodiments, R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 1 is hydroxyl. In certain embodiments, R 1 is hydroxyl attached at the 4-position of the piperidine ring. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 1 is trifluoromethyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 1 is -CH 2 OH. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 1 is methoxy.
  • R 1 represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 1 is -OCF 3 . In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkoxyl. In certain embodiments, R 1 represents independently for each occurrence -( C 1-4 alkoxy lene) -N(R 4 ) (R 5 ) . In certain embodiments, R 1 represents independently for each occurrence halo. In certain embodiments, R 1 is fluoro. In certain embodiments, R 1 represents independently for each occurrence -N(R 4 )(R 5 ).
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 0 - 3 alky lene group connecting said carbon atoms. In certain embodiments, two occurrences of R 1 attached to different carbon atoms are taken together to form a bond connecting said carbon atoms. In certain embodiments, two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alky lene group connecting said carbon atoms.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl.
  • R 1 is selected from the groups depicted in the compounds in
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or - N(R 4 )(R 5 ).
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ).
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, halo, or cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, or halo. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, halo, or cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or halo. In certain embodiments, R 2A represents independently for each occurrence halo or cyano.
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 2A represents independently for each occurrence halo, cyano, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence halo, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl.
  • R 2A represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 2A is trifluoromethyl. In certain embodiments, R 2A represents independently for each occurrence halo. In certain embodiments, R 2A is fluoro. In certain embodiments, one instance of R 2A is fluoro attached at the 5 -position of the pyrrolo [2,3 -b]pyridine ring. In certain embodiments, R 2A is cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 hydroxyalkyl.
  • R 2A is -CH 2 OH. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 2A is methoxy. In certain embodiments, R 2A represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 2A is -OCF 3 . In certain embodiments, R 2A represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 2A is -NH 2 . In certain embodiments, R 2A is selected from the groups depicted in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -C(O)N(R 7 )(R 8 ), or C 3-6 cycloalkyl; wherein said heterocyclyls and cycloalkyl is each substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or C 3-6 cycloalkyl; wherein said heterocyclyl and cycloalkyl is each substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyls are each substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7- 10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyls are each substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alkylene)-( C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- 6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, o
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)- (C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, - (C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is morpholinyl substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alky lene)-( C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is morpholin-2-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is morpholin- 2-yl.
  • R 2B is piperidinyl substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alkylene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is 1- methylpiperidin-4-yl.
  • R 2B is piperazinyl substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is piperazin-1-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is 4- methylpiperazin- 1 -yl.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 7-10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -(C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • R 2B is a 7- 10 membered saturated bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 7-10 membered saturated spiro-bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is an 8-membered saturated spiro-bicyclic heterocyclyl which is a cyclopropyl ring spiro-fused to morpholin-2-yl.
  • R 2B is a 7-10 membered saturated bridged bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is -C(O)N(R 7 )(R 8 ).
  • R 2B is C 3-6 cycloalkyl substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, - (C 0-4 alky lene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-CO 2 H, -N(R 4 )(R 5 ), -S(O) 2 -(C 1-4 alkyl), and halo.
  • R 2B is C 3-6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is C 3-6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is C 3-6 cycloalkyl. In certain embodiments, R 2B is cyclopropyl.
  • R 2B is selected from the groups depicted in the compounds in
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl.
  • R 3 is methyl. In certain embodiments, R 3 is C 3-5 cycloalkyl. In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 4 is selected from the groups depicted in the compounds in
  • R 5 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 5 is selected from the groups depicted in the compounds in
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 are hydrogen. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 3-5 cycloalkyl.
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, cyano, -S-(C 1-6 haloalkyl), -S- (C1-6 alkyl), -S(O) 2 -(C 1-6 alkyl), -S(O) 2 N(R 4 )(R 5 ), -C(O)N(R 4 )(R 5 ), -N(R 4 )C(O)-(C 1-6 aliphatic), - N(R 4 )C(O)-(C 1-6 alkoxy), -N(R 4 )C(O)-
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl); or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2,
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), C 1-6 alkyl, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), or C 1-6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, -N(R 4 )(R 5 ), C 1-6 haloalkyl, or halo. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl or -N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence -OCF 3 , -NH 2 , -CF 3 , fluoro, or chloro. In certain embodiments, R 6 represents independently for each occurrence -OCF 3 or - NH 2 .
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S- (C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)- (C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ) or halo.
  • one occurrence of R 6 is C 1-4 haloalkoxyl, C 1-4 haloalkyl, -S-(C 1-4 haloalkyl), or -O-(C 3 - 4 cycloalkyl), and any further occurrences of R 6 are -Nth.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , -SCF 3 , or -O- (cyclopropyl), and any further occurrences of R 6 are independently -Nth, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -Nth, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -Nth.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ), halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1 - 6 haloalkyl) or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 hydroxyalkyl.
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0131] In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 6 is -OCF 3 . In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl).
  • R 6 represents independently for each occurrence -O-(C 1-4 alkylene)-(C 3-4 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -O-(C 3-4 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 6 is -Nth. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence C 2-6 alkenyl. In certain embodiments, R 6 represents independently for each occurrence C 2-6 alkynyl. In certain embodiments, R 6 represents independently for each occurrence halo. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 haloalkyl).
  • R 6 is -S-CF 3 . In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 alkyl). In certain embodiments, R 6 represents independently for each occurrence -S(O) 2 -(C 1-6 alkyl).
  • R 6 represents independently for each occurrence - S(O) 2 N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence - C(O)N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence - N(R 4 )C(O)-(C 1-6 aliphatic). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )C(O)-(C 1-6 alkoxy). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )-(C 1-6 hydroxy alkoxyl). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )S(O) 2 -(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl. In certain embodiments, R 6 is phenyl. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • R 6 is selected from the groups depicted in the compounds in
  • R 7 and R 8 each represent independently hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom and optionally one additional heteroatom selected from nitrogen and oxygen, wherein said ring is optionally substituted with one C 1-4 alkyl.
  • R 7 and R 8 each represent independently hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 7 and R 8 each represent independently hydrogen or C 1-4 alkyl.
  • R 7 and R 8 each represent independently hydrogen or methyl.
  • R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom and optionally one additional heteroatom selected from nitrogen and oxygen, wherein said ring is optionally substituted with one C 1-4 alkyl.
  • R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom and one additional heteroatom selected from nitrogen and oxygen, wherein said ring is optionally substituted with one C 1-4 alkyl.
  • R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom.
  • R 7 and R 8 are selected from the groups depicted in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • X is -C(O)-, -S(O)-, or -S(O) 2 -. In certain embodiments, X is -C(O)-. In certain embodiments, X is -S(O)- or -S(O) 2 -. In certain embodiments, X is - S(O)-. In certain embodiments, X is -S(O) 2 -. In certain embodiments, X is selected from the groups depicted in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic saturated heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1
  • a 1 is In certain embodiments, A 1 is or In certain embodiments, A 1 i In certain embodiments, A 1 is , or [0147] In certain embodiments, A 1 i In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo- heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6- membered monocyclic partially unsaturated oxo-heterocyclyl having 1 or 2 nitrogen atoms; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is pyridin-2(1H )-on-3-yl substituted with m occurrences of R 6 .
  • a 1 is a 5-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is In certain embodiments, A 1 is [0149] In certain embodiments, A 1 is In certain embodiments, A 1 In certain embodiments, A 1 In certain embodiments, A 1 in certain embodiments, A 1
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is naphthyl substituted with m occurrences of R 6 .
  • a 1 is an 5-6 membered monocyclic saturated heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following
  • a 1 is one of the following:
  • a 1 is one of the following:
  • a 1 is one of the following: [0156] In certain embodiments, A 1 is one of the following:
  • a 1 is selected from the groups depicted in the compounds in
  • n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is selected from the values represented in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.
  • m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values represented in the compounds in Tables 1, 1- A, 1-B, 2, 3, and 3-A, below.
  • q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 2 or 3. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 1, 2, or 3. In certain embodiments, q is selected from the values represented in the compounds in Tables 1, 1- A, 1-B, 2, 3, and 3-A, below.
  • t is 0 or 1. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is selected from the values represented in the compounds in Tables 1, 1-A, 1-B, 2, 3, and 3-A, below.
  • One aspect of the invention provides a compound represented by Formula I*: or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; or two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond;
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 );
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or C 3-6 cycloalkyl; wherein said heterocyclyl and cycloalkyl is each substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, cyano, -S-(C 1-6 haloalkyl), -S-(C 1-6 alkyl), -S(O) 2 -(C 1-6 alkyl), - S(O) 2 N(R 4 )(R 5 ), -C(O)N(R 4 )(R 5 ), -N(R 4 )C(O)-(C 1-6 aliphatic), -N(R 4 )C(O)-(C 1-6 alkoxy), - N(R 4 )-(C
  • X is -C(O)-, -S(O)-, or -S(O) 2 -;
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 ; n is 1 or 2; m, q, and p are each independently 0, 1, 2, or 3; and t is 0 or 1.
  • variables in Formula I* above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I*.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1 - 3 alkylene group connecting said carbon atoms; or two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ).
  • two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • two occurrences of R 1 attached to adjacent carbon atoms are taken together with said carbon atoms to form a carbon-carbon double bond.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, or -(C 1-4 alkoxylene)-N(R 4 )(R 5 ). In certain embodiments, R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 1 is hydroxyl. In certain embodiments, R 1 is hydroxyl attached at the 4-position of the piperidine ring. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 1 is trifluoromethyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 1 is -CH 2 OH. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 1 is methoxy.
  • R 1 represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 1 is -OCF 3 . In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkoxyl. In certain embodiments, R 1 represents independently for each occurrence -(C 1-4 alkoxylene)-N(R 4 )(R 5 ). In certain embodiments, R 1 represents independently for each occurrence halo. In certain embodiments, R 1 is fluoro. In certain embodiments, R 1 represents independently for each occurrence -N(R 4 )(R 5 ).
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is hydroxyl.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms; and any additional occurrence of R 1 is C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl.
  • R 1 is selected from the groups depicted in the compounds in Tables 1, 1-A, 2, and 3, below.
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or - N(R 4 )(R 5 ).
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). [0179] In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, halo, or cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, or halo.
  • R 2A represents independently for each occurrence C 1-4 alkyl, halo, or cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or halo. In certain embodiments, R 2A represents independently for each occurrence halo or cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 2A represents independently for each occurrence halo, cyano, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence halo, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl.
  • R 2A represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 2A is trifluoromethyl. In certain embodiments, R 2A represents independently for each occurrence halo. In certain embodiments, R 2A is fluoro. In certain embodiments, one instance of R 2A is fluoro attached at the 5 -position of the pyrrolo [2,3 -b]pyridine ring. In certain embodiments, R 2A is cyano. In certain embodiments, R 2A represents independently for each occurrence C 1-4 hydroxyalkyl.
  • R 2A is -CH 2 OH. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 2A is methoxy. In certain embodiments, R 2A represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 2A is -OCF 3 . In certain embodiments, R 2A represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 2A is -NH 2 . In certain embodiments, R 2A is selected from the groups depicted in the compounds in Tables 1, 1-A, 2, and 3, below.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or C 3-6 cycloalkyl; wherein said heterocyclyl and cycloalkyl is each substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- 6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, o
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is morpholin-2-yl.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is l-methylpiperidin-4-yl.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is piperazin-1-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is 4-methylpiperazin-1-yl.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is C 3-6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is C 3-6 cycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is C 3-6 cycloalkyl. In certain embodiments, R 2B is cyclopropyl.
  • R 2B is selected from the groups depicted in the compounds in
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl.
  • R 3 is methyl. In certain embodiments, R 3 is C 3-5 cycloalkyl. In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Tables 1, 1-A, 2, and 3, below.
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 4 is selected from the groups depicted in the compounds in Tables 1, 1-A, 2, and 3, below.
  • R 5 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 5 is selected from the groups depicted in the compounds in
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 are hydrogen. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 3-5 cycloalkyl.
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, cyano, -S-(C 1-6 haloalkyl), -S- (C1-6 alkyl), -S(O) 2 -(C 1-6 alkyl), -S(O) 2 N(R 4 )(R 5 ), -C(O)N(R 4 )(R 5 ), -N(R 4 )C(O)-(C 1-6 aliphatic), - N(R 4 )C(O)-(C 1-6 alkoxy), -N(R 4 )C(O)-
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl); or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1 -6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1,
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), C 1-6 alkyl, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), or C 1-6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, -N(R 4 )(R 5 ), C 1-6 haloalkyl, or halo. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl or -N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence -OCF 3 , -Nth, -CF 3 , fluoro, or chloro. In certain embodiments, R 6 represents independently for each occurrence -OCF 3 or - NH 2 .
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S- (C 1 - 6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)- (C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ) or halo.
  • one occurrence of R 6 is C 1-4 haloalkoxyl, C 1-4 haloalkyl, -S-(C 1-4 haloalkyl), or -O-(C 3 - 4 cycloalkyl), and any further occurrences of R 6 are -NH 2 .
  • one occurrence of R 6 is -OCF 3 , -CF 3 , -SCF 3 , or -O- (cyclopropyl), and any further occurrences of R 6 are independently -NFh, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -NFh, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -NH 2 .
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ), halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1 - 6 haloalkyl) or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 hydroxyalkyl.
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 6 is -OCF 3 . In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -O-(C 1-4 alkylene)-(C 3-4 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -O-(C 3 - 4 cycloalkyl).
  • R 6 represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 6 is -Nth. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence C 2-6 alkenyl. In certain embodiments, R 6 represents independently for each occurrence C 2-6 alkynyl. In certain embodiments, R 6 represents independently for each occurrence halo. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 haloalkyl).
  • R 6 is -S-CF 3 . In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 alkyl). In certain embodiments, R 6 represents independently for each occurrence -S(O) 2 -(C 1-6 alkyl).
  • R 6 represents independently for each occurrence - S(O) 2 N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence - C(O)N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence - N(R 4 )C(O)-(C 1-6 aliphatic). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )C(O)-(C 1-6 alkoxy). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )-(C 1-6 hydroxyalkoxyl). In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )S(O) 2 -(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl. In certain embodiments, R 6 is phenyl. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • R 6 is selected from the groups depicted in the compounds in
  • X is -C(O)-, -S(O)-, or -S(O) 2 -. In certain embodiments, X is -C(O)-. In certain embodiments, X is -S(O)- or -S(O) 2 -. In certain embodiments, X is - S(O)-. In certain embodiments, X is -S(O) 2 -. In certain embodiments, X is selected from the groups depicted in the compounds in Tables 1, 1-A, 2, and 3, below.
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments,
  • a 1 is In certain embodiments, A 1 is In certain embodiments,
  • a 1 is [0225] In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is or in certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo- heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6- membered monocyclic partially unsaturated oxo-heterocyclyl having 1 or 2 nitrogen atoms; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is pyridin-2(1H )-on-3-yl substituted with m occurrences of R 6 .
  • a 1 is a 5-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is or
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is naphthyl substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is one of the following
  • a 1 is one of the following:
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following: [0234] In certain embodiments, A 1 is one of the following:
  • a 1 is one of the following: [0236] In certain embodiments, A 1 is selected from the groups depicted in the compounds in
  • n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is selected from the values represented in the compounds in Tables 1, 1-A, 2, and 3, below.
  • n 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.
  • m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Tables 1, 1-A, 2, and 3, below.
  • p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values represented in the compounds in Tables 1, 1- A, 2, and 3, below.
  • q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 2 or 3. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 1, 2, or 3. In certain embodiments, q is selected from the values represented in the compounds in Tables 1, 1- A, 2, and 3, below.
  • t is 0 or 1. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is selected from the values represented in the compounds in Tables 1, 1-A, 2, and 3, below.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms;
  • R 2A represents independently for each occurrence C 1-4 alkyl or halo
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)- (C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -
  • R 3 is hydrogen or C 1-4 alkyl
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl); or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl;
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 ; m and q are each independently 0, 1, 2, or 3; and p is 0, 1, or 2.
  • variables in Formula I-A 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-A.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl; or two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms.
  • two occurrences of R 1 attached to different carbon atoms are taken together to form a C 1-3 alkylene group connecting said carbon atoms.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 1 is hydroxyl. In certain embodiments, R 1 is hydroxyl attached at the 4-position of the piperidine ring. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 1 is trifluoromethyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 1 is -CH 2 OH. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 1 is methoxy. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 1 is -OCF 3 .
  • R 2A represents independently for each occurrence C 1-4 alkyl or halo. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A represents independently for each occurrence halo. In certain embodiments, R 2A is fluoro. In certain embodiments, one instance of R 2A is fluoro attached at the 5 -position of the pyrrolo[2,3- b]pyridine ring.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- 6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo; and wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, o
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is morpholin-2-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is morpholin-2-yl.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is 1 -methylpiperidin-4-yl.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), oxo, hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, and halo. In certain embodiments, R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is piperazin-1-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is 4-methylpiperazin- 1 -yl.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, - C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, -C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 haloalkyl), -C(O)-(C 3-5 cycloalkyl), hydroxyl, -N(R 4 )(R 5 ), and halo.
  • R 2B is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is pyrazolyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, wherein said heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is methyl.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl. [0264] In certain embodiments, R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 and R 5 are hydrogen. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl.
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl); or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), C 1-6 alkyl, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), or C 1-6 alkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, -N(R 4 )(R 5 ), C 1-6 haloalkyl, or halo. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl or -N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence -OCF 3 , -NH 2 , -CF 3 , fluoro, or chloro. In certain embodiments, R 6 represents independently for each occurrence -OCF 3 or - Nth.
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S- (C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)- (C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • one occurrence of R 6 is C 1-6 haloalkoxyl, C 1-6 haloalkyl, -S-(C 1-6 haloalkyl), or -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), and any further occurrences of R 6 represent independently for each occurrence -N(R 4 )(R 5 ) or halo.
  • one occurrence of R 6 is C 1-4 haloalkoxyl, C 1-4 haloalkyl, -S-(C 1-4 haloalkyl), or -O-(C 3 - 4 cycloalkyl), and any further occurrences of R 6 are -Nth.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , -SCF 3 , or -O- (cyclopropyl), and any further occurrences of R 6 are independently -Nth, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -Nth, -F, or -Cl.
  • one occurrence of R 6 is -OCF 3 , -CF 3 , or -O-(cyclopropyl), and any further occurrences of R 6 are independently -Nth.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), -N(R 4 )(R 5 ), hydroxyl, halo, cyano, -S-(C 1-6 haloalkyl), or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, halo, or cyano.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl), or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ), halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1 - 6 haloalkyl) or -S-(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 1-6 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 6 is -OCF 3 . In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence -O-(C 0-4 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -O-(C 1-4 alkylene)-(C 3-4 cycloalkyl). In certain embodiments, R 6 represents independently for each occurrence -O-( C 3-4 cycloalkyl).
  • R 6 represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 6 is -Nth. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl.
  • R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence halo. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 haloalkyl). In certain embodiments, R 6 is -S-CF 3 . In certain embodiments, R 6 represents independently for each occurrence -S-(C 1-6 alkyl).
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments, A 1 i In certain embodiments, A 1 is In certain embodiments,
  • a 1 is In certain embodiments, A 1 is In certain embodiments,
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is in certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo- heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6- membered monocyclic partially unsaturated oxo-heterocyclyl having 1 or 2 nitrogen atoms; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is pyridin-2(1H )-on-3-yl substituted with m occurrences of R 6 .
  • a 1 is a 5-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is In certain embodiments, A 1 i In certain embodiments, A 1 is or
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is one of the following In
  • a 1 is one of the following:
  • a 1 is one of the following:
  • a 1 is one of the following
  • a 1 is one of the following:
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is
  • p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2.
  • q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 2 or 3. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 1, 2, or 3.
  • One aspect of the invention provides a compound represented by Formula I- 1 : or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring;
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 );
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo;
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from
  • X is -C(O)-, -S(O)-, or -S(O) 2 -;
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 ; n is 1 or 2; m and q are each independently 0, 1, 2, or 3; p is 0, 1, or 2; and t is 0 or 1.
  • variables in Formula 1- 1 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 1-1.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ); or two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, -(C 1-4 alkoxylene)-N(R 4 )(R 5 ), halo, or -N(R 4 )(R 5 ).
  • two occurrences of R 1 attached to the same carbon atom are taken together with said carbon atom to form a cyclopropyl ring.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, C 1-4 hydroxyalkoxyl, or -(C 1-4 alkoxylene)-N(R 4 )(R 5 ). In certain embodiments, R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl. [0300] In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 1 is hydroxyl. In certain embodiments, R 1 is hydroxyl attached at the 4-position of the piperidine ring. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 1 is trifluoromethyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 1 is -CH 2 OH. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 1 is methoxy.
  • R 1 represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 1 is -OCF 3 . In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkoxyl. In certain embodiments, R 1 represents independently for each occurrence -(C 1-4 alkoxylene)-N(R 4 )(R 5 ). In certain embodiments, R 1 represents independently for each occurrence halo. In certain embodiments, R 1 is fluoro. In certain embodiments, R 1 represents independently for each occurrence -N(R 4 )(R 5 ).
  • R 1 is selected from the groups depicted in the compounds in
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, halo, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ).
  • R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, or halo. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or halo. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 2A represents independently for each occurrence halo, C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl, C 1-4 haloalkoxyl, or -N(R 4 )(R 5 ). In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl. [0306] In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 2A is methyl.
  • R 2A represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 2A is trifluoromethyl. In certain embodiments, R 2A represents independently for each occurrence halo. In certain embodiments, R 2A is fluoro. In certain embodiments, one instance of R 2A is fluoro attached at the 5 -position of the pyrrolo [2,3 -b]pyridine ring. In certain embodiments, R 2A represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 2A is -CH 2 OH. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 2A is methoxy. In certain embodiments, R 2A represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 2A is -OCF 3 . In certain embodiments,
  • R 2A represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 2A is - NH 2 . In certain embodiments, R 2A is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • R 2B is a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is a 5-6 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein said heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is morpholinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo. In certain embodiments, R 2B is morpholin-2-yl.
  • R 2B is piperidinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is piperidin-4-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is 1 -methylpiperidin-4-yl.
  • R 2B is piperazinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is piperazin-1-yl substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halo.
  • R 2B is 4-methylpiperazin- 1 -yl.
  • R 2B is selected from the groups depicted in the compounds in
  • R 3 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl.
  • R 3 is methyl. In certain embodiments, R 3 is C 3-5 cycloalkyl. In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl. In certain embodiments, R 4 and R 5 are hydrogen. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 and R 5 each represent independently for each occurrence C 3-5 cycloalkyl.
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom. [0317] In certain embodiments, R 4 and R 5 are selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl.
  • R 4 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl.
  • R 4 is hydrogen.
  • R 4 represents independently for each occurrence C 1-4 alkyl.
  • R 4 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 4 is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 5 represents independently for each occurrence hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl.
  • R 5 represents independently for each occurrence C 1-4 alkyl or C 3-5 cycloalkyl.
  • R 5 is hydrogen.
  • R 5 represents independently for each occurrence C 1-4 alkyl.
  • R 5 represents independently for each occurrence C 3-5 cycloalkyl.
  • R 5 is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2,
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), or C 1-6 alkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, -N(R 4 )(R 5 ), C 1-6 haloalkyl, or halo. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl or - N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence -OCF 3 , - NH 2 , -CF 3 , fluoro, or chloro. In certain embodiments, R 6 represents independently for each occurrence -OCF 3 or -NH 2 .
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, cyano, -S(O) 2 -(C 1-6 alkyl), C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ), halo, or cyano.
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl, phenyl, or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 6 is -OCF 3 . In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 6 is -Nth. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl. In certain embodiments, R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkyl.
  • R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence halo. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 represents independently for each occurrence -S(O) 2 -(C 1-6 alkyl).
  • R 6 represents independently for each occurrence C 3-6 cycloalkyl. In certain embodiments, R 6 is phenyl. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 6 represents independently for each occurrence a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, and oxo.
  • R 6 is selected from the groups depicted in the compounds in
  • X is -C(O)-, -S(O)-, or -S(O) 2 -. In certain embodiments, X is -C(O)-. In certain embodiments, X is -S(O)- or -S(O) 2 -. In certain embodiments, X is - S(O)-. In certain embodiments, X is -S(O) 2 -. In certain embodiments, X is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below.
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is or In certain embodiments,
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic partially unsaturated oxo- heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo- heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is a 6- membered monocyclic partially unsaturated oxo-heterocyclyl having 1 or 2 nitrogen atoms; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is pyridin-2(1H )-on-3 -yl substituted with m occurrences of R 6 .
  • a 1 is a 5-membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said oxo-heterocyclyl is substituted with m occurrences of R 6 .
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is or In certain embodiments, A 1 is In certain embodiments, A 1 is or In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is naphthyl substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic partially unsaturated oxo-heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following:
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following:
  • a 1 is one of the following:
  • a 1 is one of the following:
  • a 1 is selected from the groups depicted in the compounds in
  • n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is selected from the values represented in the compounds in Tables 1, 2, and 3, below.
  • m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.
  • m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Tables 1, 2, and 3, below.
  • p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is selected from the values represented in the compounds in Tables 1, 2, and 3, below.
  • q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 2 or 3. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 1, 2, or 3. In certain embodiments, q is selected from the values represented in the compounds in Tables 1, 2, and 3, below.
  • t is 0 or 1. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is selected from the values represented in the compounds in Tables 1, 2, and 3, below.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl;
  • R 2A represents independently for each occurrence C 1-4 alkyl or halo
  • R 3 is hydrogen or C 1-4 alkyl
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom;
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, - N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl;
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 ; m and q are each independently 0, 1, 2, or 3; and p is 0, 1, or 2.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above
  • the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above
  • the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I-Al.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl.
  • R 1 represents independently for each occurrence hydroxyl, C 1-4 alkoxyl, or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl or C 1-4 haloalkoxyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl or C 1-4 haloalkyl.
  • R 1 is hydroxyl. In certain embodiments, R 1 is hydroxyl attached at the 4-position of the piperidine ring. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkyl. In certain embodiments, R 1 is trifluoromethyl. In certain embodiments, R 1 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 1 is -CFhOH. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkoxyl. In certain embodiments, R 1 is methoxy. In certain embodiments, R 1 represents independently for each occurrence C 1-4 haloalkoxyl. In certain embodiments, R 1 is -OCF 3 .
  • R 1 is selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 2A represents independently for each occurrence C 1-4 alkyl or halo. In certain embodiments, R 2A represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A represents independently for each occurrence halo. In certain embodiments, R 2A is fluoro. In certain embodiments, one instance of R 2A is fluoro attached at the 5 -position of the pyrrolo[2,3- b] pyridine ring. In certain embodiments, R 2A is selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl; or R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom.
  • R 4 and R 5 each represent independently for each occurrence hydrogen or C 1-4 alkyl.
  • R 4 and R 5 are hydrogen.
  • R 4 and R 5 each represent independently for each occurrence C 1-4 alkyl.
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring having one nitrogen atom. In certain embodiments, R 4 and R 5 are selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 4 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 5 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Tables 1 and 2, below.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano; or two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), or C 1-6 alkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, -N(R 4 )(R 5 ), C 1-6 haloalkyl, or halo. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl or - N(R 4 )(R 5 ). In certain embodiments, R 6 represents independently for each occurrence -OCF 3 , - Nth, -CF 3 , fluoro, or chloro. In certain embodiments, R 6 represents independently for each occurrence -OCF 3 or -Nth.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, -N(R 4 )(R 5 ), hydroxyl, halo, or cyano. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkoxyl, C 1-6 alkoxyl, or hydroxyl. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ), halo, or cyano.
  • R 6 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl or C 1-6 haloalkyl.
  • R 6 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 6 is -OCF 3 . In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 6 is methoxy. In certain embodiments, R 6 represents independently for each occurrence -N(R 4 )(R 5 ). In certain embodiments, R 6 is -Nth. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 alkyl. In certain embodiments, R 6 is methyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 haloalkyl.
  • R 6 is trifluoromethyl. In certain embodiments, R 6 represents independently for each occurrence C 1-6 hydroxyalkyl. In certain embodiments, R 6 represents independently for each occurrence halo. In certain embodiments, R 6 is fluoro. In certain embodiments, R 6 is cyano.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 haloalkyl.
  • two occurrences of R 6 are taken together with the intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 0, 1, or 2 heteroatoms independently selected from nitrogen and oxygen, wherein said ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl.
  • R 6 is selected from the groups depicted in the compounds in
  • a 1 is phenyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- 10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with m occurrences of R 6 .
  • a 1 is phenyl substituted with m occurrences of R 6 . In certain embodiments, A 1 is In certain embodiments,
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is
  • a 1 is a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 5 -membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms; which is substituted with m occurrences of R 6 .
  • a 1 is an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is substituted with m occurrences of R 6 .
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following:
  • a 1 is one of the following: In certain embodiments, A 1 is one of the following:
  • a 1 is one of the following
  • a 1 is selected from the groups depicted in the compounds in
  • n is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.
  • m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values represented in the compounds in Tables 1 and 2, below.
  • p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is selected from the values represented in the compounds in Tables 1 and 2, below.
  • q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 2 or 3. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 1, 2, or 3. In certain embodiments, q is selected from the values represented in the compounds in Tables 1 and
  • the compound is a compound in Table 1, 1-A, 1-B, 1-C, 2, 3, or 3- A below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1, 1-A, 1-B, 1-C, 2, 3, or 3-A, below.
  • the compound is a compound in Table 1, 1-A, 1-B, 2, 3, or 3-A below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1, 1-A, 1-B, 2, 3, or 3-A, below.
  • the compound is a compound in Table 1, 1-A, 2, or 3 below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1, 1-A, 2, or 3, below.
  • the compound is a compound in Table 1, 2, or 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, or 3, below. In certain embodiments, the compound is a compound in Table 1 or 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 2 below.
  • the compound is a compound in Table 1, 1-A, 1-B, or 1-C below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 1-A, 1-B, or 1-C below. In certain embodiments, the compound is a compound in Table 1, 1-A, or 1-B below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 1-A, or 1-B below. In certain embodiments, the compound is a compound in Table 1 or 1-A below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 1-A below. In certain embodiments, the compound is a compound in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 below. TABLE 1.
  • Compounds may be further characterized according to their inhibitory activity against ERK5.
  • a preferred compound has an IC 50 less than 2 ⁇ against ERK5.
  • a more preferred compound has an IC 50 less than 0.5 ⁇ against ERK5.
  • an even more preferred compound has an IC 50 less than or equal to 0.05 ⁇ against ERK5.
  • the alkene functional group in the coupling product of bicyclic heteroaryl A with cyclic metal reagent B can be oxidized, instead of reduced, to afford, for example, an alcohol (using, for example, Mukaiyama hydration conditions) or a 1,2-diol (using, for example, OsO 4 and a stoichiometric oxidant, such as NMO).
  • the resulting alcohol(s) can be further functionalized, for example, by alkylation (using, for example, a base, such as NaH, and an electrophile, such as an alkyl halide).
  • one aspect of the invention provides a method of treating a disorder mediated by ERK5 in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder.
  • the particular compound of Formula I, I*, I-A, 1-1, or I-Al is a compound defined by one of the embodiments described above.
  • the provided compounds are inhibitors of ERK5 and are therefore useful for treating one or more disorders associated with activity of ERK5.
  • the present invention provides a method for treating an ERK5 -mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • ERK5 -mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which ERK5, or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which ERK5, or a variant or mutant thereof, are known to play a role.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with increased ERK5 expression and/or increased ERK5 activity, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of ERK5 activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • inhibitor compounds described herein are believed to bind to and inhibit ERK5, leading to reduced translocation of ERK5 to the cell’s nucleus and/or reduction of ERK5 -mediated gene transcription in the nucleus.
  • the mitogen- activated protein kinases are a group of proteins able to translate environmental signals elicited by a plethora of stimuli, including growth factors and stresses, into different biological responses such as survival, apoptosis, proliferation, migration, and differentiation.
  • MAPK MAPK-associated autosomal protein kinase kinase
  • diseases including Parkinson’s disease, inflammatory disorders, and cancer
  • MAPK enzymes Braicu, C. et al. Cancers (2019) Cancers (Basel). 11(10): 1618).
  • Extracellular signal-regulated kinase 5 (ERK5, also known as Big MAPK 1, BMK1) is a member of this family, and consists of an amino-terminal kinase domain, with a relatively large carboxy- terminus of unique structure and function that makes it distinct from other MAPK members (Drew et al. Biochim. Biophys. Acta (2012) 1825(1): 37-48).
  • cytosolic ERK5 In unstimulated cells and/or in the absence of oncogenic stimuli, cytosolic ERK5 is believed to be in an unpho sphory lated inactive folded form, such that the Nuclear localization Sequence (NLS) is hidden and nuclear translocation is prevented. After stimulus, ERK5 is thought to be activated through a MEK5-dependent phosphorylation at the Thr-Glu-Tyr (TEY) motif of ERK5. This phosphorylation can initiate the ERK5 kinase activity, which can pho sphory late itself in the C-terminus.
  • NLS Nuclear localization Sequence
  • TEY Thr-Glu-Tyr
  • ERK5 is understood to assume an open conformation, exposing the NLS sequence that allows ERK5 nuclear translocation. Once in the nucleus, ERK5 is reported to enhance gene transcription either by pho sphory lating transcription factors or, in a kinase-independent manner, by interacting with transcription factors through the transactivation domain (TAD) domain (Tubita el al. (2020) Int. J. Mol. Sci. 21(3), 938). In stimulated cells and/or in the presence of oncogenic stimuli or in response to several targeted therapies, ERK5 is believed to promote tumor growth by, for example, sustaining proliferative signals and evading growth suppressors.
  • TAD transactivation domain
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, an ERK5 inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • the cellular proliferative disorder is cancer.
  • the cancer is characterized by increased ERK5 expression and/or increased ERK5 activity, i.e., “increased activated ERK5.”
  • the cancer is characterized by ERK5 genomic amplification and/or constitutively active ERK5 signaling.
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3- fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10- fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms "increased expression” and/or “increased activity" of a substance, such as ERK5, in a sample or cancer or patient refers to an increase in the amount of the substance, such as ERK5, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3 -fold, about 4-fold, about 5-fold, about 6- fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of the substance, such as ERK5, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (
  • a subject can also be determined to have an "increased expression” or “increased activity” of ERK5 if the expression and/or activity of ERK5 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of ERK5 in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis, as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • the disorder is cancer.
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor.
  • a cancer is treated by inhibiting or reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
  • the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer.
  • NSCLC non-small cell lung cancer
  • pancreatic cancer pancreatic cancer
  • colorectal cancer colorectal cancer
  • the cancer is non- small cell lung cancer (NSCLC).
  • NSCLC non- small cell lung cancer
  • the cancer is a pancreatic cancer, such as an adenocarcinoma.
  • the cancer is colorectal cancer (CRC).
  • the cancer is a breast cancer, such as ductal breast carcinoma.
  • the cancer is an ovarian cancer.
  • the cancer is a brain cancer, such as glioblastoma.
  • the cancer is a kidney cancer.
  • the cancer is a solid tumor. In certain embodiments, the cancer is a melanoma, carcinoma, or blastoma. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is an adenocarcinoma. In certain embodiments, the cancer is a blastoma.
  • the cancer is breast cancer, lung cancer, pancreatic cancer, cervical cancer, colorectal cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, or nervous system cancer.
  • the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is cervical cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer is gastric cancer.
  • the cancer is skin cancer.
  • the cancer is liver cancer.
  • the cancer is bile duct cancer.
  • the cancer is nervous system cancer.
  • the cancer is breast adenocarcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, prostate adenocarcinoma, gastric adenocarcinoma, melanoma, lung squamous cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, or neuroblastoma.
  • the cancer is breast adenocarcinoma.
  • the cancer is lung adenocarcinoma.
  • the cancer is pancreatic adenocarcinoma.
  • the cancer is cervical adenocarcinoma.
  • the cancer is prostate adenocarcinoma.
  • the cancer is gastric adenocarcinoma.
  • the cancer is melanoma.
  • the cancer is lung squamous cell carcinoma, hepatocellular carcinoma, or cholangiocarcinoma. In certain embodiments, the cancer is lung squamous cell carcinoma. In certain embodiments, the cancer is hepatocellular carcinoma. In certain embodiments, the cancer is cholangiocarcinoma. [0411] In certain embodiments, the cancer is glioblastoma or neuroblastoma. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma.
  • the cancer is lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer.
  • the cancer has elevated ERK5 activity. In certain embodiments, the cancer overexpresses ERK5. In certain embodiments, the cancer has genomically amplified ERK5. In certain embodiments, the cancer has constitutively active ERK5 signaling.
  • the cancer is a KRAS mutant cancer.
  • the KRAS mutant cancer harbors the KRAS G12C mutation.
  • the KRAS mutant cancer harbors the KRAS G12D mutation.
  • the KRAS mutant cancer harbors the KRAS G12V mutation.
  • the KRAS mutant cancer harbors the KRAS G13 mutation.
  • the KRAS mutant cancer harbors one or more KRAS mutations selected from a KRAS G12C, a KRAS G12D mutation, a KRAS G12V mutation, and a KRAS G13 mutation.
  • the cancer is a KRAS mutant lung cancer.
  • the cancer is a leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, or a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, lipo sarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcom
  • a leukemia
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - G
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (IP A), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the cancer is mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphoc
  • the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, gastrointestinal/stomach (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST),
  • MPNST neurofibromat
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian epithelial cancer
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non- small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct
  • the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ovarian
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom
  • the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine.
  • 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 cancer.
  • 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 a medical disorder described herein (for example, cancer).
  • a compound described herein such as a compound of Formula I, or other compounds in Section I
  • a medical disorder such as a medical disorder described herein (for example, cancer).
  • the compounds described herein can inhibit ERK5 activity.
  • another aspect of the invention provides a method of inhibiting ERK5 activity. The method comprises contacting ERK5 with an effective amount of a substituted 4-piperidinyl-pyrrolo[2,3-b]pyridine or related compound described herein, such as a compound of Formula I, or other compounds in Section I, to inhibit ERK5 activity.
  • the particular compound of Formula I, I*, I- A, I- 1 , or I-A1 is the compound defined by one of the embodiments described above.
  • Another aspect of the invention provides for combination therapy.
  • Substituted 4- piperidiny 1-pyrrolo [2 , 3 -b]pyridine or related compounds described herein (e.g., a compound of Formula I, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as a cancer.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • One or more other therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or
  • one or more other therapeutic agent and a compound or composition of the invention are administerd as a multiple dosage regimen more than 24 hours aparts.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions which comprise an additional therapeutic agent, such as a second anti-cancer agent, as described above varies depending upon the host treated and the particular mode of administration.
  • a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • compositions which comprise one or more other therapeutic agent(s) can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this invention is preferably no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase "normally administered” means the amount an FDA- approved therapeutic agent is approved for dosing per the FDA label insert.
  • another aspect of the invention provides a method of treating cancer in a subject.
  • the method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted 4-piperidinyl-pyrrolo[2,3-b]pyridine or related compound described herein and (ii) a second anti-cancer agent, in order to treat the cancer.
  • the second anti-cancer agent is an ALK Inhibitor, an ATR Inhibitor, an A2A Antagonist, a Base Excision Repair Inhibitor, a Bcr-Abl Tyrosine Kinase Inhibitor, a Bruton's Tyrosine Kinase Inhibitor, a CDC7 Inhibitor, a CHK1 Inhibitor, a Cyclin- Dependent Kinase Inhibitor, a DNA-PK Inhibitor, an Inhibitor of both DNA-PK and mTOR, a DNMT1 Inhibitor, a DNMT1 Inhibitor plus 2-chloro-deoxyadenosine, an HD AC Inhibitor, a Hedgehog Signaling Pathway Inhibitor, an IDO Inhibitor, a JAK Inhibitor, a mTOR Inhibitor, a MEK Inhibitor, a MELK Inhibitor, a MELK Inhibitor,
  • the second anti-cancer agent is an ALK Inhibitor. In certain embodiments, the second anti-cancer agent is an ALK Inhibitor comprisng ceritinib, crizotinib, or alectinib. In certain embodiments, the second anti-cancer agent is an ALK Inhibitor comprisng ceritinib or crizotinib.
  • the second anti-cancer agent is an ATR Inhibitor. In certain embodiments, the second anti-cancer agent is an ATR Inhibitor comprising AZD6738 or VX-
  • the second anti-cancer agent is an A2A Antagonist. In certain embodiments, the second anti-cancer agent is a Base Excision Repair Inhibitor comprising methoxyamine. In certain embodiments, the second anti-cancer agent is a Base Excision Repair Inhibitor, such as methoxyamine.
  • the second anti-cancer agent is a Bcr-Abl Tyrosine Kinase Inhibitor.
  • the second anti-cancer agent is a Bcr-Abl Tyrosine Kinase Inhibitor such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRY CEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals).
  • the second anti-cancer agent is a Bcr-Abl Tyrosine Kinase Inhibitor comprising dasatinib or nilotinib.
  • the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor comprising ibrutinib or AVL-292. In certain embodiments, the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor comprising ibrutinib. Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention, can be found in WO2008/039218 and WO2011/090760, the entirety of which are incorporated herein by reference. [0444] In certain embodiments, the second anti-cancer agent is a CDC7 Inhibitor. In certain embodiments, the second anti-cancer agent is a CDC7 Inhibitor comprising RXDX-103 or AS-
  • the second anti-cancer agent is a CHK1 Inhibitor. In certain embodiments, the second anti-cancer agent is a CHK1 Inhibitor comprising MK-8776, ARRY-
  • the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor.
  • the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor, such as a CDK4/CDK6 inhibitor.
  • the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor selected from palbociclib (IB RANGE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor comprising palbociclib.
  • the second anti-cancer agent is a DNA-PK Inhibitor. In certain embodiments, the second anti-cancer agent is a DNA-PK Inhibitor comprising MSC2490484A. In certain embodiments, the second anti-cancer agent is Inhibitor of both DNA- PK and mTOR. In certain embodiments, the second anti-cancer agent comprises CC-115.
  • the second anti-cancer agent is a DNMT1 Inhibitor.
  • the second anti-cancer agent is a DNMT1 Inhibitor comprising decitabine, RX-3117, guadecitabine, NUC-8000, or azacytidine.
  • the second anticancer agent comprises a DNMT1 Inhibitor and 2-chloro-deoxyadenosine.
  • the second anti-cancer agent comprises ASTX-727.
  • the second anti-cancer agent is a histone deacetylase (HD AC) Inhibitor.
  • the second anti-cancer agent is a HD AC Inhibitor comprising OBP-801, CHR-3996, etinostate, resminostate, pracinostat, CG-200745, panobinostat, romidepsin, mocetinostat, belinostat, AR-42, ricolinostat, KA-3000, or ACY-241.
  • the second anti-cancer agent is a Hedgehog Signaling Pathway Inhibitor.
  • the second anti-cancer agent is a Hedgehog Signaling Pathway Inhibitor comprising sonidegib (ODOMZO®, Sun Pharmaceuticals) or vismodegib (ERIVEDGE®, Genentech).
  • the second anti-cancer agent is an IDO Inhibitor. In certain embodiments, the second anti-cancer agent is an IDO Inhibitor comprising INCB024360.
  • the second anti-cancer agent is a JAK Inhibitor. In certain embodiments, the second anti-cancer agent is a JAK Inhibitor comprising ruxolitinib or tofacitinib.
  • the second anti-cancer agent is a mTOR Inhibitor. In certain embodiments, the second anti-cancer agent is a mTOR Inhibitor comprising everolimus or temsirolimus.
  • the second anti-cancer agent is a MEK Inhibitor. In certain embodiments, the second anti-cancer agent is a MEK Inhibitor comprising cobimetinib or trametinib.
  • the second anti-cancer agent is a MEEK Inhibitor. In certain embodiments, the second anti-cancer agent is a MEEK Inhibitor comprising ARN-7016, APTO-
  • the second anti-cancer agent is a MTH1 Inhibitor. In certain embodiments, the second anti-cancer agent is a MTH1 Inhibitor comprising (S)-crizotinib, TH 2 87, or TH588.
  • the second anti-cancer agent is a Poly ADP ribose polymerase (PARP) Inhibitor.
  • PARP Poly ADP ribose polymerase
  • the second anti-cancer agent is a PARP Inhibitor comprising MP-124, olaparib (LYNPARZA®, AstraZeneca), BGB-290 (BeiGene, Inc.), talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/B iomarin) , veliparib (ABT-888, Abb Vie), niraparib (ZEJULA®, Tesaro), E7449, mcaparib (RUBRACA®, Clovis Oncology), or ABT-767.
  • LYNPARZA® olaparib
  • BGB-290 BeiGene, Inc.
  • talazoparib MDV3800/BMN 673/LT00673, Medivation/Pfizer
  • the second anti-cancer agent is a Phosphoinositide 3 -Kinase (PI3 Kinase) Inhibitor.
  • the second anti-cancer agent is a Phosphoinositide 3 -Kinase Inhibitor comprising idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); or TGR1202 (formerly RP5230, TG Therapeutics).
  • the second anti-cancer agent is a Phosphoinositide 3- Kinase Inhibitor comprising idelalisib.
  • the second anti-cancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly ADP ribose polymerase 1 and dihydroorotate dehydrogenase).
  • the second anti-cancer agent is a Proteasome Inhibitor.
  • the second anti-cancer agent is a Proteasome Inhibitor comprising bortezomib (VELCADE®, Takeda), carfilzomib (KYPROLIS®, Amgen), or ixazomib (NINLARO®, Takeda).
  • the second anti-cancer agent is a Proteasome Inhibitor comprising bortezomib or carfilzomib.
  • the second anti-cancer agent is a Topoisomerase-II Inhibitor. In certain embodiments, the second anti-cancer agent is a Topoisomerase-II Inhibitor comprising vosaroxin.
  • the second anti-cancer agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals) and topotecan (HYCAMTIN®, GlaxoSmithKline).
  • Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).
  • the second anti-cancer agent is a Tyrosine Kinase Inhibitor.
  • the second anti-cancer agent is a Tyrosine Kinase Inhibitor comprising bosutinib (BOSULIF®, Pfizer), cabozantinib (COMETRIQ®, Exelexis), imatinib (GLEEVEC®, Novartis), or ponatinib (INCLUSIG®, Ariad Pharmaceuticals).
  • the Tyrosine Kinase Inhibitor is an inhibitor of ROS1 and/or NTRK, such as taletrectinib (DS- 6051b, AB-106, AnHeart Therapeutics Co., Ltd.).
  • the second anti-cancer agent is a VEGFR Inhibitor. In certain embodiments, the second anti-cancer agent is a VEGFR Inhibitor comprising regorafenib (STIVARGA®, Bayer). In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor. In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor comprising AZD1775.
  • the second anti-cancer agent is a compound targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or
  • the second anti-cancer agent is a KRAS inhibitor.
  • the second anti-cancer agent is a KRAS inhibitor, such as adagrasib (MRTX849, Mirati Therapeutics) or sotorasib (Amgen).
  • the KRAS inhibitor is a KRAS G12C inhibitor, such as adagrasib (MRTX849, Mirati Therapeutics), sotorasib (AMG510, Amgen), D-1553 (InventisBio Inc.), GDC-6036, or JNJ-74699157/ARS-3248 (Janssen Biotech and Wellspring Biosciences).
  • the KRAS inhibitor is a KRAS G12D inhibitor, such as MRTX1133 (Mirati Therapeutics), RM-030/031 (Revolution Medicines), STX200 (SyntheX), JAB-22000 (JacoBio).
  • the KRAS inhibitor is a KRAS G12V inhibitor, such as JAB-23000 (JacoBio).
  • the KRAS inhibitor is a pan-KRAS inhibitor, such as BI-1701963 (Boehringer Ingelheim).
  • KRAS inhibitors for use as the second anti-cancer agent in the methods and uses described herein include, but are not limited to, those described in WO2020/097537,
  • WO2020/132597 WO2020/035031, WO2020/243103, WO2020/212895, WO2021/041671, WO2021/081212, WO2021/106231, WO2021/107160, WO2021/108683, WO2021/119343, and
  • the second anti-cancer agent is a SOS1 inhibitor, such as BI-
  • the second anti-cancer agent is an agonist of OX40, CD137,
  • the second anti- cancer agent is an agonist of OX40, CD137, CD40, or GITR. In certain embodiments, the second anti-cancer agent is an agonist of CD27, HVEM, TNFRSF25, or ICOS.
  • the second anti-cancer agent is a therapeutic antibody.
  • the therapeutic antibody targets one of the following: CD20, CD30,
  • B4GALNT1 interleukin- 6, and interleukin-6 receptor.
  • the second anti-cancer agent is a therapeutic antibody selected from the group consisting of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregovomab, minetumomab, cG250, J591, Movl8, farletuzumab, 3F8, chl4.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramuci
  • the second anti-cancer agent is a cytokine.
  • the cytokine is IL- 12, IL- 15, GM-CSF, or G-CSF.
  • the second anti-cancer agent is sipuleucel-T, aldesleukin (a human recombinant interleukin-2 product having the chemical name des-alanyl-1, serine- 125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N - ⁇ 3-[5-(2- aminopyrimidin-4-yl)-2-tert-butyl-l,3-thiazol-4-yl]-2-fluorophenyl ⁇ -2,6- difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane- 1 - sulfonic acid ⁇ 3-[5-(4-chlorophenyl)-1H -pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluoro-pheny 1 ⁇ - amide) , or 2-chloro-deoxyadenosine
  • the second anti-cancer agent is a placental growth factor, an antibody-drug conjugate, an oncolytic virus, or an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is a placental growth factor. In certain embodiments, the second anti-cancer agent is a placental growth factor comprising ziv-aflibercept. In certain embodiments, the second anti-cancer agent is an antibody-drug conjugate. In certain embodiments, the second anti-cancer agent is an antibody-drug conjugate selected from the group consisting of brentoxumab vedotin and trastuzumab emtransine.
  • the second anti-cancer agent is an oncolytic virus. In certain embodiments, the second anti-cancer agent is the oncolytic virus talimogene laherparepvec. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine selected from the group consistint of a GM-CSF tumor vaccine, a STING/GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anti-cancer agent is a cytokine selected from IL-12, IL-15, GM-
  • the second anti-cancer agent is an immune checkpoint inhibitor (also referred to as immune checkpoint blockers).
  • Immune checkpoint inhibitors are a class of therapeutic agents that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol. 12, pages 252-264.
  • the immune checkpoint inhibitor is an agent that inhibits one or more of (i) cytotoxic T- lymphocyte-associated antigen 4 (CTLA4), (ii) programmed cell death protein 1
  • CTL4 cytotoxic T- lymphocyte-associated antigen 4
  • programmed cell death protein 1 programmed cell death protein 1
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. In certain embodiments, the immune checkpoint inhibitor is ipilumumab. In certain embodiments, the immune checkpoint inhibitor is pembrolizumab. In certain embodiments, the immune checkpoint inhibitor is nivolumab.
  • the second anti-cancer agent is a monoclonal antibody that targets a non-checkpoint target (e.g., herceptin).
  • a non-checkpoint target e.g., herceptin
  • the second anti-cancer agent is a non-cytoxic agent (e.g., a tyrosine -kinase inhibitor).
  • the second anti-cancer agent is selected from mitomycin, ribomustin, vincristine, tretinoin, etoposide, cladribine, gemcitabine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunombicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, cytarabine, bicalutamide, vinorelbine, vesnarin
  • the second anti-cancer agent is radiation therapy.
  • the second anti-cancer agent is a MEK Inhibitor.
  • the second anti-cancer agent is binimetinib (MEK162, ARRY-438162, ARRAY BIOPHARMA INC.), cobimetinib (COTELLIC®, Exelexis/Genentech/Roche) , refametinib (BAY 86-9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib (MEKINIST®, Novartis), mirdametinib (PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA) or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • the second anti-cancer agent is binimetinib, cobimetinib, refametinib, selumetinib, trametinib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. In certain embodiments, the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • the second anti-cancer agent is trametinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anticancer agent is trametinib or a pharmaceutically acceptable solvate thereof. In certain embodiments, the second anti-cancer agent is trametinib dimethylsulfoxide. In certain embodiments, the second anti-cancer agent is trametinib.
  • the second anti-cancer agent is binimetinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anticancer agent is cobimetinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is refametinib or a pharmaceutically acceptable salt and/or solvate thereof. In certain embodiments, the second anti-cancer agent is selumetinib or a pharmaceutically acceptable salt and/or solvate thereof.
  • the second anti-cancer agent is binimetinib. In certain embodiments, the second anti-cancer agent is cobimetinib. In certain embodiments, the second anti-cancer agent is refametinib. In certain embodiments, the second anti-cancer agent is selumetinib.
  • the second anti-cancer agent is selected from: or a pharmaceutically acceptable salt and/or solvate thereof.
  • MEK inhibitors for use as a second anti-cancer agent in the methods described herein include, but are not limited to, E6201 (Eisai Co Ltd./S trategia
  • GDC-0623 RG 7421, Genentech, Inc.
  • CH5126766 RO5126766, Chugai Pharmaceutical Co., Roche
  • HL-085 Shanghai Kechow Pharma, Inc.
  • SHR7390 HENGRUI MEDICINE
  • TQ-B3234 CHIATAI TIANQING
  • CS-3006 CSTONE Pharmaceuticals
  • FCN- 159 Fosun Pharmaceuticals
  • VS-6766 Very fine- 1104
  • IMM- 1-104 Immuneering Corp.
  • MEK inhibitors for use as second anti-cancer agents in the methods and uses described herein include, but are not limited to, those described in WO2005/121142, WO2014/169843, WO2016/035008, WO2016/168704, WO2020/125747, WO2021/142144, WO202 1/142345, WO2021/149776, the contents of each of which are herein incorporated by reference in their entireties.
  • the second anti-cancer agent is WX-554.
  • WX-554 is a selective, noncompetitive MEK1/2 inhibitor, which has been tested in dose-escalation phase I/II studies (ClinicalTrials.gov: NCT01859351, NCT01581060).
  • the second anti-cancer agent is HL-085 (Shanghai Kechow Pharma, Inc.).
  • HL-085 is an orally active, selective MEK inhibitor, which has been tested in phase I clinical study.
  • the second anti-cancer agent is FCN-159 (Fosun
  • the second anti-cancer agent is selected from: or a pharmaceutic ally acceptable salt and/or solvate thereof.
  • the second anti-cancer agent is a TEAD inhibitor.
  • TEAD Inhibitors of Formulae A, and A-1 to A-50 are examples of TEAD Inhibitors of Formulae A, and A-1 to A-50.
  • a TEAD inhibitor is selected from those described in WO 2020/243415, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is a compound of Formula A or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, -
  • Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • a TEAD inhibitor is a compound of Formula A-1: or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, -
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by -halogen, -CN, -NO 2 , or -C 1-6 aliphatic substituted 0-6 times by - halogen, -CN, or -NO 2 ;
  • R 2 is -H, or an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R 3 is -H
  • R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 ;
  • R 6 is -H or -C 1-6 aliphatic substituted 0-6 times by -halogen, -CN, or -NO 2 ; and each R is independently -H or optionally substituted -C 1-6 aliphatic.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(SR)-, -CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -NCR)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, - (R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC
  • L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, -CH(N(R) 2 )-, -C(O)-, -O(O)O-, -OC(O)-, - N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, - SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -NCR)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with -CH(SR)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -S-, or -N(R)-. In some embodiments, L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -CH(OR)-, -CH(SR)-, or -CH(N(R) 2 )-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(O)O-, - OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -CH(OR)-, - CH(SR)-, -CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -NCR)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, - C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O- , -CH(OR)-, -CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is -CH(SR)-, -S-, - SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-.
  • L 1 is -O-, -S-, or -N(R)-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -N(R)-. In some embodiments, L 1 is - NH-. In some embodiments, L 1 is -CH(OR)-, -CH(SR)-, or -CH(N(R) 2 )-. In some embodiments, L 1 is -CH(OR)-. In some embodiments, L 1 is -CH(SR)-. In some embodiments, L 1 is
  • L 1 is -C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is -C(O)-.
  • L 1 is -C(O)O-.
  • L 1 is -OC(O)-.
  • L 1 is -SO-.
  • L 1 is - SO 2 -.
  • L 1 is -C(S)-.
  • L 1 is -C(S)O-.
  • L 1 is -OC(S)-.
  • L 1 is -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -C(O)N(R)-.
  • L 1 is -(R)NC(O)-.
  • L 1 is -OC(O)N(R)-. In some embodiments, L 1 is -(R)NC(O)O-. In some embodiments, L 1 is -N(R)C(O)N(R)-. In some embodiments, L 1 is -SO 2 N(R)-. In some embodiments, L 1 is -(R)NSO 2 -. In some embodiments, L 1 is -C(S)N(R)-. In some embodiments, L 1 is -(R)NC(S)-. or In some embodiments, L 1 is -(R)NC(S)N(R)-.
  • L 1 is -CH 2 -, -CH(CH 3 )-, -NH-CH 2 -, -NH-CH(CH 3 )-, -C(O)-
  • L 1 is
  • L 1 is selected from those depicted in Table A, below.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, -NO 2 , or -C 1-6 aliphatic substituted 0-6 times by halogen, -CN, or -NO 2 .
  • Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5 or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted phenyl, In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen.
  • Ring A is optionally substituted
  • Ring A is optionally substituted 1-2 times by -halogen, -CN, - NO 2 , -C 1-6 aliphatic, or -O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -O-C 1-6 aliphatic is independently substituted 0-6 times by -halogen, -CN, or -NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, -CN, -NO 2 , -C 1-6 aliphatic, or -O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -O-C 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or -NO 2 .
  • Ring A is optionally substituted 1- 2 times by halogen, -C 1-6 aliphatic, or -O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -O- C1-6 aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is a 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted 1-2 times by halogen, -CN, - NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or -NO 2 . In some embodiments, Ring A is optionally substituted 1-2 times by halogen, or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen.
  • Ring A is selected from wherein each of R 1 and R 7 is independently as described herein. In some embodiments, Ring A is selected from
  • R 1 is -H, -halogen, -CN, -NO 2 , -C 1-6 aliphatic, or -O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 1 is unsubstituted -O-C 1-6 aliphatic.
  • R 1 is -OCH3.
  • R 1 is -O-C 1-6 aliphatic substituted
  • R 1 is -O-C 1-3 aliphatic substituted 1,
  • R 1 is -O-C 1-6 aliphatic substituted 1, 2,
  • R 1 is -OCF 3 . In some embodiments, R 1 is
  • R 1 is -H, -halogen, -CN, -NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 1 is -H.
  • R 1 is -halogen.
  • R 1 is -F.
  • R 1 is -Cl.
  • R 1 is -Br.
  • R 1 is -CN.
  • R 1 is -NO 2 .
  • R 1 is unsubstituted -C 1-6 aliphatic.
  • R 1 is - CH3. In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by F. In some embodiments, R 1 is -CF 3 . In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -CN. In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -NO 2 .
  • R 7 is -H, -halogen, -CN, -NO 2 , -C 1-6 aliphatic, or -O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 7 is unsubstituted -O-C 1-6 aliphatic.
  • R 7 is -OCH3.
  • R 7 is -O-C 1-6 aliphatic substituted
  • R 7 is -O-C 1-3 aliphatic substituted 1,
  • R 7 is -O-C 1-6 aliphatic substituted 1, 2,
  • R 7 is -OCF 3 . In some embodiments, R 7 is
  • R 7 is -H, -halogen, -CN, -NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 7 is -H.
  • R 7 is -halogen.
  • R 7 is -F.
  • R 7 is -Cl.
  • R 7 is -Br.
  • R 7 is -CN.
  • R 7 is -NO 2 .
  • R 7 is unsubstituted -C 1-6 aliphatic.
  • R 1 is - CH3.
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by F.
  • R 7 is -CF 3 .
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -CN.
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -NO 2 .
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is
  • Ring A is selected from those depicted in Table A, below.
  • Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted phenyl, In some embodiments, Ring B is optionally substituted 4-, 5 or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen.
  • Ring B is optionally substituted
  • Ring B is optionally substituted 1-4 times by halogen, -
  • Ring B is optionally substituted 1-4 times by -F, -Cl, -Br-,
  • Ring B is
  • Ring B is selected from those depicted in Table A, below.
  • R 2 is -H, or an optionally substituted 4 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is -H.
  • R 2 is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl.
  • R 2 is wherein R is as described herein. In some embodiments, R 2 is wherein R is as described herein.
  • R 2 is In some embodiments, R 2 is
  • R 2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, R 2 is selected from and In some embodiments, R 2 is In some embodiments, R 2 is
  • R 2 is selected from those depicted in Table A, below.
  • R 3 is -H.
  • R 3 is In some embodiments, R 3 i or
  • R 3 is selected from those depicted in Table A, below.
  • R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or - C(O)N(R) 2 .
  • R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , or - C(O)OR.
  • R 4 is -H.
  • R 4 is halogen.
  • R 4 is -F.
  • R 4 is -Cl.
  • R 4 is -Br.
  • R 4 is -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 N(R) 2 . In some embodiments, R 4 is -S(O)N(R) 2 . In some embodiments, R 4 is -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 NHCH 3 .
  • R 4 is -S(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 3 , -C(O)OH, or -C(O)OCH 3 .
  • R 4 is In some embodiments, R 4 is or
  • R 4 is selected from those depicted in Table A, below.
  • R 6 is -H or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 6 is -H, -halogen, -CN, -NO 2 , -C 1-6 aliphatic, -OC 1-6 aliphatic, or a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 6 is -H. In some embodiments, R 6 is -F. In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -Br. In some embodiments, R 6 is -CN. In some embodiments, R 6 is -NO 2 .
  • R 6 is -C 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or -NO 2 .
  • R 6 is unsubstituted -C 1-6 aliphatic.
  • R 6 is -CH 3 .
  • R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R 6 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R 6 is -CF 3 .
  • R 6 is -OC 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or -NO 2 .
  • R 6 is unsubstituted -OC 1-6 aliphatic.
  • R 6 is -OCH3.
  • R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R 6 is -OC 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R 6 is -OCF 3 .
  • R 6 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 .
  • R 6 is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by -C 1-6 aliphatic.
  • R 6 is
  • R 6 is selected from those depicted in Table A, below.
  • R w is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R w is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R w is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl.
  • R w is wherein R is as described herein. In some embodiments, R w is wherein R is as described herein.
  • R w is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl.
  • R w is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen.
  • R w is
  • R w is
  • R w is
  • R w is selected from those depicted in Table A, below.
  • R is independently -H or optionally substituted -C 1-6 aliphatic.
  • R is -H. In some embodiments, R is optionally substituted -Ci- 6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is -CH3. In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 . In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by - F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R is -CF 3 .
  • R is selected from those depicted in Table A, below.
  • a TEAD inhibitor is a compound of Formula A-2: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and L 1 is independently as defined and described in embodiments in Section of TEAD Inhibitors of Formulae A, and A-1 to A-50.
  • the present invention provides a compound of Formula A-2, or a pharmaceutically acceptable salt thereof, wherein:
  • F 1 is -O- or -S-;
  • R 1 is -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen
  • R 2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen;
  • R 3 is -H
  • R 4 is -S(O) 2 N(R) 2 ; -S(O)N(R) 2 , or -C(O)N(R) 2 , each R independently is selected -H and optionally substituted -C 1-6 aliphatic;
  • R 6 is -H or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; and R 7 is -H; or
  • F 1 is -NH-
  • R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen
  • R 2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen;
  • R 3 is -H
  • R 4 is -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 , each R independently is selected from -H and optionally substituted -C 1-6 aliphatic; R 6 is -C 1-6 aliphatic; and R 7 is -H.
  • a TEAD inhibitor is a compound of Formula:
  • a TEAD inhibitor is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen; Ring B is phenyl or a 6-membered monocyclic hetero aromatic ring having 1 or 2 nitrogen; and each of R w and L 1 is as defined above and described in embodiments herein, both singly and in combination.
  • a TEAD inhibitor is a compound selected from the following:
  • L 1 is a C 1-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is optionally substituted -C 1-6 aliphatic, and R 2 is as defined and described in embodiments in the section of TEAD Inhibitors of Formulae A, and A-1 to A-50;
  • a TEAD inhibitor is selected from those listed in Table A, or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A-31, T-A-32, T-A-56, T-A- 57, T-A- 60, T-A-63, T-A-68, T-A-74, T-A-83, T-A-94, T-A-96, or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A-31 or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A-32 or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A-56 or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A- 57 or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A- 60 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T- A-63 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T-A-68 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T-A-74 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T-A-83 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T-A-94 or a pharmaceutically acceptable salt thereof. In certain embodiments, a TEAD inhibitor is T-A-96 or a pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is T-A-31, T-A-32, T-A-56, T-A- 57, T-A- 60, T-A-63, T-A-68, T-A-74, T-A-83, T-A-94, or T-A-96.
  • a TEAD inhibitor is T-A-31.
  • a TEAD inhibitor is T-A-32.
  • a TEAD inhibitor is T-A-56.
  • a TEAD inhibitor is T-A- 57.
  • a TEAD inhibitor is T-A-60.
  • a TEAD inhibitor is T-A-63.
  • a TEAD inhibitor is T-A-68. In certain embodiments, a TEAD inhibitor is T-A-74. In certain embodiments, a TEAD inhibitor is T-A- 83. In certain embodiments, a TEAD inhibitor is T-A-94. In certain embodiments, a TEAD inhibitor is T-A-96.
  • a TEAD inhibitor is selected from those described in WO 2020/243423, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is a compound of Formula B: or a pharmaceutically acceptable salt thereof, wherein L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -
  • Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R w is a warhead group; wherein when R w is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B; and each R is independently -H or optionally substituted -C 1-6 aliphatic.
  • a TEAD inhibitor is a compound of formula B-1 or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, -
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, -NO 2 , or -C 1-6 aliphatic substituted 0-6 times by halogen, -CN, or -NO 2 ;
  • R 2 is -H, or a warhead group
  • R 3 is -H or a warhead group
  • R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , or a warhead group;
  • R 6 is -H or -C 1-6 aliphatic substituted 0-6 times by halogen, -CN, or -NO 2 ; and each R is independently -H or optionally substituted -C 1-6 aliphatic.
  • L 1 is -O-, -CH(OR)-, -CH(SR)-, -CH(N(R) 2 )-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)- , -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -S-, or -N(R)-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -N(R)-. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is selected from those depicted in
  • Ring A is optionally substituted phenyl, In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is r
  • Ring A is selected from those depicted in Table B, below.
  • Ring B is optionally substituted phenyl.
  • Ring B is optionally substituted 4-, 5 or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is In some embodiments, Ring B
  • Ring B is selected from those depicted in Table B, below.
  • R 2 is -H.
  • R 2 is a warhead group.
  • R 2 is In some embodiments, R 2 is
  • R 2 is selected from those depicted in Table B, below.
  • R 3 is -H. In some embodiments, R 3 is a warhead group. In some embodiments, R 3 is In some embodiments, R 3 is
  • R 3 is selected from those depicted in Table B, below.
  • R 4 is -H. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -Br. In some embodiments, R 4 is -S(O) 2 N(R) 2 . In some embodiments, R 4 is -S(O)N(R) 2 . In some embodiments, R 4 is -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 ⁇ CH 3 . [0583] In some embodiments, R 4 is a warhead group. In some embodiments, R 4 is In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -Br. In some embodiments, R 4 is -S(O) 2 N(R) 2 . In some embodiments, R 4 is -S(O)
  • R 4 is selected from those depicted in Table B, below.
  • R 6 is -H. In some embodiments, R 6 is -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or -NO 2 . In some embodiments, R 6 is selected from those depicted in Table B, below.
  • R w is In some embodiments, R w is selected from those depicted in Table B, below.
  • R is -H. In some embodiments, R is optionally substituted -C1- 6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is
  • a “warhead group,” as used herein, is capable of covalently binding to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified) present in the binding pocket of a target protein, for example, TEAD, thereby irreversibly inhibiting the protein.
  • a warhead group is as defined and described in embodiments in WO 2020/243423, the content of which is herein incorporated by reference in its entirety.
  • a TEAD inhibitor is selected from those listed in Table B, or a pharmaceutically acceptable salt thereof.
  • the second anti-cancer agent is a Poly ADP ribose polymerase
  • a PARP inhibitor is selected from olaparib
  • LYNPARZA® AstraZeneca
  • rucaparib RAB RAC A®, Clovis Oncology
  • niraparib ZJULA®, Tesaro
  • talazoparib MDV3800/BMN 673/LT00673,
  • the second anti-cancer agent is a histone deacetylase (HD AC) inhibitor.
  • an HDAC inhibitor is selected from vorinostat (ZOLINZA®,
  • the second anti-cancer agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor.
  • a CDK 4/6 inhibitor is selected from palbociclib (IB RANGE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • the second anti-cancer agent is a pho sphatidy lino sitol 3 kinase
  • PI3K inhibitor a PI3K inhibitor is selected from idelalisib
  • the second anti-cancer agent is a platinum-based therapeutic, also referred to as platins.
  • a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol- Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • the second anti-cancer agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel
  • TXOTERE® Sanofi-Aventis
  • DOCEFREZ® Sun Pharmaceutical
  • albumin-bound paclitaxel AB RAXANE® ; Abraxis/Celgene
  • cabazitaxel JEVTANA®, Sanofi-Aventis
  • SID530 S Chemicals, Co.
  • the second anti-cancer agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCAS AR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene);
  • the second anti-cancer agent is a kinase inhibitor or VEGF-R antagonist.
  • Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech/Roche) an anti- VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/S anofi) .
  • VEGFR inhibitors such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche) ; MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatini
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chip screen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, II- Yang Pharmaceuticals, S.
  • ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib
  • the second anti-cancer agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
  • the second anti-cancer agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present invention include bortezomib
  • VELCADE® Takeda
  • carfilzomib KYPROLIS®, Amgen
  • ixazomib NINLARO®, Takeda
  • the second anti-cancer agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGER).
  • PDGF platelet-derived growth factor
  • EGF epidermal growth factor
  • EGER its receptor
  • Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUV O® ; Eli Lilly).
  • Approved EGER antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab
  • the second anti-cancer agent is an aromatase inhibitor.
  • an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
  • the second anti-cancer agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
  • the second anti-cancer agent is a folic acid inhibitor.
  • Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).
  • the second anti-cancer agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
  • the second anti-cancer agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • the second anti-cancer agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB 1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors
  • the second anti-cancer agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • the second anti-cancer agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab
  • GlaxoSmithKline obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZE VALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, KADCYLA®, Genentech); and pertuzumab (anti- HER2, PER JET A®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics).
  • the second anti-cancer agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).
  • the second anti-cancer agent is an inhibitor of anti-apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, Abb V ie/Genentech) ; and blinatumomab (BLINCYTO®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • the second anti-cancer agent is an androgen receptor inhibitor.
  • Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho) ; approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).
  • the second anti-cancer agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly).
  • the second anti-cancer agent is an inhibitor of bone resorption.
  • An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
  • the second anti-cancer agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma
  • the second anti-cancer agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF ⁇ ).
  • TGF-beta or TGF ⁇ transforming growth factor-beta
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; S anofi- Genzy me) , which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD-Ll/TGF- ⁇ trap compound (NCT02699515); and (NCT02517398).
  • M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF- ⁇ “trap.”
  • the second anti-cancer agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE.
  • MMAE glembatumumab vedotin-monomethyl auristatin E
  • gpNMB anti-glycoprotein NMB
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • the second anti-cancer agents is an antiproliferative compound.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti- angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AROMASINTM.
  • Formestane is marketed under the trade name LENTARONTM. Fadrozole is marketed under the trade name AFEMATM. Anastrozole is marketed under the trade name ARIMIDEXTM. Letrozole is marketed under the trade names FEMARATM or FEMArTM. Aminoglutethimide is marketed under the trade name ORIMETENTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen is marketed under the trade name NOLVADEXTM.
  • Raloxifene hydrochloride is marketed under the trade name EVISTATM.
  • Fulvestrant can be administered under the trade name FASLODEXTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEXTM).
  • CASODEXTM bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEXTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSARTM.
  • Topotecan is marketed under the trade name HYCAMPTINTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYXTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name ETOPOPHOSTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name ACRIBLASTINTM or ADRIAMYCINTM.
  • Epirubicin is marketed under the trade name FARMORUBICINTM.
  • Idarubicin is marketed, under the trade name ZAVEDOSTM.
  • Mitoxantrone is marketed under the trade name
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TAXOLTM.
  • Docetaxel is marketed under the trade name TAXOTERETM.
  • Vinblastine sulfate is marketed under the trade name VINBLASTIN R.PTM.
  • Vincristine sulfate is marketed under the trade name
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTINTM. Ifosfamide is marketed under the trade name
  • histone deacetylase inhibitors or “HD AC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine is marketed under the trade name XELODATM.
  • Gemcitabine is marketed under the trade name GEMZARTM.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLATTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATINTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (I
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to ⁇ 3 ⁇ , ⁇ 3 ⁇ , ⁇ 3 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K- C2 ⁇ , Vps34, p110-a, p110- ⁇ , ⁇ 110- ⁇ , ⁇ 110- ⁇ , p85- ⁇ , ⁇ 85- ⁇ , ⁇ 55- ⁇ , ⁇ 150, p10l, and ⁇ 87.
  • ⁇ 3 ⁇ inhibitors useful in this invention include but are not limited to ATU-027, SF- 1126, DS-7423, PB 1-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • the PI3K inhibitor is alpelisib (PIQRAY, Novartis Pharmaceuticals Corporation).
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • BTK inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to
  • BTK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512,
  • Further anti- angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition e.g., thalidomide
  • TNP-470 TNP-470.
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or a- ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREXTM), rofecoxib (VIOXXTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • CELEBREXTM celecoxib
  • VIOXXTM rofecoxib
  • etoricoxib etoricoxib
  • valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DIDRONELTM.
  • Clodronic acid is marketed under the trade name BONEFOSTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name AREDIATM.
  • Alendronic acid is marketed under the trade name FOSAMAXTM.
  • Ibandronic acid is marketed under the trade name BONDRANATTM.
  • Risedronic acid is marketed under the trade name ACTONELTM.
  • Zoledronic acid is marketed under the trade name ZOMETATM.
  • mTOR inhibitors relates to1 compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICANTM), CCT
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “famesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZARNESTRATM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADETM) and
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MM1270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 - ⁇ -D- arabinofuransy Icy to sine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative,
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17- ally lamino , 17 -demethoxy geldanamy cin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HERCEPTINTM) , Trastuzumab-DM 1 , erbitux, bevacizumab (AVASTINTM), rituximab (RITUXAN ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • HERCEPTINTM trastuzumab
  • AVASTINTM bevacizumab
  • rituximab rituximab
  • PRO64553 anti-CD40
  • 2C4 Antibody 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AMF.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AMF, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Compounds which target, decrease or inhibit activity of histone deacetylase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases.
  • HD AC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N -hydroxy-3 - [4- [[ [2-(2-methyl- 1 H-indol-3 -yl)-ethyl] - amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • the term "ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X- rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Heilman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1 , pp. 248-275 (1993).
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2 -hydroxy- 1 H-isoindole- 1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATINTM; ENDOSTATINTM; anthranilic acid amides; ZD4190; Zd 6 474; SU5416; SU6668; bevacizumab; or anti- VEGF antibodies or anti- VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors,
  • VEGFR-2 IgGI antibody IgGI antibody
  • Angiozyme RPI 4610
  • Bevacizumab AVASTINTM
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNETM and porfimer sodium.
  • Angio static steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the second anti-cancer agent is an immuno-oncology agent.
  • an immuno-oncology agent refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject.
  • the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer.
  • An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • an antibody is a monoclonal antibody.
  • a monoclonal antibody is humanized or human.
  • an immuno-oncology agent is (i) an agonist of a stimulatory (including a co- stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen- specific T cell responses.
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • IgSF immunoglobulin super family
  • B7 family which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7- H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL,
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a cytokine that inhibits T cell activation e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines
  • a cytokine that stimulates T cell activation for stimulating an immune response.
  • an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin- 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1,
  • CD28 CD137
  • 4-1BBL CD137
  • 4-1BBL 4-1BBL
  • ICOS ICOS-L
  • OX40 OX40L
  • GITR GITRL
  • CD70 CD27, CD40, DR3 and CD28H.
  • an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells.
  • an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
  • an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • block inhibitory receptor engagement e.g., PD-L1/PD-1 interactions
  • Tregs e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex
  • an immuno-oncology agent is a CTLA-4 antagonist.
  • a CTLA-4 antagonist is an antagonistic CTLA-4 antibody,
  • an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
  • an immuno-oncology agent is a PD-1 antagonist.
  • a PD-1 antagonist is administered by infusion.
  • an immuno-oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity.
  • a PD-1 antagonist is an antagonistic PD-1 antibody.
  • an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI- 0680 (AMP-514; WO2012/145493).
  • an immuno-oncology agent may be pidilizumab (CT-011).
  • an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.

Abstract

L'invention concerne des 4-piperidinyl-pyrrolo[2,3-b]pyridines substituées et des composés apparentés, des compositions pharmaceutiques, leur utilisation pour inhiber l'activité ERK5, et leur utilisation dans le traitement de troubles médicaux, tels que le cancer.
PCT/US2021/048973 2020-09-04 2021-09-03 4-pipéridinyl-pyrrolo[2,3-b]pyridines substituées et composés apparentés et leur utilisation dans le traitement d'états médicaux WO2022051568A1 (fr)

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WO2022221866A1 (fr) 2021-04-16 2022-10-20 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023060362A1 (fr) * 2021-10-15 2023-04-20 Genetolead Inc. Inhibiteurs de ras, compositions et procédés d'utilisation de ceux-ci
WO2023173053A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023173057A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023196218A3 (fr) * 2022-04-08 2023-11-16 Mirati Therapeutics, Inc. Polythérapies comprenant un inhibiteur de sos1 et un inhibiteur de mek
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022221866A1 (fr) 2021-04-16 2022-10-20 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023060362A1 (fr) * 2021-10-15 2023-04-20 Genetolead Inc. Inhibiteurs de ras, compositions et procédés d'utilisation de ceux-ci
WO2023173053A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023173057A1 (fr) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations
WO2023196218A3 (fr) * 2022-04-08 2023-11-16 Mirati Therapeutics, Inc. Polythérapies comprenant un inhibiteur de sos1 et un inhibiteur de mek
WO2023230205A1 (fr) 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

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